1,195 terms

B1

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Myristate
14:0
Palmitate
16:0
Palmitoleate
16:1 (9)
Stearate
18:0
Oleate
18:1 (9)
Linoleate
18:2 (9,12)
Linolenate
18:3 (9,12,15)
Arachidonate
20:4 (5,8,11,14)
Lipid Properties
Low solubility in water, can be neutral or amphipathic, Ex: phospholipids
Phospholipids
Amphipathic lipids
Amphipathic
Has both a hydrophobic and hydrophilic region
Micelles
Amphipathic lipids with single hydrocarbon chains (fatty acids)
Bimolecular Sheet
A.K.A. bilayer membrane; favored conformation of phospholipids (two hydrocarbon chains) in water
Hydrophobic Droplets
Neutral lipids (Ex: triglycerides) form this. Ideal for energy storage.
Lipids Containing Fatty Acid Components
Phospholipids (Ex: Phosphatidylcholine), Sphingolipids (Ex: Sphingomyelin), Acylglycerols (Ex: Triglycerides), and Eicosanoids (Ex: Prostaglandins and Leukotrienes)
Lipids Containing Isoprene Components
Sterols (Ex: Cholesterol and Steroid Hormones) and Terpenes (Ex: Ubiquinones and Dolichols)
CH3(CH2)nCOO-
Fatty acid structure.
Dodecanoate
12 Carbons, no double bonds (saturated)
Tetradecanoate
14 Carbons, no double bonds (saturated)
Hexadecanoate
16 Carbons, no double bonds (saturated)
Octadecanoate
18 Carbons, no double bonds (saturated)
Monounsaturated
1 double bond
Polyunsaturated
2-6 double bonds
Hexadecenoate
16 Carbons, 1 double bond (unsaturated)
Hesadecadienoate
16 Carbons, 2 double bonds (unsaturated)
Laurate
Dodecanoate; 12 Carbons, no double bonds (saturated)
Myristate
Tetradecanoate; 14 Carbons, no double bonds (saturated)
Palmitate
Hexadecanoate; 16 Carbons, no double bonds (saturated)
Palmitoleate
Hexadecenoate; 16 Carbons, 1 double bond (unsaturated)
Stearate
Octadecanoate; 18 Carbons, no double bonds (saturated)
Oleate
Octadecenoate; 18 Carbons, 1 double bond (unsaturated)
Linoleate
Octadecadienoate; 18 Carbons, 2 double bonds (unsaturated); omega-6 fatty acid
Linolenate
Octadecatrienoate; 18 Carbons, 3 double bonds (unsaturated); omega-3 fatty acid
Arachidonate
20 Carbons, 4 double bonds (unsaturated); omega-6 fatty acid
High Melting Point
Saturated fatty acids
Low Melting Point
Unsaturated fatty acids (the more double bonds the lower the melting point)
Beta-Oxidation Pathway
Process where fatty acids are catabolized to 2-carbon units in mitochondria
MCAD
Medium Chain Acyl-CoA Dehydrogenase Deficiency; genetic defect in Fatty Acid Catabolism (Beta-Oxidation); onset of symptoms-1st two years; precipitated by fasting; vomiting, lethargy, coma, hypoglycemia; urine contains MCFA esters of glycine and carnitine
SCAD
Short Chain Acyl-CoA Dehydrogenase Deficiency
LCAD
Long Chain Acyl-CoA Dehydrogenase Deficiency
Supportive connective tissue
- CTs that make up the skeletal framework of the body
- consists of cartilage and bone
- highly specialized
- provide support for other soft tissues
Hyaline Cartilage
most prevalent; contains large round cells (chondrocytes) separated by a large amt. of ECM (pale blue, amorphous, can't see fibers); avascular matrix; surrounded by layer of perichondrium (dense irregular CT)
Chondrocyte
Cartilage fixed cell; mature (non-dividing); maintains existing ECM; difficult to distinguish
Chondroblast
cartilage fixed cell; 2+ cells in a single lacunae; secretes and lays down new additional ECM; capable of cell division; difficult to distinguish; have well-developed Golgi and rER characteristic of protein-secreting cells
Isogenous group
aka cell nest, where two or more cells are in a single lacuna or closely associated w/ each other; site where chondroblast has recently undergone cell division & begun to lay down new matrix; example of interstitial growth
Lacunae
small spaces between the lamellae which contain osteocytes
interstitial growth
Chondrocytes divide and secrete new matrix to expand the cartilage from within; Growth from the inside; evidenced by isogenous groups
appositional growth
Cartilage forming cells from perichondrium secrete new matrix against the external face of existing cartilage; Growth from the outside
Perichondrium
Dense irregular connective tissue membrane covering cartilage
Fibrous layer
outer layer of perichondrium; dense irregular CT; vascularized and supplies nutrients to cartilage
Chondrogenic layer (of perichondium)
inner layer where cells of fibrous layer differentiate into chondroblasts and begin secreting ECM; appositional growth
Ground substance
The amorphous gel rich in proteoglycans (keeps the wandering cells out); bluish color results from acidic nature of sulfur groups; contains a territorial matrix and an interterritorial matrix
Territorial matrix
aka capsular matrix; part of cartilage matrix that directly surrounds the chondrocyte (basophilic); poor in collagen & rich in freshly secreted sulfated GAGs (chondroitin-4 and 6); darker blue staining
Interterritorial matrix
area between chondrocytes; lighter staining due to lower sulfur content
Proteoglycans
give matrix its characteristic structure; important for cartilage function; organization of proteoglycans in matrix is more organized than in CT proper
Aggrecan
predominant proteoglycan subunit, core protein w/ condroitin-4/6-suflate & keratan sulfate attached; bottle brush appearance
Proteoglycan aggregates
hyaluronic acid molecule w/ 100 aggrecan molecules attached which give the ground substance a gel-like character; Functions: diffuse nutrients, resist compression and be slippery (mother nature's teflon)
Chondronectin
Glycoprotein in cartilage responsible attaching cell membrane to ECM (using integrin)
Chondrocalcin
Glycoprotein in cartilage responsible for binding calcium to the ECM
Pericellular capsule
CANNOT SEE at LM level; forms meshwork of collagen (type 2) immediately adjacent to the lacuna; works in protecting cells from mechanical stresses
Location of Hyaline Cartilage
costal cartilage, trachea and bronchi of lungs, larynx and nasal cartilage, articular cartilage of synovial joints, fetal skeleton
Hyaline Cartilage Functions
structural support; withstand pressure and shear forces; slippery; capable of rapid growth
Development of cartilage
1. Mesenchyme (low O2 region) chondroblast cells condense → procartilage
2. Procartilage secretes cartilage matrix (interstitial growth)
Elastic cartilage
Similar to hyaline cartilage (large, round widely scattered chondrocytes); contains randomly oriented elastic fibers and collagen II (secreted by chondrocytes); tolerates repeated bending better (external ear and the epiglottis)
Fibrocartilage
Chondrocyte (large, round and widely scattered) is principal fixed cell type; strong, densely packed collagen I fibers with little ground substance (looks like dense regular CT); in structures needing to withstand tension and pressure (pubic symphysis, intervertebral discs, junction at attachment btw. tendon and bone)
annulus fibrosis
fibrocartilage found on outer layer of inervertebral disks
nucleus pulposis
gelatinous matrix inner portion of the intervertebral disc; shock absorber
Herniated disc = extrusion of nucleus pulposis into spinal cord
Synarthroses
functional classification, immovable joints
Amphiarthroses
functional classification, slightly movable joints
Diarthroses
functional classification, freely movable joints (most common)
Fibrous Joints
Structural classification, no joint cavity, bones held together by a thin layer of dense irregular CT; Types: Sutures, Syndesmoses, Gomphoses
Cartilaginous Joints
Structural classification, no joint cavity, bones joined by cartilage, Types: symphyses, synchondroses
Synovial Joints
Structural classification, most common, diarthroses movement; have a cavity, ends of bones are covered by articular cartilage
Sutures
Fibrous, synarthroses, found only btw. bones of skull
Eg. lambdoid suture btw. occipital and parietal bones
Syndesmoses
Fibrous, amphiarthroses
Eg. distal ends of tibia and fibula
Gomphoses
Fibrous, synarthroses, cone-shaped peg fits into a socket
Eg. roots of teeth in alveoli (sockets)
Synchrodroses
Cartilaginous, synarthroses, connecting material is hyaline cartilage.
Eg. Temporary joint btw. diaphysis and epiphysis of a long bone, permanent joint btw. true ribs and sternum
Symphyses
Cartilaginous, amphiarthroses, connecting material is a broad, flat disc of fibrocartilage.
Eg. Intervertebral discs and pubic symphysis
Gliding
Synovial, nonaxial, articulating surfaces are usually flat.
Eg. Intercarpal and intertarsal joints
Hinge
Synovial, monoaxial (flexion-extension), spool-like surface fits into a concave surface.
Eg. Elbow, ankle, interphalangeal joints
Pivot
Synovial, monoaxial (rotation); rounded, pointed or concave surface fits into a ring formed partly by bone and partly by ligament.
Eg. Atlantoaxial and proximal radioulnar joints
Ellipsoidal
Synovial, biaxial (flexion-extension, abduction-adduciton), oval-shaped condyle fits into an elliptical cavity.
Eg. Radiocarpal joint
Saddle
Synovial, biaxial (flexion-extension, abduction-adduciton), articular surface of one bone is shaped like a rider sitting in the saddle.
Eg. Carpometacarpal proximal to the thumb
Ball-and-socket
Synovial, triaxial (flexion-extension, abduction-adduciton, rotaion-circumduction), ball-like surface fits into a cup-like depression.
Eg. Shoulder and hip joints
Articular cartilage
specialized form of hyaline cartilage; promotes smooth movement btw. bones with structural design: lacks perichondrium (teflon function), arched collagen type 2 fibers, calcified cartilage layer (additional support), subchondral bone layer (strength); nutrients come from movement of joints/fluid since avascular
Joint cartilage repair
difficult due to limited nutrient supply, no mitosis occurs, *repair tissue is fibrocartilage (not hyaline)
1. Hole is punched in subchondral bone to allow chondroprogenitor cells to migrate into gap
2. Continuous passive motion machine used to stimulate cartilage formation
Other methods: subchondral bone grafts, autologous bone/tissue culture grafts, injection of HA to joint
Osteoarthritis
Degenerative, affects synovial joints, non-inflammatory. Characterized by fibrillation of articular cartilage (loss of GS and retention of fibers), proliferation of cartilage at periphery, replacement of cartilage w/ bone spurs → reduce degree of movement.
Rheumatoid Arthritis
Inflammatory autoimmune disease, antibodies attack synovial membrane and joint cartilage - synovial membrane thickens (inflamed) and secretion increases causing ↑ pressure and pain. Pannus forms across articular surface and erodes cartilage; exposes bone, which eventually fuses across joint.
Acetyl-CoA carboxylase
activates acetyl-CoA and is the primary regulatory site for FA synthesis
Oxidation of FAs
Location: Mitochondria
Acyl carrier: CoA
Carbon units: 2
Product: Acetyl-CoA
Oxidizing agents: NAD⁺, FAD
Enzyme proteins: Separate
Synthesis of FAs
Location: Cytosol
Acyl carrier: Acyl Carrier Protein (ACP)
Carbon units: 2
Substrate: Malonyl-CoA
Reducing agent: NADPH
Enzyme proteins: single, multifunctional
Stages of FA Biosynthesis: Activation
Acetyl-CoA is carboxylated to Malonyl-CoA with ACC; irreversible conversion; first committed step of FA synthesis; ATP req.; ACC uses a biotin prosthetic group as an intermediate CO2 carrier
Stages of FA Biosynthesis: Elongation
Hydrocarbon chain is built through repeated rxns: condensation with CO2 loss, reduction, dehydration, and reduction. Fatty Acid Synthase uses malonyl-CoA substrate w/ ACP as a cofactor to build palmitate 2Cs at a time
Malonyl-CoA
Inhibits Carnitine acyl transferase I (CPT-I) as a homeostatic mechanism to balance synthesis/degradation of FAs; substrate of fatty acid synthesis
Thioesterase
Used with H2O after reduction step in last cycle of FA synthase rxn to cleave off ACP and form palmitate
Citrate Lyase
Enzyme that converts citrate back into OXAC and acetyl-CoA, rxn occurs in the cytosol, req. 1 ATP, necessary to synthesize fats from glucose
NOTE: Reverse of TCA step 1
Malic acid
Used in cytosol to convert OXAC into a form that can re-enter the mitochondria (pyruvate), a by-product is NADPH (req. for elongation step of FA synthesis)
OXAC + NADH+H⁺ → Malate + NADP⁺ → Pyruvate + NADPH+H⁺
FA Synthesis ↑
When carbs and energy are plentiful and FAs are scarce
FA Synthesis ↓
When energy supplies are low due to starvation, exercise, or deficient glucose utilization
Local Regulation of ACC
- multi-subunit enzyme (filamentous/aggregated form is more active), allosteric regulation.
- Citrate (↑ when acetyl-CoA and ATP are ↑) activates ACC by promoting aggregation
- Fatty acyl-CoA (↑ when FAs are abundant) inhibits ACC
- ACC indirectly inhibits FA oxidation b/c malonyl-CoA blocks CPT-I
Protein phosphatase 2A
Global regulation of ACC; dephosphorylates (activates) ACC; stimulated by insulin which is plentiful in high carb diets
AMP-Activated Protein Kinase
Global regulation of ACC; phosphorylates (inactivates) ACC; stimulated by presence of AMP; inhibited by ATP
Protein Kinase A
Global regulation of ACC; inhibits protein phosphatase 2A which leads to less dephosphorylation (activation) of ACC and therefore a decrease in ACC activity; stimulated by glucagon and/or epinephrine brought on by starvation
FA desaturation
Addition of DBs, takes place in the ER, req. O2, NADH and cytochrome b5, can introduce DBs at Δ4, Δ5, Δ6, Δ9; mammalian cells do not have enzymes to introduce DB beyond C-9 so cannot synthesize linoleate or linolenate
FA elongation
Condensation/decarboxylation with malonyl-CoA as the 2-C donor, takes place in ER, adds to carboxyl end (shifts C's down 2 spaces)
Essential FAs
Can't be synthesized: Lineolate & linolenate. Used in formation of arachidonate (20:4) which is used to form prostaglandins and leukotrienes.
Essential FA Deficiency
Extremely rare in USA
Causes: infants fed EFA-deficient formula or long-term total parenteral nutrition
Symptoms: decreased growth, skin abnormalities, impaired immune response
Remedy: supplement diet with EFA
Carnitine Shuttle
Brings fatty acids across the mitochondrial membrane and into the matrix
Coenzyme A Substructures
β-mercaptoethylamine+Pantothenate=Pantetheine; ADP
Coenzyme A
Universal carrier of acyl groups (hydrolysis of thioester is thermodynamically more favorable than oxygen ester)
Acyl-CoA Synthetase (Fatty Acid Thiokinase)
Catalyzes fatty acylation of Coenzyme A
Carnitine Acyltransferase Deficiencies
Triggered by exercise, fasting. Muscle pain, stiffness, myoglobinuria (pink urine), possible enlarged liver. Treatment = high carbohydrate, low fat diet and medium-chain triglycerides
4 Recurring Steps in β-Oxidation of Fatty Acyl-CoA
1. Oxidation by FAD
2. Hydration
3. Oxidation by NAD⁺
4. Cleavage (thiolysis) by CoA
Rate Limiting Step of β-Oxidation Pathway
Oxidation by FAD (Step 1)
β-Oxidation Summary Equation
1PalmitylCoA+7FAD+7NAD⁺+7CoASH+7H₂O → 8Acetyl-CoA+7FADH₂+7NADH+7H⁺ (7 cycles)
ATP Yield from Acetyl-CoA
10 ATP
Two Accessory Enzymes β-Ox. Cycle
1. Cis-Δ³-Enoyl-CoA Isomerase
2. 2,4-Dienoyl-CoA Reductase
Cis-Δ³-Enoyl-CoA Isomerase
Shifts position of double bond. Monounsaturated fatty acids.
2,4-Dienoyl-CoA Reductase
Reduces double bond. Polyunsaturated fatty acids.
Differences with Oxidation in Peroxisomes
Oxidation cycle ends with octanyl-CoA. Different electron acceptor in the first step (O₂→H₂O instead of FAD→FADH)
Zellweger Syndrome
Rare hereditary disorder affecting infants. Problems in prenatal development, enlarged liver, high levels of iron and copper in the blood, muscle and vision abnormalities. Death by age 6. Mutations in the PXR1 gene product-a receptor found on the surface of peroxisomes. The PXR1 receptor is vital for the import of enzymes into the peroxisomes.
Regions of Articular cartilage
1. Surface cartilage-contact point (no perichondrium)
2. Calcified cartilage-2nd layer, support and strength
3. Sunchondral bone- lowest layer, support
osteocyte
mature cell embedded in calcified bone matrix
lacunae
where mature bone cells lie in matrix
osteocyte
has numerous cytoplasmic processes which extend to adjacent cells
osteocyte
maintains the extracellular matrix surrounding cell
canaliculi
tunnels through calcified matrix through which cell processes of osteocytes run
Haversian canal
where the blood vessel runs through the center of the osteon
osteon
basic structural and functional unit of compact bone
cement line
the outermost limit of the osteon deficient in collagen fibers and lighter in appearance than the rest of the osteon
osteoid
unmineralized bone matrix adjacent to the cell membrane and surrounding canaliculi
osteoblast
immature cells that are incapable of division, found on existing bone surfaces, cuboidal in shape, and closely packed together
osteoblast
appears like an epithelium forming a lining on the outside surface of the bone
osteoblast
actively lays down bone matrix on the existing surface
osteoclast
large, multinucleated cell that resorbs bone
howship's lacunae
depression in bone formed by activity of the osteoclasts
striated border
located in the ECM; is the place of active resorption (LM); due to ground substance and mineral eroded away leaving only collagen fibers
ruffled border
site of active bone resorption (EM); specialized region of cell membrane where long, finger-like processes extend out into the matrix
subosteoclastic compartment
ECM just outside the ruffled border; very acidic microenvironment
carbonic anhydrase
dissolves mineral and permits the degradation of the organic matrix; produces H+ ions that are pumped outside the osteoclast; contained in vesicles in the osteoclasts
collagenase and hydrolase
secreted by osteoclasts to degrade collagen fibers
sealing zone
zone of osteoclast that contains integrins that bind to the ECM and seals the membrane to the bone matrix to limit the extent of the subosteovlastic compartment
granulocyte-macrophage progenitor
origin of osteoclasts; from bone marrow
parathyroid hormone and calcitonin
influence development of osteoclasts
osteoprogenitor cells
origin of osteoblasts; capable of proliferation and differentiation
bone lining cells
line all vascular channels, endosteum, and periosteum
bone lining cells
maintains the microenvironment of bone tissue; initiates internal bone remodeling by sensing stress within the bone tissue
collagen fibers and ground substance
organic components of bone
aggrecan
major proteoglycan of scant ground substance
osteonectin
binds plasma membrane to the collagen fibers
osteocalcin
binds Ca2+ to the matrix
bone sialoprotein
bind cells to matrix via binding sites for integrins and collagen receptors
osteonectin, osteocalcin, and bone sialoprotein
major glycoptns in bone matrix
inorganic component
component responsible for structural strength of bone; consists of all the mineral salts in the matrix
hydroxyapetite crystals
consists primarily of Ca3(PO4)2; aligned parallel to collagen fibers and 50% lies in gap region of the fibers
hyrdation shell
water associated with hydroxyapetite crystals
collagen I
primary fiber in bone
lamella
layer of collagen fibers
lamellar bone
bone tissue with a layered arrangement of collagen fibers
woven bone
bone tissue arrangement of randomly orientation of collagen fibers
diploe
layer of trabecular bone between 2 layers of compact bone
inner and outer tableau
layers of dense bone on the inside and outside of the flat bones of the skull
sesamoid bones
bones formed within a tendon of a muscle
flat bones
contain inner and outer tableau and diploe
epiphysis
enlarged area at the end of each bone
diaphysis
shaft of long bone
metaphysis
cone shaped region connecting the epiphysis to diaphysis
epiphyseal plate
cartilage region found in metaphysis; responsible for increasing length of long bones
cortical bone
outer layer of dense bone; more bone than space per unit volume
trabecular bone
has more space than bone per unit volume; located on the inside of bone; spongy bone
trabecula
thin processes of bone tissue in spongy bone
trabecular packets
angular shaped parcels fitted together to form trabecula; composed of lamellar bone
volkmann canals
diagonally running blood vessels; supply blood to osteons; lack concentric rings
interstitial lamella
remnants of older osteons that have been partly removed; no central canal
outer circumferential lamella
laid down by periosteum; layers of bone that run all the way around the bone; bind bone together and keep osteons in place
inner circumferential lamella
laid down by the endosteum; layers of bone that run all the way around the inside of the bone next to the marrow cavity
periosteum
layer of dense irregular CT that surrounds the outside of bone; composed of fibrous layer and osteogenic layer
fibrous layer
layer of periosteum that is an outer layer of dense irregular CT; vascular
osteogenic layer
layer of periosteum that consists of osteoblasts differentiating and laying down new bone; part of bone lining network
sharpey's fibers
bundles of collagen fibers extending from periosteum to be embedded in the bone matrix
endosteum
single layer of cells lining the inner layer of the bone adjacent to the marrow cavity; has osteogenic capabilities; helps maintain proper microenvironment in bone; part of bone lining network
metabolic bone
reservoir of mineral ions
structural bone
gives bone its rigidity, strength and shape
resorption cone
region where osteoclasts are actively removing bone matrix
resorption cavity
large lumen in bone matrix lined with osteoclasts; no concentric rings
reversal zone
where there is no longer any bone resorption and bone deposition hasn't begun; macrophages scavenge debris
closing cone
blood vessel follows resorption tunnel and brings in osteoprogenitor cells that differentiate into osteoblasts which start laying down osteoid from the periphery inward
parathyroid hormone
secreted due to low blood Ca2+ level; stimulates osteoclasts to increase resorption; receptors on osteoblasts
osteoblasts
secrete osteoclastic stimulating factor after being stimulated by PH due to low blood Ca2+
calcitonin
secreted when blood Ca2+ is high; decreases osteoclastic activity and increases osteoblastic activity; receptors on clasts
3% per year
rate of compact bone internal remodeling
26% per year
rate of trabecular remodeling
7.6% per year
% overturn of all bone
intramembranous ossification
occurs within the fibrous membrane or layer; bone is formed within CT proper; typically occurs in flat bone of the skull
endochondral ossification
occurs within the hyaline cartilage model of the bone; cartilage is removed and replaced with bone
bone island
formed by mineralization of osteoid in intramembranous ossification; each are equidistant from surrounding blood vessels
compaction
formation of compact bone from spongy bone; continuation of laying down new layers of osteoid and osteocytes on the surface of trabeculae until they meet to form primitive trabeculae
ossification center
place where ossification starts; starts in the center and radiates out toward the periphery
periosteal buds
small blood vessels that erode away the uncalcified cartilage matrix
primary ossification center
where ossification first appears in the cartilage model; ossification occurs from the center outward
secondary ossification center
where ossification occurs in the same cartilage as the primary ossification center, but is in a different location than the center of the bone
zone of reserve cartilage
part of epiphyseal plate that consists of normal hyaline cartilage; attaches cartilage to bony epiphysis
zone of proliferation
part of epiphyseal plate that looks like columns of flattened cells (isogenous groups); region of rapid proliferation of chondroblasts; interstitial growth of cartilage
zone of maturation and hypertrophy
part of epiphyseal plate where chondrocytes round up and enlarge; cells begin to secrete alkaline phosphatase
zone of calcification
part of epiphyseal plate where cartilage becomes mineralized; last 2 rows of enlarged cells adjacent to resorption front
zone of ossification
part of epiphyseal plate where blood vessels invade into the cartilage matrix and erode it away; osteoprogenitor cells are brought in and differentiate into osteoblasts that lay down osteoid; trabeculae that are formed are mostly longitudonal in orientation
primary spongiosa
where spongy bone is formed; part of zone of ossification
sex hormones
cause closure of the epiphyseal plate
bone modeling
mechanism by which bones maintain their shape and proportions as they grow
reduction
2 fragments of broken bone are moved back into place
direct trauma
results in broken osteons, torn periosteum, bleeding, inflammation, etc.
indirect trauma
due to stoppage of blood flow through broken osteons
early repair
neutrophils and macrophages clean out blood clot by phagocytosis
callus formation
forming of repair tissue around ends of fragments of broken bone
granulation tissue
repair tissue of callus
external callus
formed by the prolifertion of osteoprogenitor cells from the periosteum
internal callus
forms within the marrow cavity; endosteal cells proliferate and differentiate into osteoblasts which lay down new osteoid
union
when calluses from each side meet and fuse together
fibrous union
when the mesenchymal tissue from both frags meet in the middle
cartilagenous union
when the cartilage of 2 frags fuse
bony union
when forming bone trabeculae of the 2 frags fuse
muscle
many muscle cell groups surrounded by a sheath of dense irregular CT
epimysium
dense irregular CT sheath surrounding muscle cell groups (collagen I)
collagen I
fibers of epimysium and perimysium
fascicle
groups of muscle fibers; surrounded by septa of CT from the epimysium
perimysium
surrounds fascicles; septa of epimysium
fiber
an individual muscle cell surrounded by loose CT and a basal lamina
endomysium
surrounds fibers (collagen I, IV)
collagen I and IV
fibers of endomysium
myofibrils
structural units within the muscle cell sarcoplasm
desmin, vimentin, and dystrophin
intermediate filaments that hold myofibrils in precise alignment
myofilaments
thin and thick ptn chains; gives the appearance of striations
actin and myosin
types of myofilaments
myoglobin
ptn of skeletal muscle fibers that serves as an O2 donor for the metabolic machinery of the cell
sarcomere
basic contractile unit of the muscle cell
a band
region of overlapping thin and thick filaments
i band
thin filaments only
h band
thick filaments only
m line
thick filaments and cross bridges
z line
alternately spaced thin filaments from adjoining sarcomeres anchored by ptn cross bridges
z line ptn
anchoring ptn
a actinin
binding ptn for actin; binds actin to z line
cap z
caps the + ends of the thin filaments; keeps actin from polymerizing
actin
helical dimer with a + and - end
tropomyosin
regulates the availability of myosin binding sites
troponin
Ca2+ regulation of contraction; attaches to tropomyosin at regular intervals
nebulin
anchored at z line, runs the length of each actin filament
tropomodulin
cap ptn for - end of actin filaments
TnT
subunit of troponin that binds to tropomyosin strand
TnI
subunit of troponin that inhibits the myosin binding site on actin filaments
TnC
subunit of troponin that is a binding site for calcium during the initiation of muscle contraction
myomesin
m line ptn that holds myosin bundles apart to allow for overlap of thin filaments
creatine kinase
m line ptn that catalyzes the conversion of ADP -> ATP
C ptn
binds myosin strands together into a thick filament
titin
anchors the tail regions of the myosin dimers
depolarization of membrane and release of Ca2+ from SR
muscle contraction dependent on 2 things...
sarcoplasmic reticulum
serve as a major reservior for Ca2+; completely surrounds each myofibril; forms terminal cisternae at its terminal ends near the jct of the A and I bands
T-tubules
deep invaginations of muscle cell sarcolemma; invaginate at the A/I jct and surround myofibril; make it possible for membrane depolarization to be instantaneously distributed to all myofibrils
triad
t-tubules are flanked by a pair of terminal cisternae of the SR
neuromuscular/myoneural junction
specialized contact on muscle cells where terminal ends of motor axons end
motor unit
motor axon and all of the muscle cells that it contacts
number of cells in the motor unit
determines the precision of the muscle movement
motor endplate
specialized contact that is formed from the membrane of the motor axon
primary synaptic cleft
shallow invagination of the sarcolemma where the motor endplate and the muscle cell sarcolemma become closely apposed
secondary synaptic clefts
junctional folds; smaller infoldings of the sarcolemma around the edges of the synaptic cleft that increase the total surface area of the nerve/muscle contact
acetylcholine
neurotransmitter contained in vesicles in the terminal end of the motor axon
nicotinic acetylcholine receptors
specialized receptors on the sarcolemma adjacent to the synaptic cleft
release of acetylcholine
results in 1. activation of acetylcholine receptors on the sarcolemma, 2. opening of ligand-gated Na+ channels in the sarcolemma resulting in initial depolarization of the sarcolemma, 3.opening of voltage-gated Na+ channels in the sarcolemma resulting in widespread depolarization of the muscle cell
inositol triphosphate (IP3)
formed when sarcolemma is depolarized; binds to receptors in the terminal cisternae of the SR membrane allowing for the release of Ca2+ (according to the classic story)
dihydropyridine receptor (DHPR)
activated by depolarization of the sarcolemma (according the "real story")
ryanodine receptors
mechanically coupled to DHPR; calcium channels inserted into SR membrane
10^-7M
resting intracellular Ca2+ level
3x10^-5M
Ca2+ level after depolarization
power stroke
results when ADP is released from the myosin head and the myosin neck flexes
rigor complex
myosin remains attached to the actin filament and the myosin light chains are in their flexed position; maintained indefinitely until ATP binds to head region of the myosin
muscle spindles
composed of modified muscle fibers that are length registering receptors enclosed in a CT capsule; oriented longitudinally along the axis of tension
intrafusal fibers
modified muscle fibers that make up muscle spindles
annulospiral endings
large sensory fibers penetrate the capsule and spiral around intrafusal fibers
flower spray endings
smaller fibers enter the capsule and terminate in a spray-like arbor on the nuclear chain fibers
muscular dystrophy
x-linked recessive mutation resulting in the loss of dystrophin and therefore destabilization of the cell membrane which ruptures during repeated contraction which results in chronic progressive muscle loss; death results from cumulative damage to cardiac and respiratory muscle cells
myasthenia gravis
autoimmune disorder characterized by chronic progressive weakness; acetylcholine receptors at NMJ blocked by antibodies; treated with AChE blockers
Cartilage
found in regions requiring support in conjunction with tensile strength (fibrocartilage), elasticity (elastic cartilage), or relative rigidity (hyaline cartilage); functional characteristics carried out primarily by fibers and proteoglycans of the ECM
Similarities btw. ACP and CoA
1. ACP and CoA both serve as carriers during their respective processes
2. Both contain a Pantetheine (pantothenic acid) group and use a high energy thioester bond
3. Acyl Carrier protein is linked to its reactive region via a serine
4. CoA has no protein region, but instead contains 3`P-ADP
Articulation
place of union btw. 2 bones that allows movement btw. the bones; functional classification is based on degree of movement, structural classification is based on type of tissue connecting the bones
5 Characteristics of Synovial Joints
Most common diarthroses
1. synovial cavity
2. articular cartilage (covers bone ends)
3. articular capsule
4. synovial membrane (lining cavity)
5. synovial fluid made of HA and lubrican (glycopro.)
Maltose
α-Glucose(1:4) α-Glucose
Reducing
Trehalose
α -Glucose (1:1) α-Glucose
Non-reducing
Sucrose
α-Glucose (1:2) B-fructose
Non-reducing
Cellobiose
B-Glucose (1:4) B-glucose
Reducing
Lactose
B- Galactose (1:4) B-glucose
Reducing
Amylose
α 1:4
Amylopectin
Linear α- 1:4
Branching α-1:6
Glycogen
Linear α- 1:4
Branching α-1:6
cellulose
B-1:4
Hexokinase
Glucose → Glucose-6-P
Irreversible
Phosphohexose Isomerase
Glucose-6-P ↔ Fructose-6-P
Phosphofructose Kinase (PFK)
Fructose-6-P → Fructose-1,6-BP
Irreversible
Key regulating enzyme
↑: AMP, Fructose-2,6 BP,
↓: ATP, citrate, long chain FAs
Aldolase
Fructose-1,6-BP ↔ Dihydroxyacetone-P
Phosphotriose Isomerase
Dihydroxyacetone-P ↔ Glyceraldehyde-3-P
Glyceraldehyde 3-P Dehydrogenase
Glyceraldehyde-3-P ↔ 1, 3-BP-glycerate
(1 NADH generated) x 2
Phosphoglycerate Kinase
1,3- BP-glycerate ↔ 3-P-glycerate
(1 ATP formed) x 2 via substrate level phosphorylation of ADP
Phosphoglyceratemutase
3-P-glycerate ↔ 2-P-Glycerate
Enolase
2-P-Glycerate ↔ Phosphoenol Pyruvate
Generates high energy bond via intramolecular oxioreduction
Pyruvate Kinase
Phosphoenol Pyruvate → Enol Pyruvate → Keto Pyruvate
Final step is spontaneous
Irreversible
(1 ATP formed) x 2 via substrate level phosphorylation of ADP
Lactate Dehydrogenase
Pyruvate ↔ Lactate
Proceed only under anaerobic conditions
Regenerates NAD
Cardiolipin
*Primarily found in mitochondrial membranes, particularly that of the heart
*two phosphatidate molecules are linked to a common glycerol backbone
Dipalmitoyl-phosphatidylcholine
*major component of lung surfactant, which helps to keep lungs open
*absence is basis for respiratory distress syndrome, which is common in premature infants
Plasmalogen
*is an ether lipid where C1 of glycerol binds an alkyl residue with a unit of unsaturation adjacent to the ether linkage
*indicated in name (e.g. phosphatidYl choline becomes phosphatidAl choline)
Glyceryl Ether Phospholipids
*Phospholipid what contains in ether unit instead of an acyl group on C1
PAF
*Phosphatidyl choline with an acetyl group on C2 and palmitate on C1 of glycerol
*Mediator of allergic hypersensitivity, acute inflammatory reactions, and anaphylactic shock
*Is synthesized in response to Ig-IgE comples on antigen presenting cells
Ceramide
N-acyl-sphingosine
sphingomyelin
N-acyl-sphingosine with phosphocholine attached to the C1 hydroxyl group of a sphingosine
Cerebroside
N-acyl-sphingosine with 1 glucose or 1 galactose attached to the C1 hydroxyl group of sphingosine
Gangliosides
N-acyl-sphingosine with oligosaccharides that contain sialic acid attached to the C1 hydroxyl group of sphingosine
Sulfatides
N-acyl-sphingosine with 1 sulfated glucose or 1 sulfated galactose attached to the C1 hydroxyl group of sphingosine
Globosides
N-acyl-sphingosine with oligosaccharides that do not contain sialic acid attached to the C1 hydroxyl group of sphingosine
Tay-Sachs Disease
Disease that manifests as a defect in beta-N-acetylhexosaminidase (aka hexoaminidase A). Gangliosides that end with GalNAc (GM2) will accumulate in tissue
CDP
The nucleotide diphosphate used in the synthesis of phospholipids
UDP
The nucleotide diphosphate used in the synthesis of glycolipids
Gaucher's Disease
Disease that manifests as a defect in glucocerebrosidease (aka beta-glucosidase). Glucocerebroside accumulates in neruons
Niemann-Pick Disease (Type A)
Disease that manifests as a defect in sphingomyelinase. Shingomyelin accumulates in neurons.
Metachromatic Leukodystrophy
Disease that manifests as a defect in Arylsulfatase. Sulfogalactosylceremaide accumulates in neurons.
Krabbe's Disease
Disease that manifests as a defect in beta-galactosidase. Beta-galactosylceremide accumulates in neurons.
Fabry's Disease
Disease that manifests as a defect in alpha-galactosidase. Lactosylcerebroside accumulates in neurons.
PLA1
Phospholipase that takes off fatty acid on C1 of glycerol in phospholipids.
PLA2
Phospholipase that takes off fatty acid on C2 of glycerol in phospholipids.
PLC
Phospholipase that takes off alcohol and phosphate on C3 of glycerol in phospholipids.
PLD
Phospholipase that takes off alcohol (but not phosphate) on C3 of glycerol in phospholipids.
Aspirin
A drug that permanently modifies and inactivates cycloooxygenase by acetylation of Ser residue, and has anti-inflammatory, anti-fever, and anti-clotting effects (by inhibiting formation of TXA2, a stimulator of platelet aggregation).
Ibuprofien
A drug that blocks the hydrophobic channel where arachdonate enters the active site of cyclooxygenase, and has anti-inflammatory, anti-fever, and anti-clotting effects (by inhibiting formation of TXA2, a stimulator of platelet aggregation).
Acetaminophen
A drug that inhibits cyclooxygenase by an unknown mechanism, mainly centrally, and lacks anti-clotting effects.
mevalonate
2 Aceyl-CoA→ Acetoacetyl-CoA → HMG-CoA → above structure
lovastatin, zocor, crestor, lipitor
Group of cholesterol lowering drugs which competitively inhibit HMG-CoA Reductase → ↓ cholesterol synthesis in cell → ↑ LDL receptors → ↓ circulating LDL
Rate limiting step of isoprene biosynthetic pathway
isoprene unit
isopentenyl-PP
cholesterol precursor with 1 isoprene unit
geranyl-PP
cholesterol precursor with 2 isoprene units
farnesl-PP
cholesterol precursor with 3 isoprene units
squalene
cholesterol precursor with 6 isoprene units
Dolichol
A linear polyisoprene alcohol derived from cholesterol synthetic pathway.
Forms phosphate esters which participate in transfer of oligosaccharide chains during N-linked protein glycosylation
Ubiquinone
A ring structure with a linear polyisoprene tail, the latter derived from the cholesterol synthetic pathway.
Mobile carrier of reducing equivalents between membrane bound dehydrogenases and cytochrome b-c complex (complex III) in mitochondrial respiratory chain.
Heme - A
group with farnesyl side chain derived from the cholesterol synthetic pathway

Serves as prosthetic group of class A cytochromes (cytochrome C oxidase complex)
Isoprenylated proteins
proteins with a isoprene side chain derived from cholesterol synthetic pathway.

Side chain connects at cysteine residue at C-terminus and anchors protein to intracellular membrane.

Examples: Ras, nuclear lamins, G-protein gamma subunits, Rhodopsin kinase
Lanosterol
First closed sterol ring structure derived from squalene in cholesterol synthetic pathway.
HMG-CoA formation in ketogenic pathway
A pathway in which HMG-CoA synthesis occurs inside the mitochondria
HMG-CoA then serves as a substrate for HMG-CoA Lyase to produce acetoacetate
HMG-CoA formation in cholesterol synthesis
A pathway in which synthesis of HMG-CoA occurs in cytoplasm
HMG-CoA then serves as substrate for HMG-CoA reductase in ER
Glycocholate
A major bile acid. Formed by combining cholyl CoA with glycine
Taurocholate
A major bile acid. Formed by combining cholyl CoA with taurine (a cysteine derivative)
Progesterone
prepares uterine lining for implantation of ovum
essential for maintence of pregnancy
Testosterone
Progesterone → Andriostenedione → above structure.
development of male secondary sex characteristics
Estradiol
Progesterone → Androstenedione → testosterone → above structure
development of female sex characteristics and maintenance of the ovarian cycle
Cortisol
Progesterone → above structure. 17-hydroxylase MUST occur before 21-hydroxylase
promotes gluconeogenesis and glycogen utilization
enhances fatty acid and protein degredation
inhibits inflammation
Aldosterone
Progesterone → Corticosterone → above structure
acts on distal tubule of kideny to increase Na+ resorption and K+ excretion → BP and blood volume
7-dehydrocholesterol
This structure serves as a precursor for vitamin D. When UV light hits skin, photolysis followed by isomerization gives vitamin D.
21-hydroxylase deficiency
↑ ACTH secretion → enlarged adrenals with accumulation of pregnenolone, progesterone, and androgens → early virilization (evident at birth)short stature due to early bone maturation, loss of Na+ in urine, hypotension, possible shock or sudden death
Treated with hormone replacement
HMG-CoA reductase
Enzyme in cholesterol synthesis which catalyzes the rate limiting step. Uptake of LDL-cholesterol from circulation down-regulates the enzyme.
Organ gluconeogenesis location
90% takes place in the liver and 10% in the kidneys
Cellular gluconeogenesis location
Mitochondria and cytoplasm
Gluconeogenesis
Lactate is converted to pyruvate (need NAD) followed by a series of reverse glycolytic reactions resulting in glucose formation. Highly endergonic process
Primary control step: Acetyl CoA positively modulates pyruvate carboxylase
Secondary control step: Fructose 1,6 -Bisphosphatise
+: ATP, citrate
-: AMP, cAMP (glucagon)

To syntheize 1 mole of glucose from pyruvate in liver you need:
4 ATP
2 GTP
2 NADH
Gluconeogenesis precursors
Lactate: from exercising muscles and red blood cells. Convertd to pyruvate in liver

Amino Acids: From protein breakdown and diet. Transformed to TCA intermediates by removing amino group. i.e. alanine converted to pyruvate in liver.

Glycerol: from triglyceride breakdown
Irreversible steps of glycolysis
Glucose → Glucose - 6- P (Hexokinase/Glucokinase)
Fructose -6-P → Fuctose -1,6-BP (PFK)
Phosphoenol Pyruvate → Pyruvate (PK)
Bypass of irreversible glycolytic steps in gluconeogenesis
a. Glucose 6 - P → Glucose + Pi (Glucose- 6 - Phosphatase)

b. Fructose 1, 6 BP → Fructose-6-P + Pi (Fructose 1,6- Biphosphatase)

c. Pyruvate →PEP
i. Pyruvate +CO2 + ATP → Oxaloacetate +ADP + P
Pyruvate Carboxylase (regulatory) with biotin as coenzyme
ii. OxAc +NADH + H → Malate +NAD
Malate Dehydrogenase.
Malate transported out into cytoplasm via malate shuttle
iii. Malate + NAD → OxAc + NADH + H
∆G is positive but proceeds to right since products are removed quickly
iv. OxA + GTP → PEP + CO2 + GDP
Phosphoenolpyruvate carboxylase
Pyruvate Carboxylase
This enzyme adds CO2 to pyruvate to yield OxAc in the mitochondria.
In anaplerosis regenerates a catalytic intermediate for the TCA cycle.
In gluconeogenesis it generates a stoichiometric amount in order to continually form new glucose.
stimulated by acetyl CoA
inhibited by ADP
Acetyl CoA
Molecule which cannot serve as a precursor in gluconeogenesis because TCA completely oxidizes it, therefore even number fatty acids cannot be oxidized to form precursors since their breakdown produces acetyl CoA
Positively modulates pyruvate carboxylase
negatively modulates pyruvate dehydrogenase
biotin
A coenzyme for carboxylation reactions- carries the active CO2.
Bound in amide linkage to lysine residue of the apozenzyme

Participates in carboxylation reactions such as
Acetyl CoA → malonyl CoA
Pyruvate + CO2 → OxA
Propionly CoA → Succinyl CoA
Glucose - 6 - phosphatase
An enzyme involved in gluconeogenesis which converts Glucose 6 - P to glucose. Lacking in muscle and brain.
Glycerol Kinase
An enzyme which converts glycerol to glycerol - 3- P. Lacking in adipose cells; therefore in adipose tissue glucose is needed for triglyceride synthesis
ethanol inhibition of gluconeogenesis
NAD depletion → ↓ Lactate dehydrogenase → ↓ Pyruvate
SREBP
A factor which controls transcription of HMG-CoA reductase and LDL-receptior genes


Low cholesterol → factor released from ER membrane and moves into nucles → binding to SRE of HMGR and LDLR genes → ↑ transcription
Bile salts
Polar derivatives of cholesterol
Produced in liver and stored in gall bladder
Released into intestine (20-30 g a day)
tay-sachs disease
sphingolipidosis characterized by early neurologic deterioration, blindness, deafness, paralysis, and death by age 3. Due to defect in hexosaminidase A
multiple carboxylase deficiency
results from biotin deficiency or defect in biotin holocarboxylase synthetase. Symptoms are seborrheic dermatitis, anorexia, nausea, muscular pain
biotin deficiency
rare deficiency unless accompanied by other factors intestinal bacteria killing antibiotics or ingestion of large amounts of avidin(raw egg whites)
aceruloplasminemia
accumulation of iron due to lack of ceruloplasmin(copper ferroxidase)
crigler-najjar syndrome
reduced or absent UDP glucuronosyl transferase due to a defect in the coding region of the gene
gilbert's syndrome
reduced UDP glucuronosyl transferase due to a defect in the promotor region of the gene encoding for this
increases unconjugated bilirubin
hemolytic jaundice
increase in unconjugated bilirubin, seen in conditions with increased destruction of red cells
hepatocellular jaundice
result of liver damage, results in elevated unconjugated and conjugated bilirubin
post hepatic jaundice
elevated total bilirubin as a result of interference with bilirubin glucuronide delivery to the intestine
neonatal jaundice
due to low UDP-glucuronosyl transferase activity, blood group incompatability, or g6p dehydrogenase deficiency, treatment includes phototherapy
gaucher's disease
accumulation of glucocerebroside (b-glucosidase deficiency) leads to easy bruising, fatigue due to anemia, liver and spleen enlargement, skeleton weakness
niemann-pick disease type a
sphingomyelinase deficiency resulting in enlarged spleen/liver, mental retardation, anemia, neuro/physical deterioration, death before 3
21-hydroxylase deficiency
causes increased ACTH secretion, accumulation of pregenenolone, progesterone, androgens, results in virilization, treated with hormone replacement
rickets
inadequate calcification of bones, cartilage due to lack of vitamin D
osteomalacia
weakening of bones due to vitamin D deficiency
von gierke's disease
glucose 6-phosphatase activity defective
mcardle's disease
muscle glycogen phosphorylase defective causing accumulation of glycogen
ammonia toxicity
caused by urea cycle disorders or liver failure, leads to high arterial ammonia, ATP depletion, brain swelling
argininosuccinate synthetase deficiency
recessive deficiency that causes increase in citrulline and ammonia, treated with arginine
argininosuccinase deficiency
deficiency linked to increased argininosuccinate and ammonia levels, usually fatal in first two years, treated with arginine
maple syrup disease
a-ketoacid dehydrogenase complex deficiency causing accumulation of keto acids, mental retardation
alkaptonuria
homogentisate defect, leads to accumulation of homogentisic acid in urine(turns black)
cystinosis
defect in cystein transport leading to cysteine crystal deposition, can cause renal failure
cystinuria
defect in resorption causes excretion of cys, lys, arg, orn-cystine forms calculi in kidney tubules
homocystinuria
cysathionine b-synthase deficiency causing increase in serum homocysteine, causes osteoporosis, mental retardation, increased risk for thrombotic events
phenylketonuria
defective phenylalanine hydroxylase gene, results in mental retardation if individual isn't placed on phe restricted, tyr supplemented diet
atherosclerosis
plaque formation leads to hardening of the arteries
coronary heart disease
result of arterial occlusion due to atherosclerosis
homocysteinemia
elevated homocysteine levels associated with low blood folate leading to increased risk for CHD
methemoglobin anemia
caused by defects in methemoglobin reductase I or II, diaphorase I, or hemoglobin Ms
glucose 6-phosphate dehydrogenase deficiency
x-linked disorder, distribution associated with malaria, leads to increased sensitivity to oxidative stress
hexokinase deficiency
causes decreased 2,3 DPG concentration leading to a left shift in binding curve
pyruvate kinase deficiency
reduced phosphenol pyruvate to pyruvate causing increase in 2,3 DPG and a right shift in binding curve
hereditary spherocytosis
defects in spectrin or ankyrin interfere with band 3 interaction, results in round rigid cells subject to destruction
hereditary elliptocytosis
spectrin defects that affect horizontal interactions, elliptical shaped cells
genetic hemochromatosis
excessive iron absorption due to faulty regulation of iron transport, leads to diabetes, liver cirrhosis, cardiomyopathy, treated by phlebotomy
lead poisoning
inhibits ferrochelatase and protoporphyrinogen oxidase, inactivates ALA dehydratase, interferes with iron transport
genetic porphyria
involves defects in steps in heme biosynthesis, product from previous step accumulates
cytonuclear dyssynchrony
folate deficiency causes red cell development to stall, characterized by immature nuclei with well-hemoglobinized cytoplasm
hemoglobinopathies
examples include sickle cell disease, Hb C disease, thalassemia
enzymopathies
examples include g6pd deficiency, pyruvate kinase deficiency
membranopathies
examples include hereditary spherocytosis
obesity
caused by interaction of genetic and environmental(food and physical activity) factors
koilonychia
spoon nails caused by anemia
iron deficiency anemia
caused by malnutrition(rare) or bleeding, symptoms include pica, fatigue, koilonychia, blue sclerae
microcytosis
caused by iron deficiency, thalassemias, anemia of chronic disease
small RBCs
sideroblastic anemia
characterized by increased mitochondrial Fe, ineffective erythropoiesis, low retic count, examples are ALAS-2 mut, plumbism, and myelodysplastic syndrome
acute intermittent porphyria
inherited disease caused by PBG deaminase deficiency, porphobilinogen present in urine
very common
porphyria cutanea tarda
acquired disease caused by URO decarboxylase, urophorphyrinogen III present in urine, "monkey hair" is a symptom
type 1 diabetes
destruction of pancreatic beta cells by autoimmune reaction-no insulin
type 2 diabetes
decreased response to insulin by peripheral tissues, associated with visceral obesity
metabolic syndrome
at least 3 of the following: abdominal obesity, high TGs, low HDL-C, high blood pressure, high fasting glucose
marasmus
chronic starvation-induced PEM, caused by long term inadequate food intake, decrease in blood proteins
acute catabolic insult-induced PEM
caused by physical injury or severe infection, lasting 3 to 10 days, systematic and acute hormonal response
beriberi
vitamin B1 deficiency, symptoms: weakness, paralysis, wasting away
ariboflavinosis
riboflavin deficiency, symptoms: sore throat, cheilosis, glossitis
pellagra
niacin deficiency, symptoms: dermatitis, dementia, diarrhea, death
vitamin A deficiency
deficiency common in developing countries, symptoms are blindness, keratinization of skin and mucous membranes
pernicious anemia
deficiency in intrinsic factor prevents uptake of B12
Glycine (Gly/G)
Nonpolar, aliphatic R Groups
Alanine (Ala/A)
Nonpolar, aliphatic R Groups
Proline (Pro/P)
Nonpolar, aliphatic R Groups
Valine (Val/V)
Nonpolar, aliphatic R Groups
Leucine (Leu/L)
Nonpolar, aliphatic R Groups
Isoleucine (Ile/I)
Nonpolar, aliphatic R Groups
Methionine (Met/M)
Nonpolar, aliphatic R Groups
Phenylalanine (Phe/F)
Aromatic R groups
Tyrosine (Tyr/Y)
Aromatic R groups
Tryptophan (Trp/W)
Aromatic R groups
Serine (Ser/S)
Polar, uncharged R groups
Threonine (Thr/T)
Polar, uncharged R groups
Cysteine (Cys/C)
Polar, uncharged R groups
Asparagine (Asn/N)
Polar, uncharged R groups
Glutamine (Gln/Q)
Polar, uncharged R groups
Lysine (Lys/K)
Positively charged R groups
Arginine (Arg/R)
Positively charged R groups
Histidine (His/H)
Positively charged R groups
Aspartate (Asp/D)
Negatively charged R groups
Glutamate (Glu/E)
Negatively charged R groups
cell membrane lipid composition
Phospholipids, cholesterol, and glycolipids.
major phospoglycerides
Phospotidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglcerol, phosphatidyllinositol
CDP
Major nucleotide carrier in phospholipid synthesis. Ester of cytidine and pyrophosphoric acid.
Phospholipid Synthesis via CDP-diaclyglycerol
Phosphatidate → CDP diaclyglycerol → phosphoglyceride. CDP added to C3, then exchanged for the alcohol.
Phospholipid Synthesis via CDP-alcohol intermediate
Choline → Phosphorycholine → CDP-Choline → Phosphatidylcholine.
Substrates: dietary choline, ATP, CTP, Diaclyglycerol
Plasmalogens
Glyceral ether phospholipid with a carbon double bond on C1 ether unit. "phosphatidal" instead of "phosphatidyl"
Synthesis begins with Dihydroxyacetone Phosphate instead of Glycerol-3-phospate
Ceramide
A lipid that has an N-fatty acid group at C2 and is the building block for Sphingomyelin, Gangliosides, and sulfatides. These compounds are created by binding specific groups to the C1 alcohol of this lipid.
Sphingomyelin
A sphingolipid created by adding a phosphotidylcholine to the C1 alcohol of ceramide
glycosphingolipid
cerebroside
a simple glycosphingolipid
gangliosides
complex glycosphingolipids with branched oligosaccharides and sialic acid.
has UDP-activated sugars
hexosaminidase A
degrades gangliosides that end with GalNac.
Defect → ganglioside accumulation → Tay-Sachs
glucocerebrosidase (B-glucosidase)
Cleaves at Ceramide ― Glu bond
Defect → glucocerebroside accumulation → Gaucher's disease.
Different isoforms of enzyme in different tissues
Sphingomyelinase
Cleaves at Cer -― P― choline bond
Deficiency causes sphingomyelin accumulation in neurons → Niemann-Pick Disease.
Phospholipase A1
Releases lysophosphoglyceride lacking acyl-1
Phospholipase A2 (cPLA2)
Action on phosphoglycerides generates lysophosphoglyceride lackng acyl-2.

controls release of arachidonic acid, the precursor of eicosanoid hormones. Eicosanoids stimulate inflammation, regulate blood flow, modulate synaptic transmission, and effect ion transport, smooth muscle contraction, blood flow, and coagulation.

Stimulated by hormones, cytokines, and thrombin
Phospholipase D
Releases phosphatidic acid
Arachidonic Metabolites
Leukotrienes
Prostacyclins
Prostaglandin H2
Thromboxanes
Aspirin
Inactivates both COX by acetylation of a serine residue on the enzyme → ↓ prostaglandins → ↓ inflammation and fever.
↓TXA2 → ↓platelet aggregation
Ibuprofen
Inactivates both COX by blocking the hydrophobic channel where arachidonate enters the active site → ↓ prostaglandins → ↓ inflammation and fever
↓TXA2 → ↓platelet aggregation
Acetaminophen
Reversible inhibitor of both COX. Main action in CNS and therefore lacks peripheral anti-inflammatory, anti-clotting effects. Useful for post-operative pain reduction
Vioxx and Celebrex
NSAIDS which inhibits only COX-2 (induced with inflammation) thereby theoretically reducing side effects associated with COX-1 inhibition (COX-1 maintains normal body functions)
Bile acids
synthezied in liver from condensation of cholesterol and AA; stored in gallblader (as a salt); amphipathic; emulsifies DG and TGs (forming macroaggregates); form mixed micelles with products of fat hydrolysis: hydrophobic side faces toward the fat and hydrophilic side faces outward
Cholesterol 7α-Hydroxylase
catalyzes transformation of cholesterol to 7α-hydrocholesterol; 1st and rate limiting step of bile acid synthesis; stimulated by cholesterol, insulin and glucocorticoids; inhibited by bile acids (via a cascade)
Lipid solubilization
bile salts emulsify dietary fats into stable macroaggregate globules; pancreatic lipase and colipase bind to the surface of the emulsified lipid to further digestion and promote mixed micelle formation
Cholesterol esterase
breaks down storage form of cholesterol to FA and cholesterol; more lipophilic than cholesterol; inhibited by Benecol and Promise Take Control
Mixed micelles
formed using amphipathic lipid digestion products (2-MGs, bile acids, phospholipids, FAs); submicroscopic; soluble; essential for lipid absorption; diffuse at interstitial wall and deliver lipids to brush border (microvilli) for transfer to mucosal enterocyte
Sources of cholesterol
de novo synthesis makes 700mg/day (70 in liver and 630 in other tissues) and diet constitutes 400mg/day (transported to liver and extrahepatic tissue via circulation); synthesis in liver is inhibited by dietary cholesterol in a regulated balance
Inhibition of TG uptake: Alli (Orlistat)
inhibits pancreatic lipase leaving 1/3 of TG undigested and unabsorbed; causes intestinal problems and steatorrhea (fat in feces) w/ high fat diet, thus encouraging pts to avoid dietary fat
NPC1L1
cholesterol transporter on surface of intestinal lumen enterocyte (transfers cholesterol from gut to inside cell); cholesterol taken up will either be redeposited to the lumen via active transport, utilized by the enterocyte or used for chylomicron assembly and exocytosed
Benecol and Promise Take Control
contain plant sterols or plant stanol esters which cannot be digested by humans ∴ they prevent cholesterol uptake by inhibiting micelle formation and intestinal cholesterol esterase
Zetia (Ezetimibe)
Inhibits NPC1L1 transporter preventing uptake of cholesterol to enterocyte
Cholestyramine and colestipol
aka bile sequestrants; non-absorbable resins that bind bile acids ∴ reducing the amt of bile acids recycled by the liver (more lost in feces); hepatic cholesterol is redirected to synthesis of bile acids resulting in a net ↓ of blood cholesterol
Summary of TG and cholesterol ester digestion
Hydrolyzed by esterases → incorporated into micelles → transported into intestinal epithelial cells → re-esterified in intestinal epithelial cells → packaged into chylomicrons
Chylomicron
largest and lowest density lipoprotein which transports dietary lipids (TG primarily) from intestines to tissues; only present in FED state; drops off dietary TGs at tissue, leaving remnants to be cleared by the liver after binding to LDL or LDL-receptor related proteins (allowed to occur b/c ApoE is present)
picks up apo C and E from HDL
looses TGs and apo A and C to become a remnant
apo E than binds to LDL receptors on liver and particle is recycled
Left subclavian vein
lymph duct which delivers chylomicrons to blood, bypassing the hepatic portal system
Chylomicron composition
Almost entirely made of lipids, very small amt. of protein (88% TG, 8% phospholipids, 3% cholesterol esters, 1% free cholesterol); Composed of ApoB48 (diagnostic), and Apo Cs, E, and A; ApoB48 and ApoA made in rER; TG, CE, C, PL incorporated in sER
Apolipoprotein Functions
1. Part of the structure of lipoprotien (integral and peripheral membrane proteins)
2. Co-factors for enzymes
3. Inhibitors for enzymes
4. Ligands for lipoprotein receptors
Lipoprotein lipase (extrahepatic tissues generally)
located on walls of capillaries, binds to proteoglycan chains of heparan sulfate; binds to ApoC2 of chylomicron; activated by phospholipids and ApoC2, inhibited by ApoC3; catalyzes hydrolysis of TG to glycerol, FAs and MGs. FAs and MGs → tissues via FA transporter in concentration-dependent manner; glycerol → blood toward liver and kidney (only locations of glycerol kinase)
Lipoprotein lipase (adipose tissue)
site of most TG hydrolysis in fed state (↑ insulin levels stimulate synthesis of LPL and translocation of LPL to capillaries); FA transported into fat cell and esterified w/ G-3-P (from glycolysis) to reform TGs; glycerol → blood toward liver and kidney (only locations of glycerol kinase)
Cholesterol 7α hydroxylase inhibition cascade
inhibits bile acid production

bile acid binds to farnesoid X receptor, which binds to retinoid X-receptor, which binds to small nuclear protein promoter (SNP), which stimulates transcription of SNP gene; SNP binding to C7H promoter inhibits transcription of C7H gene, thus inhibiting bile acid production
mevalonate
2 Aceyl-CoA→ Acetoacetyl-CoA → HMG-CoA → above structure
lovastatin, zocor, crestor, lipitor
Group of cholesterol lowering drugs which competitively inhibit HMG-CoA Reductase → ↓ cholesterol synthesis in cell → ↑ LDL receptors → ↓ circulating LDL
Rate limiting step of isoprene biosynthetic pathway
isoprene unit
isopentenyl-PP
cholesterol precursor with 1 isoprene unit
geranyl-PP
cholesterol precursor with 2 isoprene units
farnesl-PP
cholesterol precursor with 3 isoprene units
squalene
cholesterol precursor with 6 isoprene units
Dolichol
A linear polyisoprene alcohol derived from cholesterol synthetic pathway.
Forms phosphate esters which participate in transfer of oligosaccharide chains during N-linked protein glycosylation
Ubiquinone
A ring structure with a linear polyisoprene tail, the latter derived from the cholesterol synthetic pathway.
Mobile carrier of reducing equivalents between membrane bound dehydrogenases and cytochrome b-c complex (complex III) in mitochondrial respiratory chain.
Heme - A
group with farnesyl side chain derived from the cholesterol synthetic pathway

Serves as prosthetic group of class A cytochromes (cytochrome C oxidase complex)
Isoprenylated proteins
proteins with a isoprene side chain derived from cholesterol synthetic pathway.

Side chain connects at cysteine residue at C-terminus and anchors protein to intracellular membrane.

Examples: Ras, nuclear lamins, G-protein gamma subunits, Rhodopsin kinase
Lanosterol
First closed sterol ring structure derived from squalene in cholesterol synthetic pathway.
HMG-CoA formation in ketogenic pathway
A pathway in which HMG-CoA synthesis occurs inside the mitochondria
HMG-CoA then serves as a substrate for HMG-CoA lyase to produce acetoacetate
HMG-CoA formation in cholesterol synthesis
A pathway in which synthesis of HMG-CoA occurs in cytoplasm
HMG-CoA then serves as substrate for HMG-CoA reductase in ER to produce
Glycocholate
A major bile acid. Formed by combining cholyl CoA with glycine
Taurocholate
A major bile acid. Formed by combining cholyl CoA with taurine (a cysteine derivative)
Progesterone
prepares uterine lining for implantation of ovum
essential for maintence of pregnancy
Testosterone
Progesterone → Andriostenedione → above structure.
development of male secondary sex characteristics
Estradiol
Progesterone → Androstenedione → testosterone → above structure
development of female sex characteristics and maintenance of the ovarian cycle
Cortisol
Progesterone → above structure. 17-hydroxylase MUST occur before 21-hydroxylase
promotes gluconeogenesis and glycogen utilization
enhances fatty acid and protein degredation
inhibits inflammation
Aldosterone
Progesterone → Corticosterone → above structure
acts on distal tubule of kideny to increase Na+ resorption and K+ excretion →↑ BP and blood volume
7-dehydrocholesterol
This structure serves as a precursor for vitamin D. When UV light hits skin, photolysis followed by isomerization gives vitamin D.
21-hydroxylase deficiency
↑ ACTH secretion → enlarged adrenals with accumulation of pregnenolone, progesterone, and androgens → early virilization (evident at birth)short stature due to early bone maturation, loss of Na+ in urine, hypotension, possible shock or sudden death
Treated with hormone replacement
HMG-CoA reductase
Enzyme in cholesterol synthesis which catalyzes the rate limiting step. Uptake of LDL-cholesterol from circulation down-regulates the enzyme.
Organ gluconeogenesis location
90% takes place in the liver and 10% in the kidneys
Cellular gluconeogenesis location
Mitochondria and cytoplasm
Gluconeogenesis
Lactate is converted to pyruvate (need NAD) followed by a series of reverse glycolytic reactions resulting in glucose formation. Highly endergonic process
Primary control step: Acetyl CoA positively modulates pyruvate carboxylase
Secondary control step: Fructose 1,6 -Bisphosphatise
+: ATP, citrate
-: AMP, cAMP (glucagon)

To syntheize 1 mole of glucose from pyruvate in liver you need:
4 ATP
2 GTP
2 NADH
Gluconeogenesis precursors
Lactate: from exercising muscles and red blood cells. Convertd to pyruvate in liver

Amino Acids: From protein breakdown and diet. Transformed to TCA intermediates by removing amino group. i.e. alanine converted to pyruvate in liver.

Glycerol: from triglyceride breakdown
Irreversible steps of glycolysis
Glucose → Glucose - 6- P (Hexokinase/Glucokinase)
Fructose -6-P → Fuctose -1,6-BP (PFK)
Phosphoenol Pyruvate → Pyruvate (PK)
Bypass of irreversible glycolytic steps in gluconeogenesis
a. Glucose 6 - P → Glucose + Pi (Glucose- 6 - Phosphatase)

b. Fructose 1, 6 BP → Fructose-6-P + Pi (Fructose 1,6- Biphosphatase)

c. Pyruvate →PEP
i. Pyruvate +CO2 + ATP → Oxaloacetate +ADP + P
Pyruvate Carboxylase (regulatory) with biotin as coenzyme
ii. OxAc +NADH + H → Malate +NAD
Malate Dehydrogenase.
Malate transported out into cytoplasm via malate shuttle
iii. Malate + NAD → OxAc + NADH + H
∆G is positive but proceeds to right since products are removed quickly
iv. OxA + GTP → PEP + CO2 + GDP
Phosphoenolpyruvate carboxykinase (PEPCK)
Pyruvate Carboxylase
This enzyme adds CO2 to pyruvate to yield OxAc in the mitochondria.
In anaplerosis regenerates a catalytic intermediate for the TCA cycle.
In gluconeogenesis it generates a stoichiometric amount in order to continually form new glucose.
stimulated by acetyl CoA
inhibited by ADP
Acetyl CoA
Molecule which cannot serve as a precursor in gluconeogenesis because TCA completely oxidizes it, therefore even number fatty acids cannot be oxidized to form precursors since their breakdown produces acetyl CoA
Positively modulates pyruvate carboxylase
negatively modulates pyruvate dehydrogenase
biotin
A coenzyme for carboxylation reactions- carries the active CO2.
Bound in amide linkage to lysine residue of the apozenzyme

Participates in carboxylation reactions such as
Acetyl CoA → malonyl CoA
Pyruvate + CO2 → OxA
Propionly CoA → Succinyl CoA
Glucose - 6 - phosphatase
An enzyme involved in gluconeogenesis which converts glucose 6 - P to glucose.
final step of both gluconeogenesis and glycogenolysis
lacking in muscle and brain.
deficient in von gierke
Glycerol Kinase
An enzyme which converts glycerol to glycerol - 3- P. Lacking in adipose cells; therefore in adipose tissue glucose is needed for triglyceride synthesis
ethanol inhibition of gluconeogenesis
NAD depletion → ↓ Lactate dehydrogenase → ↓ Pyruvate
Gastric Lipase
enzyme involved with fat digestion in stomach
triaglycerol → fatty acid + 1,2 - diaclyglycerol
10-30% of intestinal TG hydrolysis
Pancreatic Lipase
enzyme involved with fat digestion in duodenum
TG → 2-Monoacylglycerol +2 FAs (78%)
TG → Glycerol +3FAs (22%)
Jejunum
Site of most fat absorption
Ileum
Absorption of cholesterol (1200mg/day each) and bile acids
bile acids
Synthesized in liver and stored in gallblader
amphipathic- emulsifies DG and TGs.
Forms mixed micelles with products of fat hydrolysis- hydrophobic side faces toward the fat and hydrophillic side faces outward.
Generalized Lipoprotein structure and function
Surface layer: Phospholipids, Cholesterol. Polar
Core: Triaclyglycerides, Cholesterol esterases.

Non-polar
Particle specific proteins (apoproteins)
Lipid/protein ratio determines density
Transports lipids though the bloodstream.
Apo A
Apoprotein found in chylomicrons and HDL particles
Acquires phospholipids and cholesterol from cell membranes
Cofactor of LCAT which catalyzes cholesterol esterification
ApoB-48
Found only in chylomicrons
A result of an mRNA edit of another apoprotein which inserts a stop codon mid-sequence
ApoC-II
Apoprotein found in chlylomicron. Binds and activates lipoprotein lipase
ApoC-III
Apoprotein found in chylomicron
inhibits lipoprotein lipase
ApoE
Found in chylomicrons, HDL, VLDL, and IDL
when IDL loses this apoprotein it transforms to LDL
Generalized functions of Apolipoproteins
Part of the structure of lipoportien
Co-factors for enzymes
Inhibitors for enzymes
Ligands for lipoprotein receptors
chylomicron
A lipoprotein which transfers triaclyglycerols from intestine to tissue. Composed of ApoB-48, Cs, E, and A
Synthesized in intestine
ApoB48 and ApoA in RER
TG, CE, C, PL incorporated in SER
Packaged in secretory vesicles of golgi.
Vesicles secreted into lymphatic system via exocytosis.
enters venous system at left subclavian vein, bypassing hepatic portal system
Composed mostly of lipids, namely TGs
Looses TGs at tissue, remnants cleared by liver after binding to LDL and LRP receptors
pro-inflammatory
VLDL
A lipoprotein composed of Apo B-100, Cs, and E.
transports TG and cholesterol from liver to extrahepatic tissue
↑ hepatic TG synthesis → ↑ size and number
Remnants (IDL) are either delivered directly to liver via LDL receptor or lose apoE and residual TG to form LDL
pro-inflammatory
synthesized in liver
LDL
A lipoprotein which carries cholesterol ester from liver to rest of body.
Composed of Apo B-100.
Formed when IDL looses ApoE and residual TG.
Apo-B100 binds to LDL receptors, and particle is endocytosed into the cell, where it is transported though a system of coated pits, endosomes, lysosomes, and finally de-esterified and released into cytoplasm.
pro-inflammatory
HDL
A lipoprotein which returns cholesterol ester to the liver
Apo proteins: A, E, Cs
and transfers ApoCs and ApoE to chylomicrons and VLDL in plasma
Lipid poor particles (apoA + PL) orginate from liver and intestine. Plasma ApoA acquires PL and C from cell membranes → discoidal (nascent) HDL .
continued uptake and esterication of C catalyzed by LCAT → spherical HDL and finally mature HDL, which is returned to liver via serum albumin
anti-inflammatory- works by:
1) inhibiting adhesion molecule expression on vessel outer surface
2) inhibiting LDL oxidation
3) inhibiting foam cell formation
colipase
Co-enzyme of pancreatic lipase
cholesterol esterase
An enzyme which breaks down cholesterol ester into cholesterol and fatty acid.
Inhibited by benecol and Promise Take Control
lipoprotein lipase
An enzyme which hydrolyzes lipids in lipoproteins into two free fatty acids (to tissues via FA transporter) and one monoacylglycerol (goes to liver and kidney)
Found in endothelial cells lining capillaries.

Insulin induces synthesis
10X enzyme affinity for substrate in heart and mammary gland vs adipocytes so these organs can get energy even when VLDL and CM concentrations in blood are low
hormone sensitive lipase
An enzyme which hydrolizes TG to glycerol and fatty acids in adipose cells.
inhibited by insulin
Stimulated by glucagon and epinepherine
hepatic lipase
An enzyme which hydrolyzes remaining TG from chylomicron remains and HDL
things that increase LDL receptor activity
Phytosterols(diet) and bile acid sequestrans(drug): ↓ micelle incorporation of C
Statins: inhibit C synthesis
Ezetimibe: ↓ C transport into intestinal cells

All of these will lower plasma cholesterol
lipoprotein (a)
a lipoprotein which is covalently linked to apoB-100 in LDL.
Has positive correlation with risk for CVD
Soluble FIber
A dietary component which ↑ conversion of cholesterol to bile acids
Phytosterols
A dietary component which ↓ micelle incorporation of cholesterol
Statins
A class of drugs which inhibit HMG-CoA reductase and cholesterol synthesis → ↓LDL levels , ↓ plaque volume
bile acid sequestrans (BAS)
A drug which ↓ micelle incorporation of cholesterol
Binds to and raises excretion of bile acids → ↑ cholesterol converted to bile acids → ↑ cholesterol excretion
Cholestyramine and colestipol
non absorbable resins that bind bile acids → ↓ BA recycling to liver- > hepatic cholesterol is redirected to liver for BA synthesis
α-linkage
Glycosidic bonds in which the OH group is below the plane of the ring at the anomeric carbon
Glycogen only has these
B-linkage
Glycosidic bond where OH group is above the plane of the ring at the anomeric carbon
glycogen
A branched chain polymer of glucose connected by α - 1,4 linkages.
About every 8-10 residues there is an α-1,6 linkage at the branch point
Muscle has greatest amount due to large surface area, but liver has the greatest concentration
starch
A polysaccharide consisting of a mixture of amylose and amylopectin
has less branching than glycogen
glycogenolysis
steps:
1. Cleave glucose and add a phosphate
glycogen(n) ↔ glycogen (n-1) + Glucose 1-P (Phosphorylase)
2. When you've gotten down to 4 residues away from the branch point, the branching enzyme(transferase) will transfer three residues to another branch and hydrolyze the remaining residue (glucosidase), giving a free glucose
glycogen primer
glycogenin + 10 glucose residues
glycogenesis
Glucose → Glucose - 6P (Hexokinase [liver] Glucokinase [muscle])

Glucose - 6P → Glucose - 1P (Phosphoglucomutase)

Glucose - 1P + UTP → UDPG(active glucose) + Pi-Pi (UDPG pyrophosphorylase)

Primer + UDPG → Primer + 1 glucose + UDP (glycogen synthase)

alpha(1-4) Glucose(n) → transfers 7 glucoses and forms α1-6 - branch (branching enzyme)

Rinse and repeat
phosphorylase
Hydrolyzes alpha 1-4 bonds
Activated by the action of ATP in the presence of phosphorylase kinase
Allosterically activated by AMP binding
Deactivated by protein phosphatase I (PPI) which removes P group.
↑ glycogenolysis →↑ glucose
glucose -1-phosphate
Main product resulting from glycogenolysis
reacts with UTP to form UDPG
glucose - 6 - phosphatase
Catalyzes conversion of Glucose-6-P → Glucose + P
Missing in muscle, so glucose-6-P is instead used in TCA cycle to produce ATP
glycogen synthase
Catalyzes the following reaction needed for glycogenesis: primer + UDPG → Primer + 1 glucose + UDP
Essentially adds glucose to the growing glycogen chain

Turned on by insulin and removing phosphate group
Turned off by epinepherine and glucagon and by protein kinase (adding phosphate group)
Insulin
A hormone which promotes glycogen synthesis
Glucagon
Hormone which promotes glycogen breakdown
acts only in the liver
cAMP
Stimulates glycogen breakdown by:
Activating protein kinase → activates phosphorylase kinase → activates phosphorylase →glycogen breakdown
Also allosterically binds to phosphorylase b to change it to a more active conformation

Switches off glycogen synthesis by:
activating protein kinase → inactiving glycogen synthase
Epinephrine
Hormone which promotes glycogen breakdown. Acts in both liver and muscle unlike glucagon
Stimulates the formation of the active, phosphorylated form of phosphorylase
Von Gierke's disease
Defective glucose-6-phosphatase → ↑ glycogen build up in liver and kidney → severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia
Andersen's disease
Defective branching enzyme → causes very long outer unbranched chains of glycogen in liver and spleen → progressive cirrhosis of liver; death by age 2
McArdle's Disease
Defective phosphorylase → ↑ increased glycogen in muscle → painful muscle cramps during strenuous exercise
Gastric lipase
enzyme involved with fat digestion in stomach (start of fat digestion); acid pH is optimum; Triacylglycerol → fatty acid + 1,2-diaclyglycerol; accounts for 10-30% of intestinal TG hydrolysis
Pancreatic lipase
enzyme involved with fat digestion in duodenum (site of most fat digestion)
TG → 2-Monoacylglycerol + 2 FAs (72%)
TG → 1-monoacylglycerol + 2 FAs (6%)
TG → Glycerol + 3FAs (22%)
Ileum
Absorption of cholesterol/bile acids; 50% cholesterol is absorbed (1200mg/day), 50% is excreted in feces (1200mg/day)
General structure of lipoproteins (pic)
General function of lipoproteins
transports lipids though the bloodstream (either to or from liver)
Apo A
Apolipoprotein produced in the liver and found on surface of chylomicrons and HDL particles; Acquires phospholipids and cholesterol from extrahepatic tissues and uses LCAT (lecithin: cholesterol acyltransferase) to catalyze cholesterol esterification; when returned to liver on HDL, some will be excreted via the kidneys, some will be recycled
Apo B-48
Found only in chylomicrons; forms as a result of an mRNA edit of another apoprotein (B-100) which inserts a stop codon mid-sequence
VLDL
A lipoprotein composed of ApoB100, ApoCs, and ApoE; transports liver TG and cholesterol from liver to extrahepatic tissues; synthesis is analogous to chylomicron except occurs in a hepatocyte rather than an enterocyte; considerably smaller than chylomicrons, but contains similarly ↑ levels of TGs compared to CE; remnants (IDL) either get delivered to liver via LDL/LRP receptors, or lose ApoE and residual TG and condense to form CE-rich LDL (which is taken up by tissues)
LDL: formation
A lipoprotein composed of Apo B-100 and CEs; formed when IDL (VLDL remnant) loses ApoE and residual TG
HDL: basic function
lipoprotein which returns CE to the liver, serving as main lipoprotein able to get rid of cholesterol; apolipoproteins: As (primary), E and Cs (reservoir; transfers ApoCs and ApoE to nacent chylomicrons and VLDL in plasma); ↑ levels of protein compared to other lipoproteins
HDL: formation
lipid poor particles (apoA + PL) orginate from liver (primarily) and intestine; plasma ApoA acquires and accumulates PL and cholesterol from tissues (released by ABCA1 and ABCG1 and SRB1) → discoidal (nascent) HDL; continued extraction and uptake of cholesterol from tissues (esterified w/ LCAT and brought to core, encourages intake of more cholesterol) → spherical HDL (HDL₃) and finally mature HDL (HDL₂) → returned to liver in reverse cholesterol transport → taken up by SRB1 receptors → cholesterol is catabolized and subsequently secreted into bile
ApoB-100
Found in LDL and VLDL particles; forms covalent linkage to lipoprotein (a); one of the largest proteins in the body; recognized for binding to LDL receptors
ApoC-II
Apoprotein found in chlylomicron, VLDL, and HDL; binds and activates lipoprotein lipase
ApoC-III
Apoprotein found in chylomicron, VLDL, and HDL; inhibits lipoprotein lipase
ApoE
Found in chylomicrons, HDL, and VLDL; recognized for binding to LDL receptors and LDL receptor related proteins in liver
Colipase
Co-enzyme of pancreatic lipase
General structure of lipoproteins
Surface layer: Phospholipids, Cholesterol; Polar; contains integral/peripheral particle specific proteins (apoproteins); lipid protein ratio determines density (↑ lipids = ↓ density)
Core: Triaclyglycerides, Cholesterol esterases; Non-polar
Hormone Sensitive Lipase
An enzyme which hydrolizes TG to glycerol and fatty acids in adipose cells; inhibited by insulin; stimulated by glucagon and epinepherine
Hepatic lipase
An enzyme which hydrolyzes remaining TG from chylomicron remains and HDL (forming small HDL which can restart cholesterol accumulation cycle)
Factors leading to ↑ LDL receptor activity
↑ LDL receptor activity = ↓ free plasma cholesterol
DIET: mono & poly unsaturated FAs (small effect), soluble fiber (↑ conversion of cholesterol to bile acids), phytosterols (↓ cholesterol incorporation into micelles, promotes cholesterol excretion)
DRUGS: Statins (inhibit cholesterol synthesis), Ezetimibe (↓ cholesterol transport into intestinal cells), bile acid sequestrants (↑ conversion of cholesterol to bile acids)
Lipoprotein (a)
a large lipoprotein synthesized in the liver which is covalently linked to apoB-100 in LDL; has a catalytically inactive kringle region homologous to plasminogen;
positively correlated with risk for CVD by an unknown mechanism
Soluble fiber
A dietary component which ↑ conversion of cholesterol to bile acids (encouraging their excretion)
Digestion of MCFAs
FAs which contain <11 Cs, derived from coconut oil; hydrolyzed and absorbed in stomach and small intestine; transported directly to liver via portal vein; good for ppl. unable to digest LCFAs due to pancreatic, bilary or intestinal problems
Factors affecting Hepatic TG synthesis de novo
aka synthesis from glucose inside body: glucose →→ acetyl CoA →→ FA
Fed state: ↑ synthesis
Fasting: ↓ synthesis
High carb diet: ↑ synthesis
High fat diet: ↓ synthesis (de novo)
High protein diet: ↑ acetyl-CoA production from AA ∴ ↑ synthesis
High ethanol consumption: acetaldehyde → acetate → acetyl-CoA ∴ ↑ synthesis
Unesterified FAs: Albumin-bound FAs (from adipose tissue); ↑ in conditions of fasting and diabetes
Factors leading to ↓ LDL receptor activity
↓ LDL receptor activity = ↑ free plasma cholesterol
DIET: cholesterol, saturated FAs, trans FAs
UDPG
The immediate donor of glucosyl units to glycogen
cholesterol 7α and 12α -hydroxylase
Enzymes which convert cholesterol into bile acids
SREBP
A factor which controls transcription of HMG-CoA reductase and LDL-receptior genes


Low cholesterol → factor released from ER membrane and moves into nucles → binding to SRE of HMGR and LDLR genes → ↑ transcription
Asteriosclerosis
general term for hardening of the arteries
Athersosclerosis
Hardening of the arteries due to the formation of plaques
Normal → fatty streak → fibrous plaque → occlusive plaque → plaque rupture & thrombosis
Considered a chronic inflammatory disease
risk of developing this is modulated by size of LDL particles and driven by number of LDL particles
Angina
Severe pain in chest, partial loss of circulation to heart, usually chronic.
M.I
Critical loss of circulation to coronary arteries, acute
Infarction
localized necrosis due to loss of blood supply
Ischemia
Local loss of blood supply
Tunica intima
layer of arterial wall composed of endothelium and internal elastic membrane. LDL entrapped here
Tunica media
layer of arterial wall composed of smooth muscle cells and elastic/collagen fibers
foam cells
macrophages filled with lipid, primarily cholesterol esterase (as opposed to TGs in adipocytes) as the result of LDL oxidation in subendothelial space
Express scavenger receptors which are NOT feeback-regulated like normal LDL receptors
Release growth factors which causes macrophage proliferage
Release metalloproteases which degrade CT matrix of vessel.
fibrous plaque
The second stage of astherosclerosis. As plaque accumulates, trapped cells are starved of blood and die, spilling out their lipids and forming a lipid core. In addition, there's a buildup of fibrous CT over this core called the fibrous cap
lipid core
Thrombogenic substance composed of lipids from dead macrophages in the arterial wall.
occlusive plaque
The stage of astherosclerosis in which plaque begins to block the lumen of the vessel. Associated with angina
plaque rupture and thrombosis
Final stage in astheroscleoris. Can cause angina, MI, coronary death, stroke, and leg ischemia
Arterial remodeling
A process that occurs in CAD whereby arterial expansion compensates for plaque build up to maintain constant lumen in moderate CAD. With severe CAD the expansion is overcome and the lumen narrows.
25-29 years old
Age at which 3% of men and 5% of women experience >=40% stenosis (narrowing) of LAD coronary artery
Framingham
Massive study which measured LDL, HDL, and CHD risk. The biggest change in risk is caused by lowering your HDL levels.
1mg/dl decrease of HDL: ↑ 2% risk in men, ↑3% in women.
Saturated FAs
↑ total C, ↑ LDL, ↑ HDL, ↑ CVD
Polyunsaturated and monounsaturated FAs
↓ total C, ↓ LDL, ↓ HDL, ↓ CVD
Trans FAs
↑ total C, ↑ LDL, ↓ HDL, ↑ CVD
lipid peroxidation
causes rancidity in food.
initiated by reactive oxygen species such as OH-
often leads to a free radical chain reaction that can be stopped by antioxidants
oxidized LDL
Fragmented ApoB-( loss of AAs, not recognized by LDL receptor, uptake by scavenger receptor[no cholesterol feedback])
↓ phosphatidyl choline ↑ oxidized form
↑ lysophosphatidyl choline (a chemotaxic for monocytes)
↑ oxidized cholesterol

↑ ↓ eNOS ↓ nitric oxide ↓ vasodilation
↑ eACE → ↑ angiotensin II → ↑ vasoconstriction→ ↑BP
last 2 is "double whammy"
Paraoxonases
HDL apolipoproteins which reduce oxidized lipids
cholesterol ester transfer protein (CETP)
transfers cholesterol ester from large HDL to VLDL.
Transfers oxidized lipids from LDL to HDL
MCP-1
Released by modified (oxidized) LDL. Causes synthesis of more adhesion proteins which are deposited on vessel surface→ ↑ more monocytes migrate across endothelial cells. Amplifies inflammatory process.
C-reactive protein (CRP)
an acute phase protein associated with inflammation
Synthesis induced in liver by inflammatory cytokines
elevated levels associated with greater CVD and MI risk (correlative not causative)
small dense LDL
a type of LDL associated with:
increased TG, VLDL, & IDL
low HDL cholesterol
insulin resistance
3X CHD risk as large LDL due to ↑macrophage uptake and ↑oxidation susceptibility
result of increased TG synthesis
fatty streak
The first stage of astherosclerosis. Gathering of foam cells in subendothelium
stable plaque
the type of plaque which has:
thick fibrous cap
smooth muscle cells with more extracellular matrix than the other type
lipid-poor plaque
vulnerable plaque
A type of plaque that has:
a thin fibrous cap
inflammatory cells
lipid-rich plaque
Endocrine signaling
a type of signaling with following characteristics:
slow: relies on passive diffusion and blood flow
dilute (<10^-8M) requires high affinity receptors → slow termination of response
paracrine signaling
autocrine signaling
rapid signal response
cellular response mediated by peptides and catecholamines. signals stored in secretory vesicles under plasma membrane. Short half life
slow signal response
cellular response mediated by steroid hormones which are not stored and must be synthesized before participating in cell signaling.
community effect
a signaling phenomena that occurs in a group of autocrine cells.
responsible for cell differentiation and growth, but also implicated in unregulated growth of tumor cells (chain reaction)
Consitutive secretion
secretion in which vesicles budding off from golgi contain proteins destined to be incorporated in the cell plasma membrane and also extracellular proteins. Steady state.
Reguated secretion
secretion in which clathrin coated vesicles bud off golgi and build up near the plasma membrane until signaled whereby many of them simultaneously exocytose.
endosomes
A membrane-bound compartment found in nerve cells which allow for rapid recycling of local plasma membrane.
nicotinic acetylcholine receptor
A type of ligand-gated channel.
Requires two molecules of ligand.
Composed of 5 transmembrane proteins with negatively charged AAs at mouth of channel forming aqueous pore, preventing anion entry
Insulin receptor
A type of tyrosine kinase receptor.
Different from rest of TKs in that it's composed of 2 alpha chains (containing hormone binding site) and 2 beta chains (containing tyrosine kinase domain).
Ligand binding induces autophosphorylation on tyrosine residues of intracelluar domain.
Tyrosoine Kinase receptor
A family of receptors characterized by a single transmembrane alpha-helix dividing receptors into:
extracellular domain containing for hormone binding site
intracellular domain contains specific activity of receptor
Prolonged hormone exposure leads to receptor degregation
IRS-1
a component which mediates three distinct pathways of the insulin signaling cascade.
phosphorylated by tyrosine residues
Growth Pathway
One of the three insulin signaling pathways
IRS-1 phosphorylates Shp →Ras → MAP kinase cascade → activates transcription factors
Glucose uptake pathway
One of the three insulin signaling pathways
IRS-1 phosphorylates P13K, initiating a phosphorylation cascade that eventually leads to placement of GLUT4 in the plasma membrane
Glycogen deposition pathway
One of the three insulin signaling pathways
IRS-1 phosphorylates P13K, initiating a phosphorylation cascade that leads to stimulation of multiple enzymatic steps in the conversion of glucose to glycogen
Cortisol
A steroid hormone ubiquitous throughout the body
Anti inflammatory and immunosupressent
Needed under conditions of major stress to supply extra glucose to the brain by:
Promoting gluconeogenesis in liver
promoting breakdown of protein into AAs in muscle
promoting FA oxidation in adipose
NF-kB
A protein complex which binds to DNA and activates transcription of inflammatory proteins(cytokines). Inhibited by binding to glucocorticoid receptors in a process called transrepression
transactivation
A process whereby glococorticoid receptors bind to DNA and activate transcription of antiinflammatory proteins
transduction
A process whereby glucocorticoid receptors directly activate anti-inflammatory proteins without changing transcription rate
TAF
A domain of the steroid receptor which promotes activity of DNA polymerase
HRE (hormone response element)
Promoter region of genes which bind to the DNA-binding domain (DBD) of steroid receptors.
ie glucocorticoid response element (GRE)
LBD
A domain of the steroid receptor which binds steroid hormones with high selectivity
Steroid receptor activation of transcription
Liganded receptor recruits steroid receptor co-activator complex, containing enzymes with histone acetyl transferase activity → histone acetylation → unwinding of chromatin which allows binding of Polymerase II
IkBα
a protein which binds to and Inhibits NF-kB which ultimately suppresses immunity
expression is increased by glucocorticoids.
G receptor
A type of receptor characterized by a chain which passes through plasma membrane 7 times.
Extracellular amino terminus and sections of transmembrane domain define the ligand binding site.
Intracellular loops contain sites for G protein interaction and phosphorylation-mediated inactivation (phosphorylation turns receptor off)
adenylyl cyclase
transmembrane enzyme which catalyzes ATP → cAMP
epinepherine acts through this mechanism
cyclic AMP phosphodiesterase (PDE)
Degrades cAMP and yields 5-amp
β/γ chain of stimulatory G(s) protein
part of the G protein which anchors the other part to the cytoplasmic face of the plasma membrane.
Identical chains for inhibitory and stimulatory G proteins
α(s) chain of G(s) protein
part of the G(s) protein which binds and hydrolizes GTP, interacts with the receptor, and activates adenylate cyclase
different variations for different second messenger systems
Inactive G protein
Active G protein
PKA
aka R2C2 or A-Kinase
A tetramer with 2 cAMP binding regulatory chains and 2 catalytic chains (C units) found within the G protein pathway
Binding of cAMP causes release of activated catalytic subunits which go on to phosphorylate substrates.
Phosphorylates receptor when cAMP levels get too high → desensitization
Response is reversed via dephosphorylation of substrates and cAMP degregation by PDE
Phospholipase C (PLC)
generates important second messengers such as DAG and IP3
Activated by G(q).
Cleaves PIP2
DAG
One of the products of PIP2 cleavage in the Ca++/phosphoinositide signal pathway
Lipophillic and remains in plasma membrane to activate protein kinase C (PKC) leading to intracellular phosphorylation cascade
Mimicked by phorbol
IP3
One of the products of PIP2 cleavage in the Ca++/phosphoinositide signal pathway.
Moves to cytoplasm to trigger Ca++ release from intracellular stores leading to Ca++/calmodulin cascade.
Mimicked by calcium ionophores (ionomycin)
CaM
effector protein which regulates a variety of enzymes and proteins (i.e. MLCK in muscle)
Activate by binding to Ca++
PKC
protein found in the Ca++/phosphoinositide signaling pathway which phosphorylates a variety of enzymes and proteins such as ion channels and transcription factors. Activated by diacylglycerol
βARK
Kinase which phosphorylates serine residues on intracellular loops of G receptor when cAMP levels get too high for regulation to be handled by A-kinase
β arrestin
The final solution for G-receptor inactivation. Protein which has multiple phospho-serine binding sites; will bind to receptor to fully inactivate it by steric hindrance.
Diabetes
Leading cause of serious disabilities such as blindness and amputation
Omega-3 fatty acids
decreases mRNA of several interleukins that increase inflammation and are elevated in astherosclerosis, arthritis, and some autoimmine diseases (like MS)
nutrigenomics
The study of the molecular level interaction of nutrients and other dietary bioactive substances with the genome
BMI
wt/ht^2
Underweight
BMI <18.5
Normal weight
BMI 18.5-24.9
Overweight
BMI 25-29.9
Obese
BMI 30 and higher
SREBP-1
A lipogenic transcription factor.
Overexpression increases insuln resistance.
Expression may be increased by high fructose
PPARα
receptors which induce an increase in the size and number of peroxisomes.
lipid oxidizers
found in liver and muscle
Activation depressed by saturated fats → ↑ inflammation
↓TGs
↑HDL
GnT-4a
A necessary enzyme for glucose transporters. Highly expressed in pancreatic tissue and allows cells to sense blood glucose lvels.
Animal studies show high fat diets suppress this enzyme's activity.
Lower activity documented in humans with type II diabetes.
resistan
An adipocyte-derived cytokine which causes insulin and glucose intolerance.
Expressed much more highly in abdominal (visceral) fat than subcutaneous fat.
Visceral fat
Metabolically active fat.
Risk factor for dementia
Increases inter-organ cycling of fat
tumor necrosis factor-alpha (TNFa)
cytokine involved in systemic inflammation
increased levels in fat people
IL-6
Activates STAT3, a tumor promoting transcription factor.
Increased levels in fat people
IGF-1
polypeptide hormone similar to insul with anabolic effects.
Enhances the growth of a variety of cancer cells.
Increased levels in fat people
AKT
a protein kinase which inhibits apoptosis and can result in increased cell growth
Activated by IGF-1
SHBG
A glycoprotein which binds to sex hormones
IGF-1 reduces levels → ↑ estradiol in men and women → ↑ endometrial and postmenopausal breast cancer and colon cancer
leptin
A peptide hormone secreted by adipocytes and affects hypothalamus (appetite control and energy metabolism)
Increased levels in fat people
high levels seen in prostate and colon cancers
Oral cancer
75% of this type of cancer is related to alcohol and smoking.
Stomach cancer
A cancer whose risk increases with salted, fermented, and preserved foods
Colorectal cancer
A cancer whose rates are 10X higher in industrial areas.
Being overweight, sedentary, and consuming preserved and red meat increases risk
Liver cancer
A cancer linked to hepatitis B and C, aflatoxin, and alcohol intake
Hypertension
Sodium restriction reduces blood pressure in 30-60% of pts. with this disease.
Older people, women, african americans, and people with renal insufficiency are all more sensitive to salt
↑ salt → ↓ calcium
DASH
A diet which lowers hypertension
Increased calcium, potassium, magnesium, phytonutrients, and fiber
lower fat and cholesterol intake
Osteoporosis
Major cause of morbidity and disability in older adults- i.e.spine and hip fractures
Vitamin D helpful
excessive thyroid hormones can cause bone loss, along with many drugs (p2740
Arginine & Histidine
conditionally essential AAs because they are not synthesized in adequate quantities by young animals
methionine
an essential AA required in large amounts for production of cysteine
phenylalanine
an essential AA required in large amounts if tyrosine is not adequate in diet
sources of amino acids
50g/day in diet (twice as much in western diet)
250g from protein turnover
stomach protease
Pepsin
Small intestine proteases
trypsin, chemotrypsin, elastase, aminopeptidases, carboxypeptideases
enterocytes
Intestinal absorptive cells.
contain dipeptidase which digests proteins.
Amino acids absorbed through these cells via diffusion and multiple Na+ dependent and Na+ independent carriers into portal circulation
Separate basolateral carriers transport AAs into blood.
Small peptides transported by a H+ driven transporter and hydrolyzed by intracellular peptidases
ATP-dependent NA+/K+ pump maintains gradeint needed to drive transport.
urea
Mechanism for nitrogen excretion in mammals.
Non toxic
Highly water soluble
Used only for excretion of excess nitrogen
formed from ammonia and bicarbonate
ammonia comes from:
purines
Mechanism for excretion of nitrogen in bats, birds, and reptiles
excreted in feces
minimizes use of water
ammonia toxicity
urea cycle enzyme disorders and liver failure causes toxic buildup of this substance → ↓ ATP, brain swelling and herniation

↑ NH4+→ ↑ glucagon release → gluconegonesis in kidney from AAs → ↑ glucose and NH4+ release

↑ glucose → ↑ insulin release→ ↑ uptake of branched AAs into muscle → ↑ NH4+

↑ NH4+ in brain → ↑ glutamine synthesis →↑ tryptophan transport into brain → ↑ 5-OH tryptamine synthesis → ↓ α-ketoglutarate and intracellular glutamate → ↑ extracellular glutamate → ...
↑ NMDA receptor activity →
↑ Mitochondrial Ca++ uptake, ↑ free radical formation, ↑ lipid peroxidation, ↓ ATP synthesis, ↓ reduced glutathione
properties of erythrocytes
Circulate 120 days on average; cleared by spleen
lack nuclei
no synthesis of macromolecules; no cell division
No intracellular organelles- energy from glycolysis
reductive power from PPP pathway
pathways to prevent oxidative damage
Biconcave
erythrocyte shape
Increases surface area/volume ratio for gas and solute exchange
increases deformability; permits passage through tight spots

Shape dependent on structure of the cytoskeleton and membrane and metabolic pathways
EPO
a glycoprotein which stimulates production of erythrocytes by binding to specific surface receptors in bone marrow
circulates in blood
synthesized in peritubular cells of kidney, regulated by oxygen
HIF-1
Transcription factors found in kidney tubules whose levels increase in response to hypoxia
stimulates EPO transcription in kidney
non-circulating- CANNOT be used as an IV therapy to increase EPO
procrit
recombinant EPO used to treat decreased erythrocyte production
used in end stage kidney disease, HIV patients treated with reverse transcriptase inhibitors, cancer patients on chemo (kills dividing RBC precursor cells), and following surgery.
erythrocyte energy metabolism
Must have glucose
90-95% of glucose gets metabolized by glycolysis which produces
2,3- BPG, ATP, and NADH(used in reducing ferric to ferrous)
5-10% metabolized in PPP
Biphosphoglycerate mutase
An enzyme found in erythrocyte glycolysis which catalyzes 1,3 Biphospho glycerate → 2,3 Biphosphoglycerate(promotes O2 release and is a feedback inhibitor of enzyme).
Forms a complex with GAPD in tissue and a complex with PGK in lungs depending on pH. This prevents product of first reaction from diffusing out into the entire cell (channeling)
Bypasses substrate level phosphorylation
Pentose Phosphate Pathway
a pathway important in NADPH production to regulate the reduction of metHb(Fe3+) and catalyze GSSH → 2GSH
Produces 4 electrons by reducing 2 molecules of NADP+ to NADPH per molecule of glucose-6-P
Produces ATP from metabolism of ribulose 5-P products
GSH
a tripeptide in erythrocytes
detoxifies hydrogen peroxidase (enzyme: glutathione peroxidase)
reduces protein thiols
reduces MetHb to Hb
unlike most peptides, not synthesized from mRNA but rather from glutamate, cysteine, and glycine via two synthetases. Requires ATP to drive reaction
cyanosis
disease caused by Hb oxidation to Hb-Fe3+, which does not bind O2. Manifests as blue skin
Bile salts
Polar derivatives of cholesterol
Produced in liver and stored in gall bladder
Released into intestine (20-30 g a day)
MetHb reductase II
enzyme which catalyzes minor pathway of metHb reduction (5-10%)
Requires NADPH
MetHb reductase I (cytochrome b5 reductase)
enzyme which catalyzes major pathway of MetHb reduction (67%)
Transfers electrons from NADH to cytochrome B5 which then reduces metHb (Fe3+ → Fe2+)
Hemoglobin M
A type of hemoglobin with mutation in α or β subunits which make iron more prone to oxidation. Causes mild methemoglobinemia
Inherited Methemoglobinemia
A disease caused by defects in various enzymes involved in Hb reduction or by mutated Hb.
Defects in metHb reductase I, II, and glutathione peroxidase all cause mild form.
Defects in cytrochrome B5 reductase can be severe depending on nature of mutation
superoxide dismutase
An enzyme which accelerates the above bimolecular reaction.
This neutralizes highly reactive oxygen species formed by a number of redox enzymes.
methylene blue
An antioxidant used therapeutically for individuals with methemoglobinemia
G-6-P dehydrogenase deficiency
An x-linked disease which affects 400 million people; afflicts 11% of African Americans.
Similar distribution to that of malaria; protects against malerial parasites
Individuals with this disease more sensitive to oxidative stress which can leads to lipid oxidation, spectrin destruction, and Hb oxidatition, and cause the following symptoms:

Neonatal jaundice → neurological damage
Acute hemolytic anemia
hemolytic attack induced by various drugs including antimalarials, sulfonamine anitbiotics, phenacetin, napthalene vitamin K, fava beans, and infection

Test for this by measuring amount of deficient enzyme in lysed erythrocytes
primaquine and pamaquine
Antimalarials which can induce a hemolytic attack in pts with G-6-P dehydrogenase deficiency
2, 3 BPG
Stabilizes low affinity (T) state of Hb.
Anemia, obstructive pulmonary disease (emphysema), cystic fibrosis, congenital heart disease, hyperthyroidism → ↑ concentration of this substance
Hexokinase deficiency
An rare enzyme deficiency which causes
↓ glycolysis
↓ [2,3 - BPG]
Shifts binding curve to left
worsens anemia
Pyruvate kinase deficiency
↑ [2,3- BPG]
Shifts O2 binding curve to the right, offloading more O2 in tissue and partly compensating for anemia
fetal Hb
A type of Hb composed of α2γ2 subunits.
Higher affinity for O2 than HbA
transaminase
An enzyme which transfers amino groups from an AA to a keto acid.
Essential for transfer of nitrogen that is ultimately eliminated as urea
glutamate dehydrogenase
catalyzes oxidative deamination of glutamate
Confined to mitochondrial matrix
NADPH for forward rxn, NAD for backwards rxn
glutaminase
Catalyzes above reaction
Important in metabolic acidosis, which suppresses urea production
rxn allows ammonium to be excreted in relatively high concentrations directly by the kidney
glucose-alanine cycle
provides for the transport of nitrogen, generated by the metabolism of AAs, from skeletal muscle as a nontoxic form
produces pyruvate for production of glucose by gluconeogenesis in the liver
important during fasting and starvation.
pyridoxal phosphate
functions as an electrophile for covalent catalysis in transaminase reactions
Carbamoyl phosphate synthetase I
catalyzes above step in urea cycle
activated 5-10 fold by N-acytylglutamate
Occurs inside mitochondria
ornithine transcarbamylase
catalyzes ornithine + carbamoyl → citrulline (step 2 in urea cycle)
occurs in mitochondira.
ornithine made in cytosol and brought in by ornithine/citrulline shuttle
argininosuccinate synthetase
catalyzes citrulline + aspartate → argininosuccinate (step 3 of urea cycle)
occurs in cytosol- citrulline brought out of mitochondria by ornithine/citrulline shuttle
aspartate brought out of mitochondria via malate/aspartate shuttle.
argininosuccinate lyase
catalyzes argininosuccinate → arginine + fumerate (step 4 of urea cycle)
occurs in cytosol
argininase
catalyzes arginine → ornithine (step 5 of urea cycle)
releases urea from arginine.
Present in liver, absent in kidney, which is a major site of arginine synthesis
Occurs in cytosol
Links between the urea and TCA cycles
regulation of urea cycle
Long term : High protein diet, starvation → ↑ metabolism of amino acids → ↑ synthesis of urea cycle enzymes. Carbon skeletons are oxidized or converted to fat and glycogen

Short term : Arginine →↑ N-acetylglutamate → allosterically activates carbamoyl phosphate synthetase I
ammonia
mechanism for nitrogen excretion in invertebrates, although small amounts are secreted normally in urine by humans
sources:
1)oxidative deamination of AAs
2)release from glutamine via glutaminase
3) Release from alanine via transaminases and glutamate dehydrogenase
Maturation and metabolism of chylomicrons
1. components synthesized and assembled in intestinal enterocytes
2. secreted via exocytosis into the lymphatic system chyle as nacent chylomicrons
3. delivered to bloodstream via left subclavian vein
4. picks up Apo C and Apo E from HDL in circulation → mature chylomicron
5. Lipoprotein lipase in capillaries of extra hepatic tissues precipitates the loss of TGs (FAs & glycerol), ApoA and ApoC
6. Chylomicron remnant is recognized (w/ ApoE) and taken up by liver for reabsorption
Hepatic uptake and distribution of cholesterol
Small amounts of dietary cholesterol delivered in chylomicron remnants, but most comes from de novo synthesis; it gets packaged in VLDL and LDL and distributed to blood; liver does not store cholesterol; cholesterol returned to liver by HDL gets converted to bile and potentially excreted
Hepatic uptake and distribution of TGs
Dietary TGs delivered in chylomicron remnants, packaged in VLDL and distributed to blood; liver does not usu. store TGs, fatty liver is pathological (chronic alcohol abuse, diabetes)
Maturation and metabolism of VLDL
1. Formed in liver from TGs and CE; contains ApoB100, C and E (nacent VLDL)
2. Released via hepatic portal system, gets absorbed into blood stream
3. Gains more ApoC and E → mature VLDL
4. Hydrolysis of TG by lipoprotein lipase in tissue capillaries yields FAs (enter tissues-esp. adipose-esterified and stored) glycerol (enters blood → liver and kidney), loss of ApoC (rejoins HDL), and VLDL remnant (aka IDL)
5. 2 fates: 1) loss of ApoE and residual TG → LDL; 2) delivery to liver as VLDL
6. LDL is taken up by tissues (mostly), delivering cholesterol to those tissues
Lipoprotein lipase-tissue specific kinetics
Affinity for LPL is 10x ↑ in heart and (lactating) mammary gland than adipocytes ∴ these organs can get energy even when VLDL and chylomicron concentrations in blood are low (i.e. during fasting)
Indirect pathway for hepatic uptake of cholesterol
Cholesterol Ester Transfer Protein (CETP) facilitates the exchange of cholesterol ester in HDL for TGs in TG-rich ApoB particles (LDL and VLDL); the now cholesterol-enriched LDL and VLDL are sometimes taken up by the liver
Direct pathway for hepatic uptake of cholesterol
Cholesterol ester is taken up via scavenger receptors (SRB1) on hepatocytes that recognize ApoA1 (on HDL) as a ligand
LDL: basic function
Apo-B100 binds to LDL receptors on all tissues → particle is endocytosed and transported though a system of coated pits, endosomes, lysosomes, and finally de-esterified → cholesterol is released into tissue cytoplasm (uptake into tissues results in ↓ HMG-CoA reductase and LDL receptor expression)
calcineurin
aka Ca++ dependent phosphatase.
found in neurons.
Activates Na+/K+ ATPase
levulose
A treatment for ammonia intoxication. This drug is metabolized in the colon into acidic products, which promotes NH4+ formation and excretion since ammonium is less readily absorbed than ammonia in the gut
sodium benzoate and sodium phenylbutyrate
treatment for ammonia intoxication.
forms covalent products with glycine and glutamine- compounds that promote nitrogen excretion in the feces.

other treatments include a low protein, high carb diet and antibiotics to kill intestinal ammonia-producing bacteria
glucogenic amino acids
amino acids which yield precursors that can be used in gluconeogenesis. These AAs are metabolized to:
pyruvate, α-ketoglutarate, succinyl CoA, furmarate, oxaloacetate
ketogenic amino acids
amino acids that are metabolized to acetyl-CoA (leucine) and acetoacetyl-CoA (lysine)
fumarate
oxaloacetate
pyruvate
acetoacetate
glutamate
methylmalonyl CoA
vaginas
make
infants
all go to succinyl CoA
Branched chain keto aciduria (maple syrup urine disease)
rare recessive disorder in isolated asian and mennonite communities.
Deficiency in α-keoacid dehydrogenase complex (BCKAD) → accumulation of α-KisoV[valine], α-KβV[isoleucine], and α-KisoC[leucine] → severe mental retardation
onset soon after birth
lethargy and no interest in feeding
weight loss and progressiv neuro degeneration
multiple forms (classic, intermediate, etc) [p 361]
alkaptonuria
A disease caused by a defect in homogentisate oxidase → accumulation of homogentistic acid in urine. Accumulation of polymerized form results in
damage to joints (arthrtitis):
calcifications in the cardiovascular system and urinary tract
reddish tint (ochre) to skin
S-adenosyl methionine
an important methyl group donor in many reactions such as norepinepherine → epinepherine and cytosine methylation of DNA.
Synthesized from methionine and ATP and catalyzed by methionine adenosyl transferase
methionine synthase
catalyzes regeneration of methionine from homocysteine.
Needs B12 as its coenzyme
Cysathionine β-Synthase
catalyzes homocysteine → cystathionine
Needs pyridoxal phosphate (vitamin B6) to function
A deficiency in this enzyme → HOMOCYSTINURIA: accumulation of homocysteine → ectopia linitis, osteoporosis, mental retardation, vascular thrombotic events.
Treated with B6, B12, and folic acid.
If vitamins don't work, restrict methionine and supplement diet with cystine and betaine (promotes remethylation of homocysteine to methionine)
homocysteine thiolactone
cytotoxic, immunogenic modified protein made from homocysteine by methionyl-tRNA synthetse.
S-nitrosohomocysteine
cytotoxic, immunogenic modified protein formed from homocysteine and NO (nitric oxide)
amino acids and their central pathway intermediate precursors
pyruvate → alanine
α-ketoglutarate → glutamate → glutamine
oxaloacetate → aspartate → asparaginine
phosphoglycerate → serine → glycine
citrulline → arginosuccinate → arginine
intrestinal-renal axis
the pathway for arginine synthesis. Begins with citrulline synthesis in the enterocytes of the small intestine, which is then carried by circulation to the kidney, which lacks arginase and is resultingly the major site for arginine production.
tetrahydro-biopterin
cofactor of phenylalanine hydroxylase, which catalyzes phenylalanine → tyrosine
Acts as a reducing agent analagous to NADPH
phenylketonuria
A disease resulting from mutations in the phenylalanine hydroxylase gene.

symptoms: mental retardation, epilepsy, peculiarities of gait, stance, and sitting posture, brain calcification, mousy odor, light pigmentation, and eczema.

Treatment: screening infants, placing those afflicted on a phenylalanine restricted, tyrosine supplemented diet until brain development is complete.

phenylpyruvate present in urine
Nitric Oxide
a membrane permeable, stable short-lived, free radical.
relaxes endothelial smooth cells, prevents agregation of platelets, reduces white cell adhesion to endothelium, neuromodulator, and immunomodulator. Made during conversion of arginine to citrulline. Many different isozymes of the synthase involved in this reaction.
LDL cholesterol guidelines
<100: optimal
100-129: near optimal/above optimal
130-159: borderline high
160-189: high
>190: very high
(mg cholesterol/dL after12 hour fast)
total cholesterol guidelines
<200: desirable
200-239: borderline high
>240: high
(mg cholesterol/dL after 12 hour fast)
HDL cholesterol guidelines
<40: low
40-60: ideal
>60 high
(mg cholesterol/dL after12 hour fast)
Friedewald formula
an indirect way to measure LDL cholesterol
LDL = total C - HDL C - (TG/5)
Apo E4/E4
A genotype which reduces efflux of cholesterol from macrophages → ↑ elevated LDL cholesterol with ↑dietary cholesterol
Dietary saturated fats and trans-fats
raise LDL cholesterol by 8-30%
Decrease hepatic LDL receptors
diet for hypertriacylglycerolemia and low HDL
high in fat (35% of caloric intake)
high in mono and poly-unsaturated fatty acids
works because:
↓ saturated fat → ↓ LDL
↓ carbohydrates → ↓ carb induced hypertriaclyglycerolemia
Maintains HDL (low fat diet can decrease HDL)
ω-3 fatty acids
a component found in oily fish and other foods that:
↓ blood triacylglycerol, thromboxane A2 synthesis (and thus inflammation), platelet adhesion, ischemic myocardial damage, restenosis after angioplasty (high doses)
↑ nitric oxide production, RBC membrane fluidity

no significant effect on LDL or HDL levels
alcoholic beverages
decrease CHD (1-2 a day)
↑ HDL cholesterol 5-8%
↓ platelet adhesion
Antioxidants (?)
↓ stress (?)
But...
Metabolized to acetate → acetyl-CoA → FA → ↑TG (liver)
niacin (nictotinic acid)
compound that:
↓ LDL and TG
↑ HDL
↓ lipoprotein synthesis and production of VLDL
↓ mobilization of unesterified fatty acids from periphery
May not be well tolerated at high doses
the above effects seen from 2g/day, much higher than the the doses this compound is needed to function as a vitamin
fibrates
compound that:
↓TG
Little or no effect on LDL
↑ HDL
Agonist for PPARα, a transcription factor for several genes in lipid metabolism
May increase morbidty (non CHD)
dyslipidemia drugs
pleiotropic effects of statins
the effects of these drugs other than their blocking of HMG-CoA reductase
small dense LDL
causes:
high carbohydrate diet and increases in blood TG

treatment:
NCEP diet (30-35% kcal from fat)
weight reduction
exercise
stain with TG-lowering benefit
Niacin or fibrate (if TG>1000)
heterozygous familial hypercholesterolemia
a hyperlipidemia:
LDL levels twice normal
premature CHD common
cause: mutation in LDL-receptor gene (one allele)
treatment: TLC + statins +BAS and/or niacin
homozygous familial hypercholesterolemia
a hyperlipidemia:
LDL levels increased 4-fold
widespread severe atherosclerosis
cause: mutation in LDL-receptor gene (both alleles)
treatment: statins, niacin, LDL-pheresis, liver transplant
familial defective Apo B-100
a hyperlipidemia:
LDL levels increased 1.5 to 2-fold
premature CHD
cause: point mutation in gene for apo B: cannot be taken up by receptor
treatment: TLC, statins, niacin, BAS
polygenic hypercholesterolemia
a hyperlipidemia:
LDL > 190 mg/dL
CHD 3x to 4x general population
cause: mutations in multiple genes and poor diet
treatment: TLC, statins, BAS, niacin
familial analphaliproteinemia (tangier's disease)
an autosomal recessive hyperlipidemia:
mature HDL and plasma apo A1 very low
plasma cholesterol low
accumulation of CE in tissue, orange tonsils
increased CHD
cause: mutation in gene for ATP-binding cassette transporter 1 (ABCA1) This transporter is responsible for shuttling phospholipids and cholesterol out of tissue onto nascent HDL particles.
very important to know about since it affects 1/120 million people.
familial abetalipoproteinemia
a hyperlipidemia:
no plasma VLDL or LDL
inability to absorb fats
TG accumulation in enterocytes
increased CHD risk
intracellular accumulation of Apo B48 : cannot make chylomicrons, which leads to rise in LDL cholesterol
cause: mutation in gene for microsomal transfer protein (MTP)- involved in lipoprotein assembly in liver and intestine
treatment: low fat diet, tocopheral supplements (vitamin E), medium chain TG supplements
Adrenoleukodystrophy (ALD)
An x-linked neurodegenerative disease
major symptoms include:
dementia
loss of sight, hearing, speech, and ambulation
difficulty swallowing, reading, and writing

caused by a malfunction in the transporter protein which moves VLCFA CoA synthase into the peroxisome
VLCFA CoA synthase
catalyzes acetyl CoA +VLCFA → VLCFA
occurs in peroxisome
VLCSFAs
1) act as a "soap" to solubilize the hydrophobic molecules of the myelin sheath
2)concentrate into the myelin sheath and stimulate local autoimmune reaction
3)concentrate in neural membranes and inhibit membrane function
lorenzo's oil
a mixture of unsaturated fatty acids (oleic and erucic acids)
these shorter unsaturated FAs act as competitive inhibitors to the elongation of saturated FAs
As ↑ [unsaturated LCFA], they will be more likely to undergo further elongation, and they will out-compete saturated LCFAs for the active site of the elongation enzyme
lypodistrophy
a medical condition characterized abnormal or degenerative conditions of the body's adipose tissue
lipoatrophy
localized loss of fat tissue
obesity and lipodystrophy similarities
adipocyte hypertrophy
increased visceral adipocyte-FFA release
insulin resistance
increased risk of cardiovascular events
hepatic malfunctions
antiretroviral therapy (ART) impact on VAT
visceral adipocyte hypertrophy (protease inhibitors implicated) [abdominall fat]
nucleoside analog reverse transciptase inhibitors (NRTIs)
a type of ART drug that is responsible for lipoatrophy in SAT
protease inhibitors (PIs)
a type of ART drug that is responsible for adipose hypertrophy in VAT
paracrine inflammatory loop
a process that occurs in obese HIV patients
Activated Macrophages invade areas with ↑ [FFA]
Macrophage produce proinflammatory cytokines (TNFα )
TNFα causes adipocytes to release more FFA
Too much FFA overwhelms mitochondrial capacities of cells, leading to toxicity
TNFα
proinflammatory cytokines secreted by HIV infected macrophages.
promotes further monocyte extravasation to adipose, potentiating infected macrophages.
increase in low level systemic inflammation
ART impact on SAT
Mitochondrial Function:
Decrease in mitochondrial function occurs prior to onset of lipodystrophy
↓ mtRNA transcription
↓ Expression of genes which code electron-transport chain components
↓ Mitochondrial Function → ↑ Oxidative Stress

Inflammation:
↑Number of macrophages
↑[α TNF]

Cortisol:
Glucocorticoid is probably involved in ART-linked central fat hypertrophy
buffalo hump
a diagnostic characteristic of HIV infected pts.
fat hypertrophy is frequently observed in central depots such as the abdomen, trunk, breast (in women), face and neck
composed of brown adipocytes which have lost the expression of the uncoupler protein (no heat production) but which still divide easily and actively
congenital generalized lipodystrophy
caused by mutation in genes that code for Seipin or Acyltransferase AGPAT2

Seipin: responsible for lipid-droplet coalescence
Acyltransferase AGPAT2: important for triglyceride synthesis and adipocytes differentiation

Complete inability of adipocytes to store fat results in TG accumulation in other tissues and lipotoxicity
Familial Partial Lipodystrophic Syndromes (FPLD)
Mutations either in LMNA, encoding the nuclear protein lamin A/C (FPLD2), or in PPARγ (FPLD3)

Mixed Lipodystrophy: Lipoatrophy of subcutaneous fat; Hypertrophy of central fat

Mutations in LMNA are also responsible for metabolic laminopathies resembling metabolic syndrome and Hutchinson-Gilford Progeria.
hypercortisolism
associated with a type of lipodystrophy manifesting as:

Fat hypertrophy in the upper body depots
Excess fat in the trunk and cervico-facial area,
Presence of a buffalo neck
Increased VAT together with decreased limb fat.
insulin resistance and increased lipolysis
carbamate
15% of CO2 transported as this molecule.
CO2 is attached to N-terminal amino group of Hb
stabilizes low affinity T state
bicarbonate
85% of CO2 transported as this molecule
in tissue: transported out of RBC by antiporter(exchanges with Cl-)
in lung: transported into RBC by antiporter
spectrin
cytoskeletal fibers composed of two subunits to form a tetramer
106 residue repeated elements form anti-parallel helix
links to band 3 (via ankyrin) and glycophorin C (via actin and band 4.1)
maintains erythrocyte shape
hereditary spherocytosis
Defective spectrin-membrane link caused by mutations in β-spectrin (most often), α-spectrin, ankyrin, band 3

results from reduced concentration of affected protein or structural defect
defective verical interaction between cytoskeloton and cell membrane → spherical shape
since abnormal cells are cleared faster by spleen, pt may get splenomegaly, cured by spenectomy
elliptocytosis
caused by defective α or β-unit of spectrin which affects terameric interaction
shape of RBC reflects loss of horizontal interaction.
hereditary ovalocytosis
caused by defect in spectrin, band 4.2, and band 3
Southeast Asian type caused by lysine → glutamate mutation in band 3. heterozygotes are resistant to malaria
shape of RBC reflects loss of horizontal interaction.
anion exchange protein I (band 3)
a dimeric, transmembrane channel specific to erythrocytes that exchanges Cl- for HCO3- (antiporter)
glycoprotein- 12 membrane spanning helices
cytoplasmic N-terminus interacts with ankyrin, linking spectrin to membrane (C-terminus also cytoplasmic)
N-terminus binds G-3-P dehydrogenase, PKG, and aldolase
C-terminus binds carbonic anhydrase, which catalyzes CO2+H20 → H2CO3
also binds antigens
ankyrin
A peripheral membrane protein which links band 3 to spectrin
Glut1
a highly specific integral RBC membrane protein.
uniporter transporter
facilitated diffusion
not stimulated by insulin unlike other channels of this family
bicarbonate exchange in peripheral tissue
bicarbonate exchange in lungs
haldane effect
deoxy Hb has greater affinity for CO2 than oxy Hb
O2 released in tissues facilitates CO2 binding to Hb
O2 binding in lungs facilitates CO2 release
aquaporin (AQP1)
a transmembrane tetrameric protein which allows cells to swell or shrink rapidly depending on osmolarity and surroundings
each subunit has a central pore lined with hydrophillic residues
passive uniporter
Na+/K+ ATPase
an energy-requiring channel which maintains ionic concrentration gradient.
phosphorylation causes conformational change
maintains integrity of erythrocytes
glycophorins
a class of membrane spanning glycoproteins
extracellular domain glycosylated - 60% of mass is carbohydrate
membrane spanning part is hydrophobic
gives erythrocyte its negative charge; prevents adherence to other erythrocytes and vessel walls
receptor for malarial parasites
in individuals lacking these proteins, glycosylation of band 3 compensates
ABO blood group antigens
oligosaccharides on ertythrocyte surface linked to:
band 3 (80%), glucose transporter, other membrane proteins, and glycolipids
H substance
a precursor of A and B substances formed by:
GDP-fuc + 2Gal-4GlcNac → Fuc-2Gal-4GLCNac-R (fucosyl transferase) [p 341]
GalNac transferase
catalyzes H substance → A substance (terminal fucose and n-acetylgalactosamine side-chain)
Gal transferase
catalyzes H substance → B substance (terminal fucose and galactose side chain)
type AB
a blood type with cell surface oligosaccharides that have:
terminal fucose plus galactose and N-acetyl-galactosamine side chains
universal recipient - will form no antibodies
type O
a blood type with cell surface oligosaccharides that have:
a terminal fucose, but no side chains (universal donor)
encoded by gene H
produce antibodies to A and B antigens
Na+ dependent imino transporter (IMINO)
apical AA transporter found in kidney and small intestine
Na+ uptake of glycine and proline
associated disease: imino glycinuria
Cationic amino acid/cysteine transporter
apical AA transporter found in kidney and small intestine
Na+ independent transporter that couples uptake of ornithine, lysine, arginine, and cystine to the efflux of neutral amino acids
associated disease: cystinuria
two subunits linked a disulfide bond. one subunit is the transporter (light chain) while the other targets the complex to the plasma membrane (heavy chain)
Na+ neutral amino acid transporter
apical AA transporter found in kidney and small intestine
Na+ dependent uptake of all neutral amino acids; activity with glycine and proline is limited
associated disease: hartnup disorder
associates with other membrane proteins, collectrin (directs it to cell surface in kidney) and ACE2 (stimulates transport activity in intestine)
Na+ dependent anionic amino acid transporter
apical AA transporter found in kidney and small intestine
Na+ dependent transporter of aspartate and glutamate
associated disease: dicarboxylic aminoaciduria
H+ dependent imino transpoter
apical AA transporter found in kidney and small intestine
H+ uptake of glycine and proline
LAT I and LAT II
Basolateral AA transporters responsible for releasing cationic amino acids into blood.
cystinuria type A
caused by mutation in the heavy chain of the transporter for cationic amino acids and cysteine
heavy chain localizes the transporter on the surface
homozygotes excrete large quanitites of cysteine, lysine, arginine, and orthinine
cystinuria type B
caused by mutation in the light chain of the transporter for cationic amino acids and cysteine
the light chain has the transporter activity
heterozygotes are slightly affected and occasioanlly get cystine kidney stones
cystinuria type A/B
caused by mutations in the light AND heavy chain of the transporter for cationic amino acids and cystine.
these pts have FULL BLOWN cystinuria
cystinuria
a disease caused by mutations in the transporter for cationic amino acids and cysteine.
accounts for 6-10% of all nephrolithiasis (kidney stones) in pediatric population
large quantities of flat hexagonal cysteine crystals excreted in urine
cyanide-nitroprusside test will be positive
in serious cases there can be acute or chronic renal failure as a result of stone obstruction
cystinuria treatment
treatment includes:
adequate hydration- dilutes urine and reduces stone formation

keeping urine slightly alkaline increases cystine solubility:
potassium citrate, sodium citrate, and sodium bicarbonate raise PH, as does limiting dietary animal protein

reduction of cystine and methionine

treatment with agents that react with cystine to form more soluble disulfides with cysteine (penicillamine, thiopronin)
hartnup disorder
a disease that arises from autosomal recessive defects in the transporter for neutral amino acids
symptoms include characteristic rash with light sensitivity (pellegra) due to poor tryptophan uptake, psychosis, and cerebellar ataxia( lack of coordination)

treated with dietary niacin since much of nicotinamide is made through a pathway that starts with tryptophan
lysinuric protein intolerance
a disease caused by autosomal recessive defects in LATI transporter. LAT II in too low concentrations to compensate
defective uptake of cationic AAs in small intestine and kidney
↑ urinary excretion of lysine, arginine, and ornithine
derangement of urea cycle due to low ornithine levels → ↑ plasma ammonia → neurological problems (e.g coma)
pts. develop aversion to protein rich food at an early age
growth retardation, enlarged liver and spleen, muscular hypotonia, and osteoporosis
episodic hyperammonemia
introduction of formula and high protein foods is accompanied by failure to thrive, postprandial vomiting and diarrhea
lysinurgic protein intolerance treatment
treatment includes:
promote nitrogen excretion- sodium benzoate and phenylbutarate. this compensates for urea cycle problems
oral citrulline (precursor of arginine and ornithine)
protein restricted diet
treatment for maple syrup urine disease (MSUD)
treatment for this disease includes:
removing toxic metabolites shortly after birth- hemodialysis
thiamine- helps maintain low concentrations of BCAAs
low protein diet
metabolic decompensation
derangement of metabolism resulting from a toxic metabolite that affects other pathways, which then exacerbates original metabolic defect
anion gap
a way to estimate the anions that are not measured e.g proteins such as albumin.
increased in acidurias and acidosis
calculated by formula:
([Na+]) - ([Cl-] + [HCO3-])
elevated in isovaleric acidemia, MMA, and PA
isovaleric acidemia (IVA)
an autosomal recessive disease caused by defects in isovarlery-CoA dehydrogenase (IVA) which catalyzes isovaleryl-CoA → β-methylcrotonyl-CoA. Prosthetic group is FAD
accumulation of isovaleric acid and 3-hydroxyvaleric acid in plasma and urine
vomiting, dehydration, listlessness, metabolic acidosis, vomiting, lethargy progressing to coma, increased anion gap, and ketonuria with a distinctive "dirty sock" odor, severe psychomotor retardation or death
treatment for isovalerica acidemia
treated with:
protein restriction
supplement diet with a leucine-free AA mixture.
oral glycine and IV carnitine during episodes of metabolic crisis
long-term prognosis better than any other organic aciduria
methylmalonic acidemia (MMA) and propionic acidemia (PA)
an autosomal recessive disease caused by defects in methylmalonyl-CoA mutase [B12 dependent] or propionyl CoA carboxylase (PCC) [biotin dependent]
accumulation of toxic metabolites- elevated propionic acid in blood and urine- inhibits various pathways including glycolysis and urea cycle. carnitine synthesis supressed with resulting abnormalities in fatty acid metabolism. elevated serum ammonia
impaired mitochondrial energy production
metabolic decompensation can be triggered by protein overload or febrile infection

Presents as poor suckling or refusing to feed, vomiting, weight loss, abdominal distention, abnormal posturing and movements, generalized hypotonia, lethargy, seizures, cardiomyopathy, chronic renal failure, infarction of globus pallidus, coma, brain edema, respiratory distress, hypothermia, and permanent brain damage or death


Lab findings: metabolic acidosis, ↑ anion gap, ketonuria, anemia, hyperuricemia, leucopenia, hyperammonemia

grim outlook, not much can be done
nonketotic hyperglycinemia
an autosomal recessive disease caused by defects in glycine cleavage system
mutations occur in the p-protein of the complex in 80% of cases. (decarboxylase)
high levels of glycine in plasma and cerebrospinal fluid (CSF)
lethargy, vomiting, convulsions, loss of primitive reflexes, myoclonic, siezures, apnea, mental retardation and death

↑ glycine → activation of inhibitory spinal chord neurons, neurons with NMDA receptors, and abnormal metabolism of H4folate derivatives.
nonketotic hyperglycinemia therapy
disease treated by:
reducing NMDA glutamate receptor activity- diazapam(glycine antagonist), ketamine and dextromethrophan (NMDA receptor antagonists)
promoting glycine excretion- sodium benzoate
controlling seizures- phenobarbital
hyperammonenia type I
urea cycle disorder caused by defect in carbamoyl phosphate synthetase I (CPI).
treated with arginine stimulates CPI
hyperammonenia type II
urea cycle disorder caused by defect in ornithine transcarbamylase.
treated with carbamoyl glutamate
arginosuccinate synthetase deficiency
recessive urea cycle disorder
citrulline & ammonia elevated in plasma, CSF, and urine
arginine reatment enhances citrulline excretion
argininosuccinate lyase deficiency
recessive urea cycle disorder
argininosuccinate and ammonia in plasma, CSF, and urine
usually fatal in first two years
treated with arginine
arginase deficiency
arginine and ammonia elevated in plasma, CSF, and urine
treated with diet of essential AAs minus arginine and low protein.
iron properties
Involved in redox reactions that generate reactive oxygen species i.e. Fenton reaction
(1)Fe2+ +H2O2 → Fe3+ + OH. +OH-
(2)Fe3+ + H2O2 → Fe2+ + OOH. + H+

FeCl3 freely soluble at acidic pH, virtually insoluble at alkaline pH
functions of iron
-O2 transport and release
-H2O2 elimination; drug and steroid hydroxylation
-electron transfer
-cGMP synthesis
-TCA cycle (aconitase)
-transporting in blood and milk -storage in liver, macrophages, and other tissues
degregation
duodenum
location of iron absorption (pH= 3-5)
1-2 mg is absorbed a day
ferric reductase
catalyzes reduction of ferric to ferrous iron
located on apical surface of enterocytes
divalent metal transporter I (DMT1)
coupled to ferric reductase
transports ferrous iron into enterocytes
also found on endosomes containing transferrin receptor complexes
ferroportin
located on basolateral surface of enterocytes
transports ferrous iron out of cell into extracellular fluid
reduced intestinal expression causes severe iron deficiency
hephaestin
a copper feroxidase coupled to ferroportin
catalyzes oxidation Fe2+ → Fe3+
ferritin
intracellular protein that stores iron in the ferric form
about 30% of body iron
soluble
iron enters and is oxidized to ferric state by H chain
forms polymer of ferrihydrate with up to 4500 atoms
hepcidin
a hormone inhibitor of iron absorption
increased by elevated levels of iron in liver
increased by inflammation and infection
binds to ferroportin and causes its degradation
stabilized by disulfide bonds
heme transporter (HT)
transports heme into the enterocyte
heme oxidase
catalyzes heme iron → Fe2+ (ferrous)f
NOT same thing as heme oxygenase, which is involved in bilirubin formation
uptake of dietary iron
Heme iron > nonheme iron
ferrous > ferric
acidic pH >> alkaline pH
dietary factors that inhibit iron uptake
Bicarbonate (antacids)
tannins (polyhenols)
phytate
non-cellulose fiber
oxalic acid (swiss chard, spinach, rhubarb, cocoa peanuts)
divalent metals- Cs2+, Cu2+ etc - competitive inhibitors of iron transport
dietary factors that promote iron uptake
ascorbate- reduces Fe3+ to Fe2+
citric acid
protein
lysine, histidine, cysteine, methionine
all form complexes with iron
conditions that enhance iron uptake
conditions:
increased erythropoiesis
-hypoxia, hemolysis, hemorrhage
low iron stores
anemia
conditions that inhibit iron uptake
conditions:
inadequate production of stomach acid
infection and inflammation
high iron stores
transferrin
an iron binding glycoprotein
transports iron in blood- 1/3 saturated
cofactor: bicarbonate
binds ferric iron released from basolateral surface of enterocytes
increased levels will increase iron excretion
transferrin receptor
forms a complex with transferrin which is then internalized.
iron released when endosomes acidify
recycled to extracellular surface and releases apo-transferrin
similar to LDL receptors
transferrin receptor regulation
like LDL, the main way cells regulate iron uptake is via the number of of cell surface receptors, not by how much transferrin is circulating in blood.
iron-free IRE binding protein (IRE-BP)
aka cytoplasmic aconitase. a protein which regulates transferrin receptor levels and ferritin.

regulation of transferrin receptors:↓ iron → ↑ protein; binds to IRE on 3' end of mRNA→ inhibits TfR mRNA degredation → ↑ transferrin →↑iron transport

regulation of ferritin: ↓ iron → ↑ protein→ ↓ ferritin mRNA translation → ↓ ferritin →↓iron storage and ↑iron circulation
binds to IRE on 5' end and blocks transcription
hemosiderin
ferritin residual bodies
large iron-containing particles
poor reversibility to free iron
measure of iron overload
mechanisms of iron loss
epithelial cells of skin, intestine (ferritin, homosiderin)
feces (salts)
desquamation (salts)
menstruation (Hb)
iron distribution
(in mg)
ver little unbound iron
free iron is toxic
Hb synthesis decreases when iron is limiting
iron deficiency
fatigue
weakness
anorexia
koilonychia (fingernails thin, flat or spoon-shaped)
increased susceptibility to infection (impaired immune response)
↓ serum ferritin
↓ % saturation of plasma transferrin (which is normally released from tissues in small amounts)
↑ plasma transferring receptor
↓ Hb
↑ small hyerchromic erythrocytes
↓ in mean corpuscular volume (MVC) of erythrocytes

if blood loss is problem, determine cause and treat
dietary iron supplementation
hereditary hemochromatosis
an excessive iron disease
defect in a membrane glycoprotein called HFE (role is unclear)
associated with decreased transcription of hepcidin gene → ↑ iron absorption
↑ hemosiderin in hepatocytes
pathological iron accumulation takes many years; often not manifested until well into adulthood
cardiomyopathy, liver cirrhosis, diabetes, and arthropathies

treatment: phlebotomy or chelation therapy (deforoxamine)
aceruloplasminemia
an excessive iron disease
due to abscence of ceruloplasmin (a copper ferroxidase which oxidizes Fe2+ to Fe 3+):
iron accumulates in liver and other organs
destroys pancreatic beta cells → diabetes mellitus
nerve damage
mild anemia

treatment:
chelating agents
plasma or ceruloplasmin concentrate
β- thalassemia
an excessive iron disease
pts. lack β chain of globin
massive increase in erythropoiesis
severe anemia due to red cell destruction
increased uptake of iron from intestine
excessive storage of iron in liver and non erythroid tissues
hemochromatosis secondary to iron overload
major globin mutation

treatment:
chelation therapy (subcutaneous desferoxamine
blood transufsions
basal metabolic rate
increases with increasing body weight
decreases with decreasing body weight
NEAT
aka BAT. contains uncoupling protein (UCP1) in inner mitochondiral membrane used to generate heat
medical complications of obesity
pulmonary disease, idiopathic intracranial hypertension, stroke, cataracts, coronary artery disease, diabetes, cancer, gall bladder disease, nonalcoholic fatty liver disease, gynecologic abnormalities, osteoarthritis, gout, phlebitis
waist circumference thresholds
high risk:
men > 40 in.
women > 35 in
diet changes that help with weight control
eat breakfast
decrease dietary fat
limit beverage calories
eat less food
drink less alcohol
eat nutrient dense but low calorie fruits and vegetables
impact of exercise on weight control
decreases loss of fat-free mass associated with weight loss
improves maintenance of weight loss
physical activity alone results in minimal weight loss
more frequent short bouts more effective than fewer long bouts
orlistat
prevents fat digestion and absorption by binding to gastrointestinal lipases
sibutramine
blocks neuronal monoamine (serotonin, norepinepherine, dopamine) reuptake
side effects include headache, dry mouth, constipation, insomnia, dizziness, and more
acts on appetite centers on brain to reduce appetite
indications for bariatric surgery
BMI of 40 or higher for men, 35 or higher for women
previous failed weight loss attempts including dietary, behavioral, and exercise changes
appropriate motivation and psychological stability

restrict gastric contents:
gastroplasty
lap band

malabsorptive:
duodenal switch- accelerated gastric emptying and intrstinal transit time
usually the most weight loss- used for BMI > 55

combination:
roux-en Y gastric bypass (RYGB)- most common
hemostasis
the process of blood clot formation at the site of injury
the process must be quick, localized and regulated
hemostasis
phases of _____
1) initiation and formation of the platelet plug
2) propagation of the clotting process by coagulation cascade
3)termination of clotting by antithrombotic control mechanisms
4)removal of the clot by fibrinolysis
formation of platelet plug
1) activation
2)adhesion; deposition of platelets on subendothelial matrix
3) aggregation; platelet to platelet cohesion
4)secretion; the release of platelet granule proteins
5) procoagulant activity: the enhancement of thrombin generation
platelet collagen receptors
integrin glycoprotein receptors which are exposed and change conformation upon platelet activation
this leads to binding of both immobilized VWF and fibrinogen
protease-activated receptors (PARs)
G-protein receptors which mediate thrombin activation of cells
platelet secretion substances
ADP and serotonin: stimulate and recruit additional platelets
fibronectin and thrombospondin: release adhesive proteins that form stabilizing network
fibrinogen
thromboxane A2
platelet derived growth factor (PDGF)
protein disulfide isomerase (PDI)
platelet adhesion
following activation platelets change shape and produce elongated pseudpods
primarily mediated by binding of platelet surface receptor complex to VWF factor in subendothelial matrix
phosphatidylserine
a platelet procoagulant phospholipid
exposure begins assembly of enzyme complexes in the clotting cascade on the platelet surface
intrinsic pathway (contact activation pathway)
the pathway of the coagulation cascade initiated by the exposure of blood to a negatively charged surface
proteins involved:
factor XII (hageman factor), prekallikrein (fletcher factor), high molecular weight kininogen (HWMK, fitzgerald factor), factor XI, IX, and VIIIa
extrinsic pathway
pathway of coagulation cascade activated by tissue factor exposed at the site of injury.
TF forms complex with VII
proteins involved:
TF-VIIA, factor VIIA, Xa , IX , VIIIa (last two more important in other pathway)
common pathway
Va and Fa form prothrombin complex which converts prothrombin to thrombin
thrombin converts fibrinogen to fibrin
factor XIII stabilizes and crosslinks overlapping fibrin strands
bleeding disorder - platelet defect
site of bleeding: skin, mucous membranes
bleeding after minor cuts
petechiae present
small, superficical ecchymoses
immediate and mild bleeding after surgery
mechanism for modulation of coagulation
1)dilution of procoagulants in flowing blood
2)removal of the activated factors through the reticuloendothelial system, especially in the liver
3)control of the activated procoagulants and platelets by natural antithrombotic pathways. these pathways are all anchored on the vascular endothelial walls
Antithrombin (AT)
a coagulation modifier
circulating plasma protease inhibitor
neutralizes most of the enzymes in the coagulation cascade
composed of two functional sites, the reactive site, and the heparin binding site
activated protein C (APC)
a coagulation modifier
thrombim binds to thrombomodulin (TM) and activates this protein, which then associates with protein S to inactivate factors V and VIIIa → inactivates prothrombinase and intrinsic X-ase
protein S
a coagulation modifier
this protein circulates in two forms
the free form is an anticoagulant
the bound form is complexed to C4b binding protein of the complement system and is inactive
C4b binding protein
an acute phase reactant that increases in inflammatory states → reduced free protein S → increased likelihood of thrombosis
tissue factor pathway inhibitor (TFPI)
a coagulation modifier
inhibits factor X activation by
1) direct factor Xa inhibition
2) complexes with factor Xa which inhibits TF/FVIIa → impairs triggering mechanism of extrinsic pathway
prostacyclin (PGI2)
arachadonic acid catalyzed by COX-2 will be converted to this protein
blocks platelet aggregation and antagonizes TxA2-mediated vasoconstriction
thromboxane A2 (TxA2)
arachadonic acid catalyzed by COX-1 will be converted to this protein
potent stimulator of platelet aggregation and vasoconstrictor
Nitric Oxide
formed from L-arginine in endothelial cells
a vasodilator which inhibits platelet adhesion and activation
rapidly destroyed by Hb and therefore functions as a local hormone
plasmin
cleaves fibrin, fibrinogen, and many other plasma proteins including clotting factors
D-dimers
the products of cleavage of cross linked fibrin.
diagnostic for major clot
plasminogen
plasmin precursor
activate by binding to fibrin and tPA
tissue type plasminogen activator (tPA)
serine protease plasminogen activator responsible for intravascular fibrinolysis
urokinase
serine protease plasminogen activator responsible for extravascular fibrinolysis
PAI-1
a plasminogen activator inhibitor synthesized by endothelial cells and platelets
deficiency can lead to bleeding tendency
PAI-2
a plasminogen activator inhibitor synthesized by white blood cells and the placenta
levels rise greatly during pregnancy
biological significance uncertain
alpha-2-antiplasmin
a fibrinolysis inhibitor
crosslinked into fibrin clot by factor XIIIa and inactivates circulating plasmin
thrombin activatable fibrinolysis inhibitor (TAFI)
a fibrinolysis inhibitor
circulates in plasma
activated by thrombin-thrombomodulin complex
vitamin K dependent hemostatic proteins
factors II, VII, IX, and C
proteins C and S all need this.
necessary for post-ribosomal carboxylation of the terminal glutamic acid residues of all these proteins.
factor VII, protein C and S all have shorter half lives
disorders of platelets or blood vessels
manifests as muco-cutaneous bleeding
-nosebleeds or gum bleeding
peticiae (tiny spots) or ecchymoses (group of peticiae)
blood bullae (purple blood bubble) on oral mucosa
-menorrhagia (heavy period)

no delay of bleeding
platelet count and peripheral smear
measures number and size of platelets (MPV)
if MPV is higher than normal it could mean:
1) the platelets are young and sticky
2) the marrow is sick
prothrombin time (PT)
measures the factors of the extrinsic and common pathway
activated partial thromboplastin time (aPTT)
measures the factors of the intrinsic and common pathways
thrombin clotting time (TCT)
measures the conversion of fibrinogen to fibrin
whole blood platelet functioning
a substitute test for bleeding time with more specificity and sensitivity
bleeding disorder - clotting factor deficiency
site of bleeding: deep in soft tissue (joints, muscles)
no bleeding after minor cuts
large, palpable ecchymoses
hemarthroses and muscle hematomas common
delayed, severe bleeding after surgery
obesity comorbidities
type II diabetes
CVD
hypertension
arthritis, gout
sleep apnea
systemic inflammatory responses
cancer
PPARγ
the master adipogenic transcription factor
a nuclear hormone receptor
involved in lipid storage
causes preadipocyte differentiation into adipocytes which reduces FFAs in circulation- stimulation is treatment for diabetes
PPRE (peroxisomal proliferator response element)
a gene regulatory region which binds PPARγ
leptin
an adipokine that acts as key long term regulator in negative feedback loop regulating body weight
obesity→ ↑ expression→ ↓ food intake and ↑ energy expenditure
adiponectin
a protective adipokine secreted signal
antiinflammatory
obesity→ ↓ expression
TNFα
A proinflammatory adipokine
Obesity → ↑ expressiom
Induces adipocyte apoptosis
Induces TAG lipolysis and release of FFA from WAT
Leads to development of insulin resistance
hypoxia
leads to "bad" WAT expansion
-no angiogenesis
-high fibrosis
-adipocyte cell death
-macrophage infiltration
adipocyte expandibility hypothesis
due to disregulation, obese people WAT is different than lean people WAT
lipids overflow to non adipose tissue where they are lipotoxic.
these tissues are called "ectopic tissues"
MCP1 (macrophage chemo-attractant protein)
a secreted factor from obese WAT.
causes macrophage infiltration and subsequent damage (TNFα release)
this promotes a pernicious cycle called "polarity switching"
effects of obesity on WAT
hypertrophy
eventual hyperplasia
macrophage recruitment
macrophage polarity switch
↑ cytokine production
↑lipolysis, FFA release
ER stress, further degredation
effects of obesity on liver
steatosis- (fatty liver)
kupffer cell activation
↑ cytokine production
ER stress
effects of obesity on skeletal muscle
↑ FFA uptake
↑adipocytes
macrophage activation and recruitment
inflammatory responses
insulin resistance
BAT
unlike WAT, its major function is fatty acid oxidation and thermogenesis ( UCP1 uncouples proton gradient from ATP synthesis)
mitochondria rich
inducing WAT to turn into this may combat obesity (Brite adipocyte)
type I diabetes
destruction of beta cells of pancreas by autoimmune reaction
primary tratment is insulin injection
type 2 diabetes
decreased response to insulin in peripheral tissue
initital hyperinsulinemia, eventually leading to β-cell dysfunction and insulin deficiency
often preceded by metabolic syndryome
associated with visceral obesity
diagnostic criteria for diabetes
fasting blood glucose (FBG) >= 126 mg/dL
2-hour plasma glucose >= 200 mg/dL during glucose tolerance test (75 g oral glucose)
diabetes + random blood glucose >= 200 mg/dL
FBG 100-125 is prediabetes
polyuria
protein glycation (hemoglobin A1C) (>6.5%)
thirst
glycosuria
small LDL size predominates
diagnostic criteria for metabolic syndrome
abdominal obesity: men >40 in waist; women > 35 in
triglycerides: >= 150 mg/dL
HDL cholesterol: men <40; women <50
BP: >130/85
fasting glucose > 110

3 or more factors is diagnostic
thiamine (vitamin B1)
ATP production
synthesis of RNA and DNA
part of coenzyme TPP- oxidative decarboxylation reactions
-pyruvate dehydrogenase
-α-ketoglutarate dehydrogenase
- branched chain keto-acid dehydrogenase
sources of thiamine
lean meat (pork)
whole grains
legumes
thiamine deficiency
beriberi
-wet: with edema
-dry: muscle wasting
-weakness, paralysis, wasting away
wernicke's encephalopathy and korsakoff's psychosis (from severe alcoholism)
riboflavin (vitamin B2)
flavin coenzymes
-energy metabolism
-redox reactions
-beta-oxidation
-converts vitamin A and folate to active forms, tryptopan to niacin
-formation of vitamins B6 and K
sources of riboflavin
milk, grains, green vegetables
destroyed by UV
riboflavin deficiency
ariboflavinosis- sore throat, cheilosis(lesion at corner of mouth), glossitis (inflammation of tongue)
niacin (nicotinic acid and nicotinamide)
precursors of NADH and NADPH
synthesis of fatty acids, cholesterol, steroid hormones, and DNA
↓ LDL, TG
↑ HDL
sources of niacin
protein rich foods, enriched grains, some vegetables
tryptophan
niacin deficiency
pellagra
4 Ds: dermatitis, dementia, diarrhea, death
also found in hartnup's due to genetic defect in tryptophan euptake
niacin toxicity
skin inflammation and flushing
heart burn
nausea
↑ plasma glucose
liver damage
pantothenic acid
use of glucose, AAs, and fatty acids for ATP production
synthesize:
heme
cholesterol
bile salts
phospholipids
fatty acids
steroid hormones
pantothenic acid, B6, biotin deficiencies
deficiency is rare since these are in most foods
vitamin B6
coenzyme of pyridoxal phosphate (PLP) and pyridoxamin phosphate(PMP)
-amino acid metabolism- transamination and decarboxylation
- FA metabolism
- needed for typtophan to niacin and serotonin
vitamin B6 toxicity
at >2g/day can cause neurological problems- difficulty in walking and numbness of hands and feet
biotin
cofactor for the transfer of CO2 in carboxylation reactions
active form is covalently bound to lysine residues of enzyme
folate
coenzyme involved in transfer of single carbon groups to form organic substances
homocysteine →methionine
part of THF and DHF (used in DNA synthesis)
sources of folate
beans and legumes
fresh fruits and veggies
cereal
folate deficiency
macrocytic anemia- RBCs remain immature
most likely in:
alcoholics
elderly
genetic variations
medication interactins

neural tube defects
vitamin B12
activates folate
production of succinyl CoA
protects nerve cells
B12 deficiency
pernicious anemias:
macrocytic anemia
fatigue
numbness
difficulty sleeping
memory loss
methylmalonicaciduria
vitamin C
collagen synthesis- prevents scurvy
antioxidant
accepts and donates electrons
enhances iron absorption
hydroxylation of carnitine
synthesis of thyroid formone and CCK
neurotransmitters serotonin and norepinepherine
vitamin C sources
citrus fruits
cabbage type vegetables
dark green veggues
strawberrieres
tomatoes
potatoes
vitamin C toxicity
nausea
cramps
diarrhea
kidney stones
adversely affect those with iron overload
vitamin A (retinol)
act as retinal pigments
donors of mannose in glycogen synthesis
bind to nuclear receptors RAR and RXR to regulate genes for epithelial cell development
antioxidants- may decrease breast tumors, lower prostate cancer, decrease macular degeneration
vitamin A deficiency
night blindness
keratinization of skin and mucous membranes
vitamin A toxicity
increases osteroporosis and fractures
birth defects
accutane causes loss of pregnancy
vitamin D
regulates calcium homeostasis by:
-increasing intestinal absorption
reducing excretion by the kidney
-mobilizing bone mineral
regulates cell proliferation
may play a role in preventing tumor development
vitamin D deficiencies
rickets
osteomalacia
vitamin D sources
fortified milk
fat fish
cereals
eggs
sunlight
vitamin D toxicity
dehydration
vomiting
decreased appetite
irritability
constipation
fatigue/lethargy
not from sun, only supplements
vitamin E
antioxidant, particularly in preventing peroxidation of polyunsaturated fatty acids (PUFAs) in membranes
vitamin E sources
polyunsaturated plant oils
leafy green vegetables
whole grains
egg yolks
nuts
seeds
vitamin K
cofactor for carboxylation of glutamate which enhances Ca++ binding
carbocylation of prothrombin and other proteins required for clotting reaction
carboxylation of proteins for bone and tooth
sources: green leafy veggies

deficiencies caused by warfarin and long term antibiotic use
heme functions
transport and retention of O2
electron transport- cytochromes in mt
O2 activation -cytochome c oxidase, P450 oxidases
activation of H2O2- peroxidases
decomposition of H2O2 - catalase
heme nomenclature
pyrrole rings: 1-1V
methyne bridges: α-δ
ring subsitutents : 1-8
ALA synthase 2
first and rate controlling step of porphyrin biosynthesis
mitochondrial
requires B6
expression regulated by factors that regulate erythropoiesis and by iron
expression not regulated by heme
regulated by IRE binding protein- high iron blocks active site and prevents IREBP from blocking transcription →↑ this enzyme →↑heme
δ-aminolevulinate (ALA)
product of first and rate controlling step on porphyrin biosynthesis
mitochondrial
requires B6
ALA dehydratase
condensation reaction- produces porobilinogen- first pyrrole precursor in porphyrin biosynthetic pathway
cytosilic
contains zinc; inhibited by lead
porphobilinogen deaminase
cytosolic
uroporphyrinogen III synthase
dominates over spontaneous reaction
asymetric side chains in uroporphyrinogen III
cytosolic
uroporphyrinogen decarboxylase
cytosolic
replaces acetyl groups with methyl groups
defect in this enzyme causes porphyria cutanea tarda
final reactions of porphyrin biosynthetic pathway
these reactions occur in mitochondria
coproporphyrinogen III →protoporphyrinogen III→ protoporphyrin III→heme
ferrochelatase
final step of heme synthesis
ferrous iron inserted
2Fe-2S center
activity elevated in erythroid cells
mitochondrial
hereditary porphyrias
defects in heme synthesis
substrate of affected enzyme accumulates
levels of heme decrease
may be hepatic, erythroid, or both
symptoms of herditary porphyrias
photosensitivity (blistering)
anemia
red urine due to porphyrins
acute intermittent porphyria (AIP)
lead poisoning
an acquired poryphria:
inactivates ALA dehydratase (displaces Zn++)
ALA appears in urine
inhibits protoporphyrinogen oxisase (binds SH groups)
free protoporphyrinogen IX and Zn-protoporphyrin IX (Zn++ replaces Fe++) accumulate
inhibits ferrochelatase
interferes with iron transport into mt
acquired porphyrias
lead poisoning
alchohol
presticides
tumors
iron overload
porphyria cutanea tarda
decreased activity of uroporphyrinogen decarboxylase
hepatic ALAS1
housekeeping isoform of ALAS
inhibited by heme at multiple levels:
enzyme activity
transcription
translation
mt import

short half life insures rapid response to changes in translation and transcription

expression stimulated by heme inducing drugs (ie phenobarbital)
repressed by dietary glucose
UDP-glucose pyrophosphorylase
protein phosphatase I
deactivates phosphorylase a → glycogenolysis inhibition
AMP blocks this enzyme, since in low energy conditions you want to increase glucose levels
insulin resistance
two leading theories of how visceral fat contributes to this:
1.inflammatory cytokines from adipocytes and macrophages in visceral adipose stores inhibit insulin signaling
2. diacylglycerol released from excess intracellular fat in muscle and liver directly inhibits insulin signaling
diet therapy for diabetes
lose weight
change carbohydrate-fat caloric distribution
maintain optimal blood lipid levels
saturated fat <7% of calories
sulfonylurea agents and meglitinides
insulin secretagogues
inhibits ATP-dependent K+ channel
increases insulin secretion from pancreatic beta cells
biguanides (ie metformin)
increases insulin sensitivity of target tissue
decreases hepatic gluconeogenesis
only anti-diabetic that reduces cardiovascular complications
activates AMP-activated protein kinase to up-regulate insulin targets
tZDs (thiazolidendiones)
increases peripheral insulin sensitivity
binds to nuclear transcription factor PPAR-gamma
increases lipid storage in adipocytes
↑ adiponectin
↓ resistan
causes leptin sensitization in the brain
→ ↑glucose uptake by muscle and ↓ gluconeogenesis in liver
major effects of insulin
adipose tissue:
↑ lipogenesis
↑ glucose uptake
properties of senescent erythrocyts
↓ [glycolytic enzymes]
Membrane damage- oxidation
↑ Hb concentration
↓ pliability
↑ phosphatidyl serine in outer membrane leaflet
↑ cross linking of Hb to band 3 and spectrin → aggregation
↓ size and ↑ density
more spherical, less likely to clear splenic capillary bed
heinz bodies (denatured Hb)
siderocytes (iron aggregates)
recognition of senescent erythrocytes
senescent epitopes recognized by autologous antibodies:
band 3- oligomerization or cleavage
glycophorin - desialated glycophorin
clearance of senescent erythrocytes
macrophages in spleen, liver, and bone marrow accomplish this process (reticuloendothelial system)

a splenectomy will increase # of famaged RBCs in circulation
classical pathway
in this pathway:
1. auto antibodies bind to surface of senescent cells
2. macrophages recognize Ab-taged cells and phagocytose them
alternate pathway
in this pathway:
1. phosphatidy serine increases in outer leaflet of senescent cell membrane
2. macrophage receptor recognizes phosphatidyl serine on surface of senescent cells and phagocytizes them
haptoglobin (Hp)
acute phase protein elevated in inflammatory states
glycoprotein made in liver
prevents filtration of free Hb by kidney
prevents loss of iron and oxidative damage to kidney by Fe
complexes with Hb; taken up by liver and recycled into AAs and iron
albumin
major plasma protein
binds nonpolar ligands (fatty acids, bilirubin, drugs, etc)
binds heme and hemin (oxidized heme)
transfers hemen to liver or hemopexin
hemopexin (Hx)
glycoprotein made in liver
binds heme and hemen
prevents heme-coupled peroxidation and consequent oxidation damage to tissues, esp. kidney
complexes with hemin; complex taken up by liver and metabolized to bilirubin; iron reutilized
bilirubin
nonpolar, sparingly soluble in water
toxic to many biochemical and neurologic functions
scavenges
peroxyl radicals; potent antioxidant
prevents deleterious effects of iron in hemolytic crisis
transported to liver by plasma albumin
binds to ligandin and protein Y in hepaticytes
conjugated to glucuronic acid in liver
heme oxygenase
membrane bound in ER
complex with NADPH cytochrome P450 reductase
produces 85% of CO in body
HO1 isozyme induced by hemin, insulin, epinepherine, endotoxin, heavy metals, UV light and other agents
carbon monoxide
product of heme oxygenase reaction
transported to lung complexed with Hb heme
indirect measure of heme turnover
activaes guanylate cyclase
acts as a neurotransmitter
inhibits proinflammatory processes and endothelial cell apoptosis
biliverdin reductase
catalyzes conversion of biliverdin IX to bilirubin
cytoplasmic
forms reversible complex with HO and NADPH ctochrome p450 reductase
bilirubin diglucuronide
formed by conjugation of UDP-gluronic acid and bilirubin monoglucuronide
water soluble
secretion of bilirubin glucuronides (BGs) into bile
active transport process that is rate limiting for bilirubin excretion
involves multidrug resistance-like protein (MRP-2)
-these ABC transporters are in plasma membrane of bile canaliculi
β-glucuronidases
cleave BGs into colorless urobilinogens which are oxidized to urobilins in colon (dark color)
enzymes are bacterial in gut flora
some urobilinogens are reabosrbed from terminal ileum and colon; taken up by liver and kidney; reexcreted into bile and excreted in urine
δ-bilirubin
a bilirubin glucuronide covalently linked to albuminin
present with elevated serum BGs
diagnostic for biliary obstruction and effectiveness of biliary drainage
jaundice
hypyerbilirubinemia (>1mg/dL)
skin and sclera take on yellowish tint (icterus)
causes:
1. increased production of bilirubin
2.decreased hepatic metabolism of bilirubin
↓ hepatic uptake
↓ conjugation
↓ transport of conjugates into bile
3. blockage of bile flow
bilirubin toxicity (kernicturus)
hearing defects
progressive lethargy
muscular rigidity
convulsions
death
mental retardation
impaired motor functions
neonatal physiologic jaundice
heme production elevated due to degredation of fetal Hb
low bilirubin conjugation (low UDP glucoronosyl transferase activity)
reabsorption of unconjugated bilirubin from gut

treatment:
phototherapy
exchange transfusions
phenobarbital to induce UDP-glucuronosyl transferase
heme oxygenase inhibitors
prehapatic hemolytic jaundice
increased destruction of red cells with release of Hb
increased unconjugated bilirubin
increased urobilinogen in urine
liver enzymes normal
caused by:
hematoma
hemolytic anemia
hepatic jaundice
damage to liver- may cause BG release
increased unconjugated bilirubin
seen in:
-hepatitis
-cirrhosis
liver enzymes elevated in serum
obstructive jaundice
blockage in delivery of bilirubin to gut
increase in total bilirubin
urinary bilirubin glucuronide elevated
fecal urobilinogen reduced or absent
extrahepatic causes:
-gallstones
- carcinoma of pancreas or bile duct
intrahepatic cause
-inflammation/scarring
-micro-obstruction of intrahepatic ductules
gilbert's syndrome
inherited disorder
reduced UDP-glucuronosyl transferase due to mutations in promoter region of gene
exacerbated by acute hemolytic attacks
elevated unconjugated bilirubin
short term fasting
accelerated catabolism of proteins which have a high turnover rate
-visceral tissue protein (liver, intestine, pancreas, etc)
- blood proteins
- immune proteins
75 g from muscle
160 g TG
16g of glycerol → Liver for for gluconeogenesis
40g → Liver for ketone body synthesis
120g → Peripheral Tissues
extended starvation
Significant decrease in muscle protein utilization for gluconeogenesis
75g in short-term →20g in long-term; ↓ glucose synthesized
no change in amount of fatty acid metabolism, but instead of ketone bodies being used by the periphery (as is true in short-term), nerves increase ketone body utilization
overarching principles of muscle sparing during long-term fasting
Decrease in BMR
Increased Ketone utilization by neural cells
56% decrease in glucose production per day
Decrease in urinary nitrogen
nitrogen/protein balance
nitrogen intake - nitrogen loss
90% of loss occurs through urine
Positive Nitrogen balance: Growth, Pregnancy, LBM repletion
Neutral: Typical healthy adult (maintenance)
Negative: Starvation, Cancer, Trauma/Surgery
severe trauma or other catabolic stress
Trauma/Surgery/Burn/Infection can all induce hypermetabolism
Duration is usually 3-10 days
Magnitude is related to extent/severity of insult
Systemic response (not limited to injury site)
Acute hormonal response: ↑ Cortisol, ↑ Glucagon. ↓ Insulin sensitivity

Alterations of Energy Metabolism in Acute PEM, leading to hypermetabolism
Accelerated gluconeogenesis
Increased glucose requirement of injured tissues
Decreased glucose utilization by other tissues
Large negative nitrogen balance
Accelerated catabolism of proteins of high turnover (albumin, immune proteins)
Muscle wasting not evident
starvation vs trauma
Chronic-Starvation-Induced PEM
Gradual onset
Indicated by significant, involuntary weight loss
Muscle wasting (after months of weight loss)
Decrease in blood proteins not common until after significant depletion of fat and muscle
DECREASE in BMR

Acute, Trauma-Induced PEM
INCREASE in BMR
Accelerated gluconeogenesis
PEM recovery
Provide protein to replace nitrogen loss: 1.2-2.0 gm/kg body weight
Provide energy in the form of carbs and lipids: 20 - 30 gm/kg body weight
Overfeeding inhibits recovery from PEM
routes of nutrient hyperalimenation
Oral Feeding
Preferred when possible
Can supplement with nutritionally-complete liquid supplements
Enteral Tube Feeding
Either temporary (nasogastric) or long-term (gastrostomy)
Nutrient influx into the blood is regulated by the enterohepatic system
Cheap
Parental feeding:
Infuse nutrients directly into blood via IV (short-term) or central line (long-term)
Lack of the "first pass" effect through liver necessitates close monitoring
Expensive
phosphorylase kinase
phosphorylates phosphorylase
↑ gluconeogenesis
von Willebrand Factor (vWF)
acts as a bridge between platelets
activated by GP1b resulting from platelet activation
deficiency causes bleeding tendency; most common hereditary coagulation disease
differences in PPARs
thrombin
converts fibrinogen to fibrin
accelerates activation of factors XI, VIII, and V
factor XIIIa is formed by complexing of thrombin, fibrin, and factor XIII
globoside
a complex glycosphingolipid WITHOUT sialic acid
CCK
a factor released from intestine that inhibits appetite
ghrelin
released from intestine
stimulates appetite
atherogenic triad
↑TG
↓HDL
small LDL particles
the perfect storm of atherosclerosis
tyrosine, phenyalanine, tryptophan
AAs that can go to both ketogenic and glucogenic pathways
GnT-4a (glycosyltransferase)
necessary for glucose transporters
expressed in pancreas and allows cells to sense glucose level
lower in pts with type II diabetes
ceruloplasmin
Copper ferroxidase synthesized in liver and brain
Oxidizes Fe2+ to Fe3+
Transferrin binds Fe3+ but not Fe2+
Facilitates iron release from cells
iron regulation
1. levels of transferrin receptors
2. ferritin levels
both regulated by IRE-BP
singulair
blocks leukotriene receptors
alleviates asthma
accolate
blocks lipooxygenase
alleviates asthma by ↓leukotriene
impact of weight loss on risk factors
garrow study
found that some subjects had
difficulty gaining weight during overfeeding and
that they easily lost the gained weight
bouchard study
studies of identical twins
reported that overfeeding resulted in 6 times
more variance between pairs than within the pair
marasmus
chronic starvation induced PEM
PEM
22 % of hospital pts have this
biggest risk factors for this type of malnutrition are:
being dumb
being old
being lonely
being sick
a severe protein deficiency
liebal study
study that shows :
↑ body weight →↑ BMR
↓bodyweight →↓BMR
steroid hormones precursor-product relationships
cpnversion of cholesterol to pregnalone initiates synthesis of steroid hormones
hydroxylation carried out by monooxygenases with activation by p450 cytochromes
components of daily energy expenditure
in physically active people:
↓resting energy expenditure %
thermic effect of feeding stays at 8%
drugs that cause weight gain
psychotrpics
steroids
diabetes medications
retroviral therapy
tamoxifen
β-adrenergic receptor blockers
anemia of chronic disease (ACD)
seen in pts. with chronic illnesses
↑hepcidin →↓ferroportin →↑ferritin and ↓Hb, heme, RBCs
test
test
tay-sachs disease
sphingolipidosis characterized by early neurologic deterioration, blindness, deafness, paralysis, and death by age 3. Due to defect in hexosaminidase A
multiple carboxylase deficiency
results from biotin deficiency or defect in biotin holocarboxylase synthetase. Symptoms are seborrheic dermatitis, anorexia, nausea, muscular pain
biotin deficiency
rare deficiency unless accompanied by other factors intestinal bacteria killing antibiotics or ingestion of large amounts of avidin(raw egg whites)
aceruloplasminemia
accumulation of iron due to lack of ceruloplasmin(copper ferroxidase)
crigler-najjar syndrome
reduced or absent UDP glucuronosyl transferase due to a defect in the coding region of the gene
gilbert's syndrome
reduced UDP glucuronosyl transferase due to a defect in the promotor region of the gene
hemolytic jaundice
increase in unconjugated bilirubin, seen in conditions with increased destruction of red cells
hepatocellular jaundice
result of liver damage, results in elevated unconjugated and conjugated bilirubin
post hepatic jaundice
elevated total bilirubin as a result of interference with bilirubin glucuronide delivery to the intestine
neonatal jaundice
due to low UDP-glucuronosyl transferase activity, blood group incompatability, or g6p dehydrogenase deficiency, treatment includes phototherapy
gaucher's disease
accumulation of glucocerebroside (b-glucosidase deficiency) leads to easy bruising, fatigue due to anemia, liver and spleen enlargement, skeleton weakness
niemann-pick disease type a
sphingomyelinase deficiency reulting in enlarged spleen/liver, mental retardation, anemia, neuro/physical deterioration, death before 3
21-hydroxylase deficiency
causes increased ACTH secretion, accumulation of pregenenolone, progesterone, androgens, results in virilization, treated with hormone replacement
rickets
inadequate calcification of bones, cartilage due to lack of vitamin D
osteomalacia
weakening of bones due to vitamin D deficiency
von gierke's disease
glucose 6-phosphatase activity defective
andersen's disease
defect in branching enzyme
mcardle's disease
muscle glycogen phosphorylase defective causing accumulation of glycogen
ammonia toxicity
caused by urea cycle disorders or liver failure, leads to high arterial ammonia, ATP depletion, brain swelling
hyperammonenia type 1
caused by carbamoyl phosphate synthetase deficiency or N-acetylglutamate synthase deficiency
hyperammonenia type 2
x-linked disorder caused by ornithine transcarbamylase deficiency
argininosuccinate synthetase deficiency
recessive deficiency that causes increase in citrulline and ammonia, treated with arginine
argininosuccinase deficiency
deficiency linked to increased argininosuccinate and ammonia levels, usually fatal in first two years, treated with arginine
maple syrup disease
a-ketoacid dehydrogenase complex deficiency causing accumulation of keto acids, mental retardation
alkaptonuria
homogentisate defect, leads to accumulation of homogentisic acid in urine(turns black)
cystinosis
defect in cystein transport leading to cysteine crystal deposition, can cause renal failure
cystinuria
defect in resorption causes excretion of cys, lys, arg, orn-cystine forms calculi in kidney tubules
homocystinuria
cysathionine b-synthase deficiency causing increase in serum homocysteine, causes osteoporosis, mental retardation, increased risk for thrombotic events
phenylketonuria
defective phenylalanine hydroxylase gene, results in mental retardation if individual isn't placed on phe restricted, tyr supplemented diet
atherosclerosis
plaque formation leads to hardening of the arteries
coronary heart disease
result of arterial occlusion due to atherosclerosis
homocysteinemia
elevated homocysteine levels associated with low blood folate leading to increased risk for CHD
methemoglobin anemia
caused by defects in methemoglobin reductase I or II, diaphorase I, or hemoglobin Ms
glucose 6-phosphate dehydrogenase deficiency
x-linked disorder, distribution associated with malaria, leads to increased sensitivity to oxidative stress
hexokinase deficiency
causes decreased 2,3 DPG concentration leading to a left shift in binding curve
pyruvate kinase deficiency
reduced phosphenol pyruvate to pyruvate causing increase in 2,3 DPG and a right shift in binding curve
hereditary spherocytosis
defects in spectrin or ankyrin interfere with band 3 interaction, results in round rigid cells subject to destruction
hereditary elliptocytosis
spectrin defects that affect horizontal interactions, elliptical shaped cells
genetic hemochromatosis
excessive iron absorption due to faulty regulation of iron transport, leads to diabetes, liver cirrhosis, cardiomyopathy, treated by phlebotomy
lead poisoning
inhibits ferrochelatase and protoporphyrinogen oxidase, inactivates ALA dehydratase, interferes with iron transport
genetic porphyria
involves defects in steps in heme biosynthesis, product from previous step accumulates
cytonuclear dyssynchrony
folate deficiency causes red cell development to stall, characterized by immature nuclei with well-hemoglobinized cytoplasm
hemoglobinopathies
examples include sickle cell disease, Hb C disease, thalassemia
enzymopathies
examples include g6pd deficiency, pyruvate kinase deficiency
membranopathies
examples include hereditary spherocytosis
obesity
caused by interaction of genetic and environmental(food and physical activity) factors
koilonychia
spoon nails caused by anemia
iron deficiency anemia
caused by malnutrition(rare) or bleeding, symptoms include pica, fatigue, koilonychia, blue sclerae
microcytosis
caused by iron deficiency, thalassemias, anemia of chronic disease
sideroblastic anemia
characterized by increased mitochondrial Fe, ineffective erythropoiesis, low retic count, examples are ALAS-2 mut, plumbism, and myelodysplastic syndrome
acute intermittent porphyria
inherited disease caused by PBG deaminase deficiency, porphobilinogen present in urine
porphyria cutanea tarda
acquired disease caused by URO decarboxylase, urophorphyrinogen III present in urine, "monkey hair" is a symptom
type 1 diabetes
destruction of pancreatic beta cells by autoimmune reaction-no insulin
type 2 diabetes
decreased response to insulin by peripheral tissues, associated with visceral obesity
metabolic syndrome
at least 3 of the following: abdominal obesity, high TGs, low HDL-C, high blood pressure, high fasting glucose
marasmus
chronic starvation-induced PEM, caused by long term inadequate food intake, decrease in blood proteins
acute catabolic insult-induced PEM
caused by physical injury or severe infection, lasting 3 to 10 days, systematic and acute hormonal response
beriberi
vitamin B1 deficiency, symptoms: weakness, paralysis, wasting away
ariboflavinosis
riboflavin deficiency, symptoms: sore throat, cheilosis, glossitis
pellagra
niacin deficiency, symptoms: dermatitis, dementia, diarrhea, death
vitamin A deficiency
deficiency common in developing countries, symptoms are blindness, keratinization of skin and mucous membranes
pernicious anemia
deficiency in intrinsic factor prevents uptake of B12
Diabetes
Defective insulin signaling, affecting the function of glucose transporters
Hereditary spherocytosis
RBCs have weakened membrane protein interactions, causing a loss of biconcave shape and clogging in sinusoids of spleen
Type II Diabetes
Insulin resistance due to malfunction in GLUT4 insulin receptor
Epilepsy
hyperexcitability defect in the nerves
Cystic Fibrosis
Transport defect in the epithelial cells preventing ion transport leading to systemic complications such as lung infections
Myasthenia gravis
autoimmune disease in which antibodies are formed against the acetylcholine receptors. Causes skeletal muscle weakness
Cardiotonic steriods
drugs that inhibit the fuction of Na+/K+ ATPase to treat heart disease
Oubain
a cardiotonic steroid which inhibits dephosphorylation of E2-P form, preventing conformational change. This increases levels of Ca2_ in cells to increase the contraction strength of the heart
MDR1
Multiple Drug Resistance 1 Pump uses ATP to export small planar drugs out of the cells, preventing the drugs from acting on the cell. Often amplified in tumor cells.
Cytochalasins A,B,C,D,E
Molecules that binds to the end of actin filaments to stop further polymerization. Produced by various fungi
Phallodin
Found in "Death Cap" mushrooms. Binds to actin to prevent depolymerization. (also used to stain actin in histology)
Colchicine, Colcemid
Inhibitor of tubulin addition, leading to depolymerization of microtubules
Taxol
Anti-cancer drug that prevents depolymerization of microtubules.
HIV
virus that binds to CD4 to initiate infection. Destroys T Helper Cells (leading to AIDS)
Spongiform encephalopathies
Disease caused by prion aggregates that cause nervous degradation. known as Creutzfeld-Jacobs Disease, Mad Cow, Scrapie
Hypercellular obesity
Excess of adipocytes, more dangerous form of obesity. Caused by infantile overfeeding.
Hypertrophic obesity
Excess accumulation of fat in unilocular adipocytes. Cause Type II diabetes
Anaphylactic shock
excessive release of histamine by mast cells that leads to vasodilation of smooth muscles in bronchioles
Scurvy
Vitamin C deficiency. Proline is not hydroxylated in tropocollagen and can not H-bond with other alpha fibers.
Ehler Danlos Type VII
1 amino acid change in procollagen peptidase preventing self aggregation that causes hyperflexible joints, dislocations, and soft skin
Ehler-Danlos Type IV
Deficiency in collagen type III that causes aneurysms and intestinal ruptures
Emphysema
lung dysfunction caused by breakdown of elastic fibers
Marfan's Syndrome
poor microfibril formation in elastic fibers leading to rupture of blood vessels
Edema
Accumulation of excess interstitial fluids caused by prolonged inflammatory response. Causes include poor circulation, poor lymph uptake, liver disease, or starvation
Hb-S
"Sickle cell disease" genetic disease that causes the polymerization of hemoglobin into fibers, conforming the cell into a sickle shape. Causes anemia and damage in filtering organs.
Hb-C
Alternate form of Hemoglobin that con contribute to mild anemia when combined with a Hb-S gene
thalassemia
deletion of portion of gene for alpha or beta-subunit of hemoglobin
Dry Beriberi
diet chronically contains less thiamine then required, resulting in fatigue and peripheral neuropathy
Wet Beriberi
severe deficiency of thiamine. Produces edema, anorexia, heart and neural complications
Wernicke-Korsakoff syndrome
chronic thiamine deficiency often found in alcoholics that results in weakness, paralysis, and impaired mental functions
Pellegra
Niacin deficency that causes dermatitis, diarrhea and dementia
Retinoblastoma
malignant tumor of retina in infants caused by lack of Rb
Melinoma
Tumor caused defect in p13 gene (which prevents cell division when excessive cellular damage occurs)
Li-Fraumeni syndrome
Rare inherited cancer that occurs in various tissues at a young age due to mutation in p53 gene
Alkaloids
Drugs that prevent chromosome spindle formation, used to treats cancers
Anti-tumor antibiotics
Anti-Cancer drug that binds to DNA and blocks S phase
CDK inhibitors
drugs that prevent cell cycle progression by inhibiting CDKs
Leukocyte Adhesion Deficiency
improperly produced integrin and leukocytes cannot effectively migrate out of blood vessel. Leads to life threatening infections
Glanzman's Disease
clotting failure caused by lack of Beta-3 integrin
Ischemia
oxygen deficiency
Infarct
death or damage to tissue due to ischemia
Rotenone
insecticide that blocks FP1 to CoQ electron transport
Sodium Anytal
barbituate that blocks FP1 to CoQ electron transport
Antimycin
blocks e- flow between cytochrome b and cytochrome c1
Cyanide
blocks e- flow from cyt (a + a3) to oxygen in electron transport
Dinitrophenol
Uncoupler of oxidative phosphorylation that reduces ATP production by destroying the protein gradient.
Oligomycin
Inhibits ATP synthase
Atractyloside
inhibitor of ADP/ATP exchange
Osteoarthritis
Non-inflammatory arthritis that is characterized by fibrillation of articular cartilage, proliferation of cartilage a the periphery, and replacement of cartilage spur with bone tissue
Rhematoid Arthritis
Inflammatory autoimmune disease where the synovial membrane becomes inflammated
Gigantism
Caused by an excess of growth hormone in growing child
Pituitary Dwarfism
Caused by a deficiency of growth hormone in growing child
Acromegaly
Caused by an excess of growth hormone in adults
Vitamin A deficiency
Failure of cranial cavity and spinal column to enlarge fast enough to accommodate growing brain and spinal cord
Vitamin A excess
Causes rapid erosion of cartilage resulting in premature closure of epiphyseal plate
Rickets
Caused by a deficiency of Vitamin D in children
Osteomalacia
Caused by a deficiency of Ca2+ in adults; causes weak bones that break easily
Scurvy
Caused by a deficiency of Vitamin C in adults; causes weak bones and poor growth and repair of fractures
Osteoporosis
Severe bone loss of bone mass with aging
Achondroplasia
Genetic disease of epiphyseal plate that causes dwarfism
Lactic Acidosis
A high level of blood lactate; can be caused by hypoxia
Muscular Dystrophy
Caused by an X-linked recessive mutation in the gene coding for dystrophin; Results in chronic, progressive muscle loss
Myasthenia Gravis
Caused by production of antibodies that block acetylcholine receptors; results in muscles that are weak and fatigue easily
MCAD
Deficiency of medium-chain acyl-CoA dehydrogenase; Symptoms include vomiting, lethargy, coma, hypoglycemia
Zellweger Syndrome
Caused by mutations in the PXR1 receptor which is essential for the import of enzymes into peroxisomes; causes problems in prenatal development, enlarged liver, high levels of iron and copper in blood, muscle and vision abnormalities
Hereditary Fructose Intolerance
Caused by absence of phophofructoaldolase B; causes hepatic failure
Fructose Uria
Benign disorder caused by the lack of fructokinase
Galactosemia
Absence of galactose-1-phosphate uridyl transferase. Afflicted infants fail to thrive; milk consumption causes vomiting and diarrhea; can cause mental retardation
Multiple Sclerosis
Most common demyelinating disease
Essential Fatty Acid Deficiency
Extremely rare condition in USA; causes decreased growh, skin abnormalities, impaired immune system; caused by infants being fed EFA-deficient formula and long term total parenteral nutrition
Type I Diabetes
Condition in which insulin is not produced by pancreas
Type II Diabetes
Condition in which insulin is produced but effects of insulin on glucose transport/utilization are unknown
Carnitine Acyltransferase Deficiencies
Triggered by exercise, fasting. Muscle pain, stiffness, myoglobinuria (pink urine), possible enlarged liver. Treatment = high carbohydrate, low fat diet and medium-chain triglycerides
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