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MCB II Block III
Terms in this set (235)
The liquid portion of blood
The liquid left over after blood has clotted
Process whereby blood loss is minimized following vascular injury
Pathologic process in which blood clots form inside blood vessels
Breakdown of the blood clot
Name the events important in clotting
2) Platelet activation (forms a platelet plug)
3) Formation of the fibrin meshwork (forms hemostatic plug)
What are the three fundamental processes in platelet activation?
3) Secretion of granule contents (Alpha and dense granules)
What are some activators of platelets?
Negatively charged phospholipid exposed by activated platelets that provides an excellent surface for the assembly of the clotting cascade
Binds to specific receptors on the platelet surface
Cleaves a specific receptor on the platelet surface
Binds to GPIIb/GPIIIa (integrins) and forms a bridge between activated platelets
Severe bleeding tendency due to mutations in the GPIIb/GPIIIa genes
Anti-thrombotic agent that interferes with GPIIb/GPIIIa/fibrinogen mediated platelet aggregation
Upon activation what do platelet granules secrete?
ADP (platelet activator)
Von Willebrand factor (promotes platelet adhesion to collagen)
Fibrinogen (promotes platelet aggregation)
Potent platelet activator
Formed when Phospholipase A2 becomes active after platelet activation. Phospholipase A2 liberates arachidonic acid from membrane phospolipids. Arachidonic acid is then converted to Thromboxane A2 by intermediary prostoglandins
Von Willebrand Factor (vWF)
Complex multimeric adhesive glycoprotein
Synthesized in vascular endothelial cells and megakaryocytes
Has binding sites for GPIb, collagen, and Factor VIII
Essential for formation of the platelet plug and stabilizing Factor VIII in the circulation
Von Willebrand Disease (VWD)
Most common congenital bleeding disorder
Caused by a deficiency in VWF
Results in defective platelet adhesion
Type 1 VWD
Decreased normal [vWF]
Type 2A VWD
Abnormal intracellular transport and processing
Missense mutations affect processing
Type 2B VWD
Abnormal binding of GPIb; thrombocytopaenia
Gain of function
Type 2M VWD
Mutations in A1 domain
Type 3 VWD
Severe vWF deficiency (also Factor VII deficiency)
Heterozygotes are essentially normal
Affecteds are homozygous or compound heterozygous
List the series of activation steps in a typical coagulation reaction
1) Serine protease binds to its protein cofactor on a membrane surface
2) Serine protease cuts the peptide bond at the carboxy terminal side of particular arginine residues in the zymogen
3) Substrates are serine protease zymogens or procofactors; both ae activated by limited proteolysis
4) Products (active enzymes and protein cofactors) catalyze next step in the cascade
5) Cofactors accelerate clotting cascade ~10,000 fold
How is prothrombin (Factor II) converted to thrombin (Factor IIa)?
It is cleaved at two sites by Factor Xa (in the presence of Factor Va)
Tissue Factor (TF)
Cell-surface protein that triggers blood clotting when exposed to plasma
Abundant in adventitial cells of almost all blood vessels larger than capillaries
Always some circulating
Never catalytically active without tissue factor
What makes the connection between carboxylated Glu in the gla domain and the negatively charged surface?
How does thrombin limit its own formation?
When thrombin bind to thrombomodulin on the endothelial cell's surface it activates Protein C
When activated protein C (APC) in complex with protein S, binds to the platelet membrane, the activated complex begins destroying Factors Va and VIIIa
Factor V Leiden
Common in European populations
Point mutation in the Factor V gene that cause the replacement of an Arg with a Gln in the preferred site of cleavage by APC
Heterozygous individuals have 6-8 fold increased risk of deep-vein thrombosis
Homozygous individuals have a 30-140 fold increased risk
What are the serine proteases involved in the activation of prothrombin? Receptors? Cofactors?
What are the serine proteases involved in the inhibition of thrombin? Receptors? Cofactors?
Types A & B
Spontaneous bleeding in joints and muscle
Prolonged bleeding following trauma or surgery
Treatment: infuse missing clotting factor
~1 in 4,000 male births
More common due to recurrent inversion
~1 in 20,000 male births
Milder cases tend to have missense mutations
What is fibrinogen composed of?
An Aα, Bβ, and γ chains organized into a dimer
Explain how fibrin is polymerized
Fibrinogen has N-terminal ends that are highly negative preventing aggregation through repulsion
These negatively charged ends, that are due to fibrinopeptide A & B, are released by thrombin and a "soft" fibrin clot is formed
Covalent cross-linking by Factor VIIIa stabilizes the fibrin cot
What is Factor VIIIa?
One of the most important natural anticoagulants
It is a serpin (serine protease inhibitor)
Irreversibly inactivates serine proteases
Mainly targets Factor Xa and thrombin
Removes from circulation by the liver
What is heparin or heparan sulfate proteoglycans' affect on antithrombin?
Antithrombin's affects are stimulated
17,000 fold for Factor Xa
9,000 fold for thrombin
Serine protease that degrades fibrin clots
Inactive precursor of plasmin
How is plasminogen converted to plasmin?
1) Tissue-type plasminogen activator (tPA)
2) Urinary-type plasminogen (uPA; urokinase)
Antagonize the Vitamin K-dependent carboxylation of several clotting factors
Not properly carboxylated clotting factors are not secreted from liver cells
Activators of plasminogen are being used to treat MI and stroke
Promote the dissolution of thrombi, by locally activating plasminogen to plasmin
Examples of drugs include:.
How is N2 unique when compared to O2 & CO2?
Inert - Stable (reactive only with large energy input N2 + 16 ATP -> NH3)
NH3/NH4+ hugely unstable, thus toxic
Poorly H2O soluble
No carrier system
What do aberrations of amino acid metabolism usually include?
1) Abnormal AA levels (usually too high but, when too low due to transport issues)
2) Highly toxic compounds (i.e. NH4+)
3) Poorly soluble products (i.e. uric acid)
4) Excretory products not tolerated
Why is there such a large & variable DIT for protein?
1) Na+-linked AA transport
2) AA-supported gluconeogenesis
3) Synthesis of Asn & Gln (amidations)
4) Recyclying of purines & critical proteins
5) Detoxification of ammonia via the urea cycle
Respiratory Quotient (RQ)
CO2 produced/O2 consumed
The more reduced the fuel is the greater the amount of O2 consumed in its degradation
What kind of proteases perform the 1st digestion of protein?
What is protein degradation determined by?
1/2 life of protein
Usual marker is the N-terminal AA acid
Proteins rich in proline (P), glutamate (E), serine (S), and threonine (T)
All have short 1/2 lives and are degraded by the ubiquitin-proteasome destruction mechanism
What happens to ubiquitin levels in response to trauma? Why?
Removal of damaged proteins
Both a marker and destroyer
Heterodimer - large and small subunit
Binds to protein
Autolyses to smaller, active but unstable proteolytic enzyme
Degrades target protein
Why is glutamate unique?
Only AA to undergo oxidative deamination or reductive amination
Both involve free NH4+/NH3
The sole AA that accepts free NH3
Glutamate Dehydrogenase (GDH)
Enzyme responsible for deamination/amination of glutamate
In all tissues, high in liver
Reaction is freely reversible
Requires pyridoxal phosphate (PLP) as a prosthetic group
Mostly use glutamate or α-ketoglutarate
Most AA's go through this
How is the reversibility of a transamination valuable?
Able to maintain appropriate levels of all reactants
AA's and α-ketoacids for entry to glycolysis, gluconeogenesis, and the TCA cycle
Compound with a N=C
Covalently binds to PLP
What is released by deamination?
D-Amino Acid Oxidase
Oxidatively deaminates D-AA's
What is the #1 source of free NH3?
The deamidation of glutamine by liver mitochondrial glutaminase
Carbomoyl Phosphate Synthetase (CPS I)
First enzyme of the urea cycle
Ignites sequence and is tightly regulated
Requires a mitochondrial allosteric activator
NH3 + HCO3- + 2 ATP = carbomoyl-P + 2 ADP + Pi
Allosteric activator of CPS I
Created by its own mitochondrial synthase enzyme
Activated by arginine
Intracellulr index/signal of high N load
Glutamate + Acetyl CoA = NAG
NAG + H2O = acetate + glutamate
9 Major Points of the Urea Cycle
1) NH3, CO2, & 2 ATP comprise CP
2) CPS activated by NAG
3) CP + ornithine = citrulline
4) 2nd N donated by aspartate
5) Aspartate's C-skeleton released as fumarate which then enters the TCA cycle/gluconeogenesis
6) Two N's remain (from NH3 & aspartate) as part of arginine
7) Last rxn: Arginase breaks up arginine & makes 2N urea
8) 2 non-protein AA's (citrulline & ornithine) exchange between the mitochondria and cytosol to shuttle CP's N into cytosol
9) 4 ATP equivalents - while on 3 ATP are directly used
What happens to BUN when the liver is failing? Kidney?
BUN is low or normal
BUN rises sharply
What are possible results of urea cycle failure?
Most common urea cycle enzyme deficiency?
Ornithine trans-carbamoylase (OTC) deficiency
Why is NH3 so toxic?
Because it is constantly diverting α-KG from the TCA cycle via glutamate dehydrogenase which depletes ATP output
Starts vicious cycle of additional ATP being used to remove more NH3 by glutamine synthetase
Blood shunts around cirrhotic liver & accelerates CNS-related pathogenesis
Rising plasma urea and creatinine levels lead to osmotic stress
Treatments for urea cycle failure
1) Replacing essential AA's with their cognate α-keto-acids - very costly
2) Alternative routes of nitrogen excretion
Why do benzoic acid, phenylacetate, and phenylbutyrate work?
They are able to conjugate with 2 N-rich AA's (glycine & glutamine) and therefore be excreted via urine
Severe retardation, even with treatment
Phenylalanine Hydroxylase (PAH) - expressed only post-partum, so early detection isn't possible
Restrict phenylalanine specifically and protein in general
PKU smaple- no less than 12 hours post-partum! (best: 1-7 days); results in a few days
Normal plasma AA levels
What does defective degradation of amino acids cause?
Diversion & dead-end metabolite accumulation
Results in serious disease
Most common cause of pathologies in AA degradation?
3 universal α-KA's
What AA's can be converted to glutamate?
4) Histidine (irreversible)
What AA's readily degrade to pyruvate?
What are the methods of -NH2 removal?
Enzyme used to convert serine to glycine
Release/uptake of NH4+
Enzyme used to convert serine to pyruvate
Release of NH4+
1 of 2 sources of 1-C groups that are carried by THF
Glycine is second
What are folate's 3 components?
1) Pteridine ring
Origin of THF
Folate going through two succesive reductions by dihydrofolate reductase using NADPH
Glycine cleavage enzyme/system (GCE/GCS)
Cleavage releases NH4+
aka glycine encephalopathy
rare (after PKU most frequent)
Some survive with severe mental retardation; bursts of nonstop hiccuping; entirely CNS-related
What results when glyoxylate transamination is blocked?
Glyoxalate backs up and begins creating oxalic acid
Oxalic acid is poorly soluble
It precipitates in the renal tubule and causes kidney stones
Products of threonine degradation
NH3 & α-KB - to be converted to propionyl-CoA
NH3 produced by threonine dehydratase
Yields glutamate then α-KG
Enzyme that is used to convert histidine to urocanate
Modified into glutamate and formimino-THF
Main deficiency in histidase
~1/10,000 live births
Rare-yet most prevelant inborn error in Japan
Motor-mental retardation, speech problems, hyperactivity
Treatment: Histidine restriction
Deficiency can also be in either TH4 or formimino transferase -> FIGLU
Degraded to form cysteine
Also important for S-adenosylmethionine (SAM) - primary methyl group donor
Cysteine's body - C from serine, S only from methionine
The formation of homocysteine from methionine can proceed in what two ways?
1) Synthesis of cysteine
2) Methylation to remake methionine
What are the essential cofactors in homocysteine formation?
Methyl-B12 & Methyl-FH4
Methyl-FH4 cannot be recycled because of Vit-B12 deficiency
Defect in cystathionine synthase
Pectus excavatum ("funnel chest")
Treatment: Restrict dietary methionine, Vitanin B6, B12, & folate
Formed from cysteine
No codon for it, thus no protein incorporation
Essential in early CNS development (no synthesis in neonate)
Attach -SO4 to sugar moieties
1 costs 3 ATP equivalents to make
Used sparingly & strategically
Why is cysteine's sulfate clinically significant?
-SO4 makes certain drugs more soluble
What are the steps for the degradation of the BCAA's?
2) Oxidative decorboxylation
Where are BCAA's primarily degraded?
BC-α-ketoacid dehydrogenase (BCKAD)
Closely resembles pyruvate dehydrogenase (yields CO2, same coenzymes, etc.)
Severe enzyme block/defect causes maple syrup urine disease
Maple Syrup Urine Disease
The major disorder in BCAA metabolism
~1:200,000 in NA
BCKAD decarboxylates 3 branched ketoacids & yields NADH + H+
Severe mental retardation
Sweet smelling urine
Early death frequent
Treatment: Megadoses of thiamine; restrict dietary valine, leucine, & isoleucine
What makes a substrate ketogenic?
If the sole yields are acetyl-CoA or acetoacetyl-CoA
What are the essential AA's that are ketogenic? What is a characteristic they share?
Leucine & lysine
More likely to be degraded late in extended starvation
What is the major product of lysine degradation? Why is lysine important?
Key substrate in carnitine synthesis
What is carnitine made from?
Protein-bound trimethyl-lysine (liver only; diet)
3 methyl groups from 3 SAMs
Costs 9 ATP
Glucogenic & ketogenic
Has aromatic ring - important because they are not synthesized in humans
1st step: Phenylalanine hydroxylase (PAH) - produces tyrosine
Requires: 1/2 O2, & reducer BH4 (from NAD(P)H)
1st step: Tryptophan pyrrolase (oxidase) - oxidative cleavage of pyrrole ring (requires O2 & NADPH)
Portion becomes aceto-acetyl CoA and indole ring yields niacin (B2)
Important to know errors in degradation can lead to alkaptonuria & tyrosinemia
Defect in homogentistate oxidase
Leads to an accumulation of homogentistic acid that turns urine black upon exposure to air & light
With age dark pigments accumulate in CT (ochronosis) which can lead to arthritis in older patients
Condition is benign
What does the synthesis of homogentistate require?
Type I: Defect in fumaryl-acetoacetate hydrolase (last rxn)
Patient: Cabbage-like odor, impairment of tubular absorption, liver failure, & death)
Type II: Defect in tyrosine transaminase (Tyr->hydroxy-phenylpyruvate - PLP required)
Classically caused by deficiency in PAH
Patient unable to degrade PA and make tyrosine (robbing tyrosine from body protein)
Causes accumulation of plasma phenylalanine and diversion to other dead-end metabolic routes
Treatment: Very restrictive diet (primarily fruits & veggies, low protein)
What forms does PAH take? What activates it? Mutant forms?
Activated by phosporylation at serine residue after cAMP-mediated signal transduction
Splice mutation (affects tetramer stability)
Missense (affects tetramer stability and catalytic activity)
What is the cause of "malignant" PKU?
Low BH4 (reductase deficiency)
What are the 2 dead end metabolic pathways seen in PKU? Effects?
1) Transamination to phenylpyruvate
2) Reduction or decarboxylation to phenylacetate (disinctive musty odor)
Has profound effects on the development of nervous and cardiac cells
Why is preconceptional PA restriction essential if the mother is homozygous for PKU?
High maternal [PA] is strongly teratogenic ad the teratogenic effects tightly correlate with maternal plasma [PA]
What do PA, Tyr,& Tryp have in common?
Hydrophobic (benzene) ring (add BCAAs due to their 2 methyl carrying groups)
Inappropriate degradation leads to major illness that involves CNS, neurologic defects, & development aberrations
What are the three main α-KAs? What are their cognate α-AAs?
What do transaminations require?
PLP bound to a schiff base
Remember transaminations are REVERSIBLE
What is the sole source of proline?
What does cyclization do?
Confers aliphatic properties & creates a stable schiff base
Why is proline important?
Sole AA to get multiple -OH groups
Key substrate for vitamin C based -OH groups
Collagen's constant remodeling (based on reversibility, economy, & high output)
What are the roles of the 3 distinct coenzymes in the Glutamate/Proline rxn?
FAD & NAD+ (degradation)
1) Reductive amination via glutamate dehydrogenase (α-KG + NADPH + H+ + NH3 -> glutamate + NADP+)
2) Glutaminase's breakdown of glutamine (mitochondrial, irreversible, & cells primary source of NH3 detox in first step of urea cycle)
What do virtually all reductive syntheses require?
NADPH or a coenzyme directly or indirectly reduced by NADPH
Synthesized by amidation (-NH2 on terminal C=O)
Cost of 10 ATP overall (enzyme control critically important)
High cost/value suggest multiple roles
Major NH3 detoxifier
Very active in the kidneys and especially the brain due to NH3's neurotoxicity
Made from aspartate & glutamine
Amidation that costs 2 ATP
High demand in rapid tissue growth (i.e. cancers)
1) PEP transaminated to 3-phosphoserine
Then hydrolyzed to serine
2) Glycine and hydroxymethyl group from N5-N10 FH4
Removal of hydroxymethyl from serine
Lysis of cystathione (created by combining serine and homocysteine)
How is FH4 made? Components of folate? Most important 1-C sources
2 consecutive NADPH dependent reductions
Pteridine ring, PABA, & glutamate
Serine & glycine
What is the other Me carrier?
What are two byproducts of cysteine's synthesis?
NH4+ & α-KG
From defective cystathionine synthase
High risk of CHD, stroke, atherosclerosis
Insuff. cysteine->defective collagen prod.->week vascular wall
Only AA disorder to due to defective lysosomal membrane transporter (requires ATP)
Free, non-protein cysteine accumulates and forms 4-sded crystals
"prismatic needles" (cornea)
Symptoms: Fanconi syndrome (renal tubule dysfunction), glucosuria, etc.
Why is tyrsine synthesis so important?
Plays a role in:
1) Catecholamine metabolism
2) Thyroid hormone synthesis
3) Melanin synthesis
Body's most common porphyrin (tetra-pyrrole ring)
What is heme's role in the body? Where is it synthesized?
1) Bone marrow (erythropoietic, constantly active, produces ~70-80% of total body heme)
2) Liver (most adaptive, mostly for Cytochrome P450 enzymes which consume NADPH; adjusts continuously to changing needs, ~15% of total body heme)
Virtually all known diseases in heme metabolism are _____.
Partial & AD (variable expressivity)
1st step of heme synthesis
Succinyl CoA + glycine + Fe2+
Where does feedback inhibition by heme occur?
Heme also represses production of ALA synthase in these tissues
2nd step of heme synthesis
2 ALA molecules condense to make porphobilinogen
Uses enzyme ALA dehydratase (requires Zn2+)
Pb is a competitive inhibitor of ALA dehydratase and ferrochelatase
How do the liver and bone marrow differ in their regulation of heme synthesis?
Liver: Allosteric regulation by heme at 1st step (ALA synthase)
Also, indirect heme induced inhibition of Fe2+ uptake (not allosteric)
Bone marrow: Control by Fe2+ availability at final step (not allosteric)
Intact porphyrin ring with Fe oxidized (Fe3+)
Inhibits ALA synthase (Fe3+ must be within porphyrin ring because it is not itself inhibitory)
How does hematin work?
1) Transported by albumin and hemopexin
2) Uptaken by hepatocyte
3) Inhibits and represses ALA synthase
4) Reduced porphyrin precursor levels-plasma & urine
5) Induction of degradative heme oxygenase
6) Some evidence that it stimulates globin synthesis
What is the most common porphyria?
Porphyria cutanea tarda
What is the only porphyria that is AR?
Congenital erythropoietic porphyria (CEP)
What is the one unifying characteristic of all porphyrias?
Decreased heme synthesis
Acute Intermittent Porphyria (AIP)
Caused by defective hydroxymethylbilane synthase
CNS involvement (highly variable)
Treatment: Hemin (expensive) or IV glucose
Congenital Eryhtropoietic Porphyria (CEP)
Caused by bone marrow defect of uroporphyrinogen III synthase
Photosensitive present due to build of of phototoxic hydrocymethylbilane
What do the first two steps of heme degradation require?
Heme oxygenase (HO)
Enzyme used in 1st step of heme degradation
Produces CO, Fe3+, & biliverdin (BV)
Enzyme used in 2nd step of heme degradation
Turns BV into bilirubin (BR)
After this albumin is required to carry BR to the liver
Enzyme used in 3rd step of heme degradation
Conjugates BR with 2 glucuronates
Essential for BR's water dependent excretion
BV & BR are potent antagonists of what?
Does CO have any "normal" functions?
Acts as a vasodilator relaxing pulmonary vasculature
hepatocyte transporter of organic anions & non-polar compounds
Has glutathione-S-transferase activity
Caused by defect in active transport of BR-diglucoronide into bile canaliculi
The result of the hydrolysis of BR-diglucuronide by gut bacteria
Some is resorbed and transported to the kidneys becoming yellow and giving urine its characteristic yellow color
The result of the oxidation of urobilinogen in the large intestine
Responsible for poop's brown color
What is the proximal cause of jaundice?
Excessive unconjugated BR in blood plasma
What is the distal cause of jaundice?
Overproduction of BR and/or insufficient BR glucuronyl transferase
Whe excessive unconjugated BR accumulates in lipid-rich regions of the brain
Results in neural damage of varying severity, particularly in the developing CNS
Massive lysis of RBCs (i.e. malaria, sickle cell, etc.) results in bilirubin being produced at a rate that exceeds the liver's capacity to degrade it
Unconjugated BR levels rise sharply in blood - leading to jaundice
The result of naturally low levels of BR glucuronyl transferase that doesn't reach adult activity until ~ 2 weeks post-partum
This is coupled with very high BR production in the fetus
In pre-term infants BR far exceeds albumin's carrying capacity and as a result diffuses into CNS basal ganglia and causes nuclear jaundice
Treatment: Alteration of BR (lots of =) structure using UV-phototherapy
However, UV destroys riboflavin (B2) as well thus, UV-treated neonates must also receive riboflavin
Caused by bile duct obstruction (i.e. cholestiasis, tumor, etc.)
Caused by damage to the fabric of liver cells (i.e. cirrhosis, hepatitis, hepatotoxicosis, etc.)
What is the primary cholesterol carrier?
Pathological changes in the intima of large arteries
Created by the accumulation of foam cells
What is the most reliable predictor of CHD?
Ratio of LDL/HDL
How does [HDL] differ in men and women?
Healthy, non-diabetic premenopausal women have ~20% more HDL than men of the same age
What are the 3 major risk factors for atherosclerosis & CHD? Novel risk factors?
3) High serum cholesterol
1) Low antioxidant intake
2) Diabetes mellitus
3) Lipoprotein(a) levels
4) Physical inactivity
5) Human cytomegalovirus (HCMV)
6) Low reduced glutathione (GSH)
Unusual form of LDL-glycoprotein
disulfide-bonded to apoB-100 of LDL
High levels are a strong independent risk factor
No response to dietary manipulation
Level determined by rate of gene expression
Major function is ensure proper lipid delivery
Aberrant form of apo E
Major disruptor of lipid delivery
Homozygotes for apo ε-4 develop Alzheimers by 80
Binds strongly to extracellular amyloid proteins on/near lipid rich neural membranes - especially junctions
Favors ROS generation
Association with amyloid proteins common in neurodegenerative disorders
Microsomal TAG transfer protein of ER absent
VLDL, LDL, & chylomicrons are esentially absent
Familial Hypercholesterolemia (FH)
Accumulation of LDL
Caused by deficiency in LDL receptors (both liver and extrahepatic)
Xanthoma/xanthomata commonly seen in patients 20+ years of age
Familial LCAT Deficiency
No esterification of cholesterol acquired by HDL
Sharp rise in FC/CE ratio
2) Inhibit cholesterol absorption
3) LCAT stimulation
Cholesterol esters formed by LCAT cannot be transferred from HDL to other lipoproteins
Hyperchylomicronemia (Type I hyperlipoproteinemia)
Hydrolysis of TAG impaired
LDL formation reduced
Most plasma cholesterol is in VLDL
Symptoms: Discomfort after fatty meal, cutaneous xanthomas, pancreatitis
Treatment: Restrict dietary fat
Hypercholesterolemia (Type II hyperlipoproteinemia)
Elevated VLDL & LDL often
Patient: Weight gain, obesity, & Type II diabetes
Very high risk of CHD & atherosclerosis
Dys-beta-lipoproteinemia (Type III hyperlipoproteinemia)
Homozygous for apo E variant cannot bind hepatic apo E receptors
Accumulation of CM & IDL-like VLDL remnants (all with apo B)
Results in dysfunctional cargo delivery by B-containing LPs
Diagnosis: Accumulation of cholesterol rich B-migrating LPs with VLDL-like density
Atherosclerosis (especially in peripheral arteries)
Typer IV Hyperlipoproteinemia
Elevated VLDL very common
Type V Hyperlipoproteinemia
Elevated VLDL & CM
Often seen with uncontrolled diabetes, alcoholism, & kidney disease
Dietary treatment often effective
Major disruptor of lipoprotein economy
1) Glycation of apoproteins
2) Spontaneous formation of acetaldehyde adducts
3) Chemicaaly moddified LPs bind to vascular endothelium
4) Narrowing of vascular diameter
Leads to vascular insufficiency, higher plasma TAG, & lower HDL levels
And later premature CV disease
Inhibitors of HMG-CoA reductase
Indirectly increases dependence on cholesterol from plasma lipoproteins; elevating synthesis of LDL receptors
Blocks the absorption of cholesterol
Binds bile salts in the small intestine preventing their absorption
They are excreted which cause increased synthesis of bile salts, reduction of cellular cholesterol, upregulation of LDL receptors, & subsequent lowering of LDL levels
What amino acid is a precursor to creatine and nitric oxide?
What are some important aspects of creatine
1) Direct precursor of creatinine
2) Constant, reliable urinary loss of 1.7% of body's burden
3) Accepts Pi in unusual high energy N-P bond, becoming creatine phosphate
What cells benefit the most from the rxn of creatine to creatine phosphate being reversible?
Myocytes & the CNS
What is the ratio of CP:ATP in muscle (at rest)?
What is the function of CP?
Acts as a -P reservoir to maintain ATP's ability to support massive muscle (mechanical & electrical) work
Glycine + Arginine -> Guanoidino-acetate + SAM -> Creatine
What is responsible for the uptake and concentration of creatine?
Na+-dependent transport in brain & muscle
How is creatinine made?
Spontaneous cyclization of CP after loss of -Pi
No enzymatic degradation
What is the clinical significance of creatinine?
By back-calculating from urinary creatinine levels you are able to find an accurate measure of CP loss and in turn muscle mass
Also, spikes in plasma creatinine are a reliale index of kidney malfunction because a healthy glomerulus efficiently removes it
And an accurate index of N balance
What is needed for arginine to give rise to NO?
NO synthase (Heme, FAD, FMN, BH4), O2, and NADPH
What are the function of NO?
1) Dilator of vascular smooth miscle
2) Blocks platelet aggregation
4) Induces an inflammation and immune response where NOS synthesizes toxic bacteriocidal, antifungal, & antiprotozoal amounts
How does NO induce dilation of vascular smooth muscle?
NO is able to directly travel from cell to cell
By doing this it is able to enter a vascular smooth muscle cell and activate guanylate cyclase
Guanylate cyclase uses GTP to make cGMP a vasodilator
GABA synthesis from glutamate
Histamine synthesis from histidine
Histamine degradation (periphery)
Histamine degradation (brain)
What is serotonin inactivated by? What else does it do?
Melatonin synthesis from serotonin
Serotonin + Acetyl-CoA -> N-acetyl serotonin + SAM -> Melatonin
How does melatonin work in the treatment of Alzheimer's?
Prevents the hyperphosphorylation of tau proteins
Where are catecholamines synthesized?
Are catecholamines stored?
Production is very fast and can keep up with immediate demand
Catecholamine synthesis from tyrosine
L-tyrosine + BH4 -> Dopa + PLP -> Dopamine + Vitamin C -> Norepinephrine + SAM -> Epinephrine
Uses Catechol-O-methyltransferase (COMT) & Monoamine oxidase (MAO)
What is MAO's function in catecholamine degradation? What happens when MAO activity is too high?
To mop up excess NT (including serotonin)
Can lead to depression in the patient due to MAO scavenging NTs too quickly (MAOIs as antidepressants)
What else does tyrosine give rise to? How?
From tyrosine residues on colloidal thyroglobulin (Tgb)
I, H2O2, & NIS play important roles
T3 & T4
Regulate overall metabolism in many tissues
Involves gene activation
T3 more active
Hypertrophy of the thyroid due to its attempts to obtain any available iodine
European Alps, Central Eurasia, NA prairies, Appalachia, Himalayas, etc.
aka Graves' disease
Immune system disorder
Overproduction of THs
Thick, red skin on shins or tops of feet
What is required to to produce melanins?
Tyrosine & cysteine
Tyrosine + Tyr hydroxylase (activated by UVB) -> DOPA -> Dopaquinone + Cysteine -> 5-S-cysteinydopa -> -> Pheomelanin becomes oligomeric Eumelanin
Pink/red with light skin & red hair
Can become carcinogenic after UV bombardment
Usually high when melanin is low
"Ultrafast internal conversion" with >99.9% of UV radiation dissipating as heat (reducing carcinogenic power)
Synthesis strongly stimulated by UVB
Inducer of tyrosine hydroxylase
In brain S nigra and L ceruleus
Possible anti-ROS activity
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