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Biochemistry Test 2
Terms in this set (257)
What is the function of gluconeogenesis?
To maintain blood glucose Levels
What is the main organ for gluconeogenesis?
When does the Kidney assist in gluconeogenesis?
Sever hypoglycemia (Liver can't handle it by itself)
Glutamine is the preferred substrate
What locations inside the cell does gluconeogenesis take place?
Mitochondria and Cytosol
Normal Blood Glucose Level
What is diabetic (hyperglycemic) fasting blood sugar level?
If the body doesn't receive glucose from food, what is the process that it reverts to to get glucose and what are the hours it corresponds to?
1. Glycogen storage (18-20hrs)
2. Glucagon --> Gluconeogenesis by the liver (after 18-20 hrs)
What are the 3 main precursors for gluconeogenesis? And their sources?
1. Glycerol - from triglycerides (TG)
2. Lactate - anaerobic metabolism in skeletal muscle, RBC
3. Gluconeogenic amino acids - from proteins
What is the name of the cycle that allows lactate to go from muscle to liver? (Precursor for gluconeogenesis)
Cori cycle (recycles lactate from muscle to liver)
What is the name of the cycle that allows alanine to go from muscle to liver to create glucose?
What are the 3 reactions in glycolysis that are irreversible?
3. Pyruvate Kinase
What enzymes help gluconeogenesis to go in the reverse and bypass pyruvate kinase? Where are they located?
1. Pyruvate Carboxylase (mito.)
2. PEP Carboxylase (PEPCK) (mito., cytosol)
What enzyme is responsible for gluconeogenesis to occur and bypass PFK-1? Where is it located?
Fructose- 1,6 Bisphosphatase (cytosol)
What enzyme is responsible for gluconeogenesis to occur and it to bypass Hexokinase?
Glucose-6-Phosphatase (ER membrane)
How many energy molecules does it take for the process of gluconeogenesis?
6 high energy (GTP and ATP)
2 NADH as well
What are the main regulators of gluconeogenesis?
1. Hormonal Regulation
2. Availability of Gluconeogenic Precursors
3. Allosteric Activation of enzymes
4. Energy availability
Under fasting conditions what provides the main fuel for liver and energy for gluconeogenesis?
What is the ratio of Insulin/Glucagon in Gluconeogenesis?
Insulin Low/Glucagon High
What are the Gluconeogenic precursor regulators of gluconeogenesis?
1. High protein diet --> glucogenic a.a.
2. Decreased insulin --> mobilization of a.a. from muscle
3. Odd-chain fats --> succinyl-CoA -> glucogenic
What are the allosteric activators on Pyruvate Carboxylase in Gluconeogenesis?
Acetyl-CoA (+) activator
What is a allosteric inhibitor on F1,6 bisPtase in Gluconeogenesis?
(AMP) and (F2,6 bisPhosphate) (-) inhibitor
What is Von Gierke disease?
(a.k.a. = glycogen storage disease Type 1a)
deficiency of liver G-6Ptase
- Hyperlipidemia & Hyperuricemia
Told Not to fast
What does PEPCK deficiency and F 1,6 - BPtase deficiency show?
How does ethanol (alcohol) effect gluconeogenesis?
Increase NADH/NAD+ ratio
- fatty liver
- Increase in Lactic Acid --> Acidosis
- Excess lipids
What happens if you drink methanol?
Makes formaldehyde *
toxic to the optic nerve and can produce blindness
What is the first source of glucose during fasting?
Liver Glycogen (quick but limited quantity)
What are the different sources of blood glucose?
2. Gluconeogenesis (slow to respond but sustainable)
3. Liver Glycogen (quick, short lived)
Why does the body store glucose in glycogen and not in the monomer form?
Does not create an osmotic problem for cell as would glucose monomers
What is the role of glycogen in Liver vs. glycogen in muscle?
Liver- blood glucose homeostasis
Muscle - energy for contraction
What is the significance of glycogenin in glycogen synthesis?
Initiates glycogen polymer
Where does glycogen synthesis occur and what are the enzymes that function there?
2. UDP- glucose --> UDP Glucose "activated form"
3. Glycogen Synthase --> UDP-Glucose added to the non-reducing end of existing glycogen polymer
4. Branching enzyme (4-6transferase) --> alpha (1-6) increases solubility/branching
What is linear between amylose and amylopectin?
During a well fed state what happens to glycogen synthase?
Activated (forms glycogen for storage)
What is a allosteric effector of glycogen synthase and how does it effect it?
(+) Glyogen 6-P, causes glycogen to be made
When glycogen synthase is dephosphorylated what happens, and when does it happen?
Glycogen Synthase (Activated) - When there is a increase in insulin (more glycogen synthesis)
What is GSD type 0?
Glycogen Synthase deficiency
- Fasting hypoglycemia
**Mutation in glycogen synthase-2 gene (GYS2)
What is GSD type 4, Andersen Disease?
Deficiency of glycogen branching enzyme (glucose 4:6 transferase)
-usually fatal by 5
What is the importance of glycogenolysis in in the liver?
Respond to low blood glucose "Homeostasis"
What is the importance of glycogenolysis in the muscle?
Rapid response to need of energy for contraction
Do glucagon and epinephrine effect liver glycogen and muscle glycogen?
- Glucagon (low blood sugar)
- Epinephrine (under stress)
What is the main enzyme in Glycogenolysis?
cleaves alpha 1-> 4 linkage only
CoEnzyme - Pyridoxal Phosphate (Vit B6)
Can glycogenolysis occur if there is no Vit B6?
Where does glycogenolysis occur? Is it the reversal of glycogen synthesis?
Cytosol, No it is not the reversal
What does the 4:4 transferase enzyme in glycogenolysis do?
(1 of 2 Debranching enzyme)
Transfers 3 glucose units --> to make alpha 1:4
What is a product of 1:6 Glucosidase?
(2 of 2 Debranching enzyme)
What are the glycogen Storage diseases?
Type 1a, von Gierke - Glucose 6-Ptase deficiency (liver)
Type 2, Pompe - Lysosomal acid alpha- 1, 4- glucosidase deficiency
Type 3, Cori - Debranching enzyme deficiency
Type 5, McArdles: Skeletal muscle phosphorylase
Type 6, Hers: Liver Phosphorylase
Type 1a, Von Gierke
Liver Glucose 6-Ptase deficiency (muscle contains very little amounts of G-6Ptase)
Type 2, Pompe
(Acid Malatase Deficiency)
- Lysosomal *
only one that is lysosomal, every other glycogen storage disease is cytosolic
- Lysosomal acid, alpha 1-4-glucosidase deficiency (GAA)
Type 3, Cori
Debranching enzyme deficiency
- Accumulation of abnormally structured glycogen having very short outer chains
Type 5, McArdles
Skeletal muscle phosphorylase
No rise in blood lactic acid after exercise
- Myoglobinemia and Myoglobinuria
Type 6, Hers diseases
Liver phosphorylase deficiency
What are the allosteric inhibitors of Liver glycogen metabolism?
3) Glucose 6-P
What are the allosteric activators of Muscle glycogen metabolism?
1) Ca2+ (Calmodulin Complex)
How does glucagon or epinephrine hormonally effect glycogenolysis?
Epinephrine (muscle and Liver)
Activate glycogen degradation
Can Ca2+ and AMP effect the glycogenolysis cascade without having the intermediate substrates being phosphorylated?
- Glycogen phosphorylase kinase a (active) *
Ca2+ calmodulin complex
- Glycogen phosphorylase a *
where AMP can act
- Phosphorylating = activating
- 30H groups replaced with Cl
- Not metabolized
- Eliminated unchanged in the stool
What is the major source of Fructose?
Where does Fructose metabolism take place?
What is the major enzyme of in Fructose metabolism?
and Aldolase B
What does Aldolase B split Fructose into?
Glyceraldehyde and 1 dihydroxyacetone w/ phosphate
What happens when you have Fructokinase deficiency?
- Fructose eliminated (detected as a reducing sugar)
What happens when you have Aldolase B deficiency?
- Hereditary Fructose Intolerance (poisoning) HFI
- Seen after a baby starts eating food or formula
- Hepatic failure and Death
Trx. - removing fructose and sucrose from diet
What occurs when you have too much sorbitol?
Gastro-Intestinal Problems (draws in H2O)
What is unique about the Lens, Nerve, Kidney, and Retina?
Sorbitol dehydrogenase is Low --> Sorbitol stays and draws in H2O, causing Edema
**Sorbitol dehydrogenase doesn't use any ATP
- Neuropathies, Macular edema and poor vision
What is the main dietary source of galactose?
Lactose (Galactose and Glucose Beta 1--> 4 bond)
- Non-Insulin dependent transport
- Rare genetic deficiency
- not severe
- lead to cataract formation
What causes Classical Galactosemia?
Galactose 1-phosphate Uridyltransferase deficiency
- Galactose 1-P increases
- Mental Retardation, Liver and Kidney damage, Cataracts
- Major problem bc new borns ingest up to 1g of galactose a day
Part of Newborn screening panel in NY
Where can Fructose come into glycolysis?
Aldolase B splits Fructose 1-P --> Dihydroxyacetone-P which can go into glycolysis
Where can Mannose go into glycolysis?
Hexokinase; it actually is similar to glucose and can be interconverted with a isomerase
What is the entry point for Galactose into the Glycolytic pathway?
Galactose 1-phosphate Uridyl transferase splits Galatcose 1-P --> Glucose 1-P
What is the main properties, functions and enzymes involved in the Pentose Phosphate Pathway?
Main Properties - NO ATP, oxidative (Part 1) and Non-oxidative (Part 2)
Main functions- (2) NADPH, Ribose 5-P, sugar interconversions
Main enzymes - Glucose 6P DH (Part 1) and Transketolase (Part 2)
Is the First part of Monophosphate Shunt irreversible? Second part?
MPS = PPP
Which enzyme in the PPP does Thiamine effect?
Transketolase (Part 2)
Used to measure thiamine levels in blood
Beriberi --> Heart Failure
**often associated with alcoholism - due to poor nutrition
What are the 5 roles of Glucose 6P?
1) Glycolysis --> energy
2) Gluconeogenesis --> blood sugar
3) Glycogenolysis --> blood sugar and muscle energy
4) Glycogen synthesis --> sugar storage
5) PPP --> NADPH + Ribose
Nicotinamide Adenine Dinucleotide phosphate is produced where?
NADP(H), is a electron carrier produced in the PPP....REDUCED form
What enzymes in the Hexose Monophosphate Pathway is responsible for producing NADPH?
1) Glucose-6-P dehydrogenase
2) 6-P-gluconate dehydrogenase
Ribulose-5-phosphate is created where and is the precursor to what?
PPP and is the precursor of ribose for DNA and RNA
Why does RBC need NADPH?
1. Deal with superoxide production (Both O2- & H2O2 produce reactive free radical species, damage cell membranes, and cause hemolysis)
2. Glutathione production
synthesized - enzymatically w/o RNA using ATP
main functions - antioxidant, NO synthesis, detox. heavy metals, modulate activity of lymphocytes and T cells, regulate apoptosis
Glutathione Synthetase Deficiency
1. causes hemolytic anemia, seizures, mental retardation
2. RARE AUTOSOMAL RECESSIVE TRAIT
What enzymes are involved in the detox. of Superoxide anion and hydrogen peroxide?
1) Superoxide dismutase
2) Glutathione peroxidase **needs vit. Selenium (reduces the occurrence of prostate cancer in men)
3) Glutathione reductase (Needs NADPH)
How does smoking cause emphysema?
Smoke (abundant oxygen-free radical) --> inflammation --> neutrophil --> Oxidative injury --> decrease local anti-elastase activity (similar to alpha-1-antitrypsin) --> (Decrease) NADPH detox. --> Lung tissue damage and alveolar wall break down
What does NADPH do in the microsomal system?
NADPH provides the reducing equivalents in the mitochondrial system (steroids) and in the microsomal system (xenobiotics)
What is required to make Nitric Oxide?
Enzyme - NO synthase
Reactants - L-Arginine, (2)O2 and (2) NADPH are required
What is the process by which NO relaxes smooth muscle? Which part does Sildenafil work on?
NO --> guanylate cylcase activated -->
--> protein kinase G activated --> myosin light chain kinase (phosphorylated- INACTIVE) --> Smooth muscle relaxation
**Viagra (Sildenafil) is a COMPETITIVE inhibitor, which Increases cGMP due to decreased degradation --> Vaodilation
G6PD deficiency and hemolytic Anemia
- Most common genetic enzymopathy
- X-linked recessive
- Prone to hemolytic anemia, caused by Inability to produce NADPH
- increased resistance to falciparum malaria
What factors can cause G6PD Deficiency?
1) Antibiotics (
, ch. Phen)
2) Antimalarials (primaquine)
3) Antipyretics (acetanilide = TYLENOL)
Favism- eating the Fava Bean
HEINZ bodies = precipitation of hemoglobin due to disulfide bond formation between Hb molecules
What are the 3 Symptoms of G6PD Deficiency
1) Black colored urine
- Hemolysis may result in urinary excretion of hemoglobin
2) Low RBC count and Low hemoglobin
- result of high rate of hemolysis
3) Elevated bilirubin
- catabolism of heme
What does excess ethanol due to NADH
Excess ethanol --> Increase NADH --> Decrease Glucose
What is the difference between proteoglycans and glycoproteins?
Proteoglycans - 95% carbs,long carbs, Repeating units (GAGs), Linear
Glycoproteins - mainly PROTEIN, short carbs, NO REPEATING units, Branched, variable carb. amount
What makes up Glycosaminoglycans (GAGs)?
Long UNBRANCHED chain of REPEATING disaccharide units
1) Acidic Sugar - (D-glucuronic Acid or L-Iduronic Acid)
2) N-Acetylated Amino Sugar, Acetyl sugar - (Glucosamine)
What makes up Proteoglycans?
"core protein with GAGs attached"
Core Protein (w/ Serine,-OH) + XYLOSE + Galactose + Galactose [Uronic acid + N-acetylated sugar (glycosaminoglan)]n
Where are the different types of proteoglycans found?
1) Hyaluronic Acid?
2) Chondroitin Sulfate?
3) Dermatan Sulfate?
5) Heparan Sulfate?
1) Hyaluronic Acid (NO sulfated groups) - cell migration and Lubricant
2) Chondroitin Sulfate - bone, cartilage, tendons, ligaments, AORTA
3) Keratan Sulfate - 1) cornea 2) loose conn. tissue
4) Dermatan Sulfate - skin, heart valves, blood vessels
5) Heparin (MORE sulfated than heparan sulfates) - Blood clotting and anchors lipoprotein lipase to the capillary walls of tissues
6) Heparan Sulfate - cell surfaces (basement membrane)
What is a mucopolysaccharidoses?
Genetic proteoglycan storage disorder,
, absent or deficient lysosomal hydrolases
**All are autosomal recessive except HUNTER's SYNDROME (X-linked).
- Iduronate Sulfatase deficiency
*X-linked deficiency (recessive)
Trx. IV enzyme
Mucopolysaccharidose, MPS 1H
- Alpha - L - Iduronidase deficiency
- Autosomal recessive
Trx. IV enzyme
Sanfilippo Syndrome Types A-D
(mucopolysaccharidose, MPS 3)
A - Heparin Sulfamidase deficiency
B - N-Acetylglucosulfatase deficiency
C - Glucosamine-N- acetyltransferase deficiency
D - N-Acetylglucosamine-6-sulfatase deficiency
All autosomal recessive
SLY Syndrome (MPS 7)
- Beta- Glucuronidase deficiency
- Autosomal recessive
Why are GAGs able to absorb things?
Due to the change of the sulfate groups present, they are able to absorb a great deal of water (act like a sponge) so they are good Lubricant for joints
Mainly protein, No repeating unit, Branched
- complex oligosaccharides
- mostly membrane bound or in extracellular glycoproteins
- High mannose content in core
- N or -O linked
NaNa is the terminal group and serves as the end point of the side chain
What are the functions of glycoproteins?
1) Cell surface recognition
2) Cell surface antigenicity
3) Extracellular matrix structures
4) Mucins (lubricants)
5) Membrane proteins: cell-cell interactions, receptors (G-Protein)
Is collagen a prototype of glycoprotein?
What is the difference between O-linked and N-linked oligosaccharides?
N-linked- sugar added via amide nitrogen *
O-linked- sugar added via the oxygen (-OH) *
Serine, Threonine, Hydroxylysine, Hydroxyproline
What is the difference between the attachments on the blood groups?
Blood groups are (O-linked)
O antigen - nothing on galactose
A antigen - GalNAc on galactose (Aceylase enzyme has to occur)
B antigen - Galactose attached to Galactose
Where does N-linked glycoprotein synthesis occur?
ER and Golgi
Requires Dolichol Pyrophosphate
Briefly describe the biosynthesis of N-Linked glycoproteins
1. Synthesis in ER
2. Branched oligosaccaride synthesized and bound to DOLICHOL PYROPHOSPHATE
3. Oligosaccharide is transferred from DOLICHOL to an Asparagine residue
4. In golgi, further trimming and/or addition of monosaccharides
What state is Iron present in Transferrin?
Transport Iron (Fe3+)
**Hemoglobin and Storage (Ferritin, Fe2+)
Which lipid is important in nervous tissue?
Steroids are made from?
What has a higher melting temperature saturated or unsaturated Fatty Acids?
SATURATED F.A. (long linear)
What fatty acid is the end product of mammalian fatty acid synthesis?
What are the essential fatty acids?
Linoleic and Linolenic Acid
What Fatty acid is the precursor of eicosanoids (prostaglandins)?
What are the acid lipases and what type of TAG does it work on?
Lingual Lipase and Gastric Lipase (Mouth and Stomach) "Short/Medium-Chain FA"
important for neonates and people with Cystic Fibrosis
What does Pancreatic Lipases effect?
1. Cholesterol Esters (CE)
3. Long-Chain TAG at positions 1 and 3
Product = 2-monoacylglerol and (2) FA (absorbed by intestinal epithelial cells)
COLIPASE is required
What are the primary products of Fat Digestion via Acid lipases and Pancreatic Lipases?
1) Free Fatty acids
Emulsification of Fats
- Increases surface area of fats
1. Bile Salts (produced in Liver, secreted in gall bladder) - has detergent properties
2. Peristalsis - mechanical mixing
Polar derivatives of cholesterol
Amphipathic = detergents
Which enzymes are involved in digestion of lipids?
1) Lingual Lipase (tongue) MC-FA
2) Gastric Lipase (stomach) *
3) Pancreatic Lipase **Major enzyme in ADULTS affecting triglyceride hydrolysis (LC-FA)
4) Colipase (Pancreas) - zymogen activated by trypsin
5) Lipid Esterase (Pancreas) - acts on cholesterol esters, *
activated by BILE
6) Phospholipase A2 - cleave phospholipids, *
activated by trypsin and bile salts
Why do people with CF have malabsorption of Fats?
pancreatic lipase Deficiency
Drug that inhibits lipases --> cause an oily bowel movement
1) Phospholipase A1 - Carbon #1
2) Phospholipase A2 - Carbon #2 **Activated by trypsin, requires BILE salts --> Lysophospholipid (snake venom, causes hemolytic anemia in the patients)
3) Phospholipase C -phosphoryl - X (before P)
4) Phospholipase D - X (after P)
Hormones affecting digestion
1) Cholecystokinin (CCK) prod. by jejunum and duodenum - (+) enzyme release from pancreas and bile from gall bladder...slows down gastric motility
2) Secretin, prod. by intestinal cells in response to chyme acidity - (+) bicarbonate release by pancreas and bile from liver into gall bladder...changes pH to slightly basic for pancreatic enzymes with bicarb.
How do short and medium chain FA get into enterocytes?
Can go in directly do NOT require a Mixed micelle
(formed from Free FA, Cholesterol, and Monoacylglycerol)
responsible for absorption of TAG through the brush border into the enterocyte
What is responsible for Lipids to transfer into the lymphatics?
(Outside Apolipoprotin B-48)
(Inside Triacylglycerol and Cholesteryl ester)
What is the process in which chylomicrons pass from the intestinal cells into the blood?
1) Chylomicrons (from enterocytes)
2) Lacteals (lymphatic vessels)
3) Thoracic Duct
4) Left subclavian Vein
6) Tissues, Organs, and adipocytes
What is the ONLY function of chylomicrons?
Transfer of lipids and cholesterol esters from the intestines to the adipose site
(Outside of Enterocyte - ApoC-2 and ApoE are added Chylomicron via HDL)
What activates Lipoprotein Lipase at the capillary, adipose site junction?
Apo C-2 *
Stimulated by INSULIN
Lipoprotein Lipase responsible for allowing Free fatty acids to cross
- also releases glycerol and chylomicron remnant
How are Free Fatty acids transported in the blood?
via serum ALBUMIN
can enter muscle cells or adipocytes
Does Adipocyte have glycerol kinase?
NO, although it makes glycerol it has to be brought back to the Liver which can convert it to glycerol 3-phosphate --> Glycolysis or gluconeogenesis via DHAP
What are the 4 Plasma Lipoproteins? From Largest/Most Dense to Smallest/Least Dense?
1) Chylomicrons (HIGEST TAG and LOWEST Cholesterol)
3) LDL (BAD FORM)- (HIGHEST CHOLESTEROL)
4) HDL (GOOD) - (LOWEST TAG)
Created - Intestines
Composed - HIGHEST TAG and LOWEST Chol.
Function - Deliver dietary TAG to adipocyte
Created - Liver
Composed of - High TAG and Low Cholesterol
Function - deliver De NOVO TAG to peripheral tissues
Created - VLDL
Composed - HIGHEST Cholesterol and Low TAG
Function - deliver cholesterol to the peripheral tissues
Created - Liver and Intestines
Composed - LOWEST TAG and High Cholesterol
Function - *
DELIVER cholesterol to the liver for elimination
REASON WE WANT HIGH LEVELS of HDL
What are the Fasting Levels of Serum Triglycerides?
Normal < 150mg/dL
Borderline High : 150-199 mg/dL
High : 200-499mg/dL
Very High : > 500mg/dL
Malabsorbed Lipid (oily bowel movement)
- Caused by disturbances in lipid digestion and/or absorption
- Complications from Cystic fibrosis, Common bile duct obstruction shortened bowel
Hereditary Abnormal Utilization of Lipids
1) Type 1 hyperlipoproteinemia (familial lipoprotein lipase deficiency)
- rare autosomal rec.
- DEFICIENCY in LIPOPROTEIN LIPASE or its coenzyme, apo C-2
- Abnormally HIGH levels of chylomicrons
2) Type 3 Hyperlipoproteinemia (familial dysbetalipoproteinemia)
- Defective chylomicron Remnants removal by the liver
What regulates Lipoprotein Lipase?
Insulin and need coenzyme Apo C-2
- Adipocyte - INCREASE KM (affinity for it has diminished)
- Cardiac - Decrease KM
after 90% of TAGS degraded by lipoprotein lipase, particle increases in density
- Apo-proteins are returned to HDL
- Remnants are removed by the LIVER
How does the liver transport Fatty Acids?
(in Liver Apo B-100 added to leave)
(Blood - Apo C-2 and Apo - E added from HDL)
After liprotein lipase removes Free Fatty Acid into adipose -->
What is the Difference between Hormone-Sensitive Lipase and Lipoprotein Lipase?
1) Hormone- Sensitive (inside adipocyte)
- Influenced by Epinephrine
- Triglycerides --> Diglycerides
2) Lipoprotein Lipase (capillary/adipocyte interface)
- Stimulated by INSULIN
- Triglycerides --> Free FA and glycerol
Apo B-48 vs. Apo B-100
Apo B-48 (Chylomicrons)
- synthesized in RER and glycosylated in the Golgi
Apo B-100 (VLDL and IDL)
FA produced in the body from acetyl CoA
- 16 carbon chain (SATURATED)
What are the Essential Fatty Acids (taken from the diet)?
1) Linoleic Acid (Unsaturated) 18 carbon chain: 9, 12
- precursor of arachidonic acid
2) Linolenic Acid (Unsaturated) 18 carbon chain: 9, 12, 15
- precursor of other omega 3-fatty acids
Arachidonic Acid - becomes essential if linoleic acid is deficient
What is the precursor to prostaglandins?
- 20 carbon chain (Unsaturated: 5, 8, 11, 14)
Order of Dicarboxylic Acids (with methylene group as difference in the middle)
"Oh My Such Good Apple Pie"
O) Oxalic - n = 0
M) Malonic - n = 1
S) Succinic - n = 2
G) Glutaric - n = 3
A) Adipic - n = 4
P) Pimelic - n = 5
What enzyme and factors are needed for the initial, rate-limiting step of FA synthesis?
E) Acetyl CoA carboxylase
1) HCO3- (from CO2)
Acetyl-CoA --> Malonyl-CoA
acyl carrier domain of fatty acid
What is the Long-Term (slow) control of FA Synthesis?
Dietary glucose stimulates --> Liver production of FA biosynthetic enzymes (*
ABSENT in an untreated diabetic and during fasting
What is the Short-Term control of FA Synthesis?
Acts on Acetyl CoA carboxylase (rate limiting enzyme in FA synth.)
1) Allosteric Reg. (+) Citrate
(-) Long-Chain Fatty acyl CoA
2) Covalent Reg. (+) Insulin -> Protein Phosphatase
(-) Glucagon/Epi -> cAMP-dependent protein kinase
Where do we get the NADPH that is ESSENTIAL for FA synthesis?
1) PPP or Hexose Monophosphate pathway
2) Cytosolic conversion of malate to pyruvate - MALIC enzyme
(Malate --> Pyruvate)
What is NADPH used for in the body?
1) Reductive synthesis of FA, steroids, sterols
2) Cytochrome P450 system
3) Detoxification of reactive oxygen intermediates
What is the process of producing Palmitate from FA from dietary Glucose?
1) Glucose (glycolysis)
2) (2) Pyruvate (IN CYTOSOL)
3) OAA + Acetyl CoA (IN mito. matrix)
= shuttle for acetyl coA to get passed the Inner Mito. membrane
5) Acetyl Co + OAA (x7)
6) Palmitate --> Lipids
Storage of FA as components of TAG
1) formed by esterification of FA to glycerol phos.
2) Means for storing FAs in adipocytes
3) slightly soluble in water
4) coalesce within adipocytes to form oily droplets
5) the MAJOR energy reserve of the body
6) Neutral Fats
What does Insulin INCREASE? DECREASE?
1) Glucose transport
4) FA synthesis
5) TAG synthesis
6) Protein synthesis
1) TAG degradation
What is the INITIAL acceptor of FA in TAG synthesis?
What are two synthetic sources of GP (Glycerol Phosphate)?
1) Adipose tissue - glycolysis
2) Liver - GLYCEROL KINASE (converts glycerol --> glycerol phosphate) reaction OR glycolysis
(TAG Synthesis) FA must first be activated by thiokinase to form?
Fatty acyl CoA
- subsequent reactions add two FAs, followed by dephosphorylation
What is the fate of TAG in the liver and adipocytes?
Adipocytes - Energy reserve
Liver - TAG is packaged as
which deliver lipids to the peripheral tissues
How does fatty acid degradation occur?
BETA-oxidation (MITOCHONDRIAL PATHWAY)
*cleaves between the #2-#3 carbon so removing 2 carbons
Can Long-Chain Fatty Acyl CoA be transported from the outside to the inside of the mitochondria?
**Carnitine shuttle is needed
What enzyme brings Long-Chain Fatty acyl CoA through the outer mitochondrial membrane? Inner mitochondrial membrane?
Outer = Carnitine Palmitoyl-transferase 1 *
Malonyl CoA INHIBITS it
Inner = Carnitine Palmitoyl-transferase 2
Number of ATPs produced/TCA
3NADH --> 3x3
(1)FADH2 --> 1x2
(1) GTP --> 1x1
Total = 12 ATP
Is the coenzyme form of Vitamin B12 (Deoxyadenosyl cobalamin) need in ODD Chain FA degradation?
YES works with the enzyme Methylmalonyl CoA mutase
creates Succinyl CoA
lose an ATP
Net total ATP produced with 15 carbon FA? 16 carbon FA?
15 - 105ATP
16 - 131 ATP
Can even-chained FA's produce glucose? Can Odd-chained FA's produce glucose?
Even - NO (pyruvate --> acetyl CoA irreversible)
Odd - Yes (Succinyl CoA --> oxaloacetate, a participant in gluconeogenesis)
(Decreased transport of Very Long Chain FA --> Increased accumulation)
Deficiency of alpha-hydroxylase
* Branched-chain alpha-oxidation (alpha-hydroxylase active)
Acute Fatty Liver of Pregnancy
Beta-Oxidation enzymes are overwhelmed
(Disorder oxidation of FA by maternal mitochondria, leading to accumulation of medium- and long-chain FA deposits within heptaocytes)
Energy source when glucose not available or used
FA --> Beta-Hydroxybutyrate (ketone body)
Ketoacidosis in Diabetics who do not take insulin
KETONE Bodies produced and can pass the BBB, BRAIN can use it
Can all peripheral tissues use ketone bodies?
Liver can't because it does not contain the enzyme THIOPHORASE (breaks down Acetoacetate --> Acetoacetyl CoA, 2 acetyl CoA/TCA)
C27H46O (very hydrophobic w/ 1 polar head, OH on 3 carbon)
- Steroid Nucleus (A,B,C,D) rings
- 2/3 Cholesterol Ester in plasma
- 1/3 Free cholesterol
increased serum cholesterol associated with atherosclerosis
Does cholesterol effect MEMBRANE fluidity?
- reduces membrane fluidity by reducing phospholipid movement
- hinders solidification at low (rm) temp.
What is cholesterol a precursor to?
1) Bile Acids and Salts
- Aids in Fat digestion
2) Precursor to Steroid
- Glucocorticoids: cortisol
- Mineralocorticoids: Aldosterone
- Sex hormones: Testosterone & Beta-estradiol
3) Precursor to Vit. D.
- 7 dehydrocholesterol --> Vit. D3
What should cholesterol intake be? Foods that have <100mg.
Beef, chicken, turkey in small (3oz) <100mg
Liver (synthesizes cholesterol) = highest cholesterol
What are the sources of NADPH for Cholesterol Synthesis?
1) Pentose Phosphate Pathway (HMPS):
- Glucose-6P DH
- (6-P gluconate DH)
Produces 2 moles of NADPH for every 1 mole of Glucose-6P
2) Malic Enzyme
- Malate --> Pyruvate + CO2
Malic enzyme = NADP+ (dependent Malate DH, cytosolic)
What are the sources of ATP for cholesterol synthesis?
Aerobic metabolism of glucose and proteins
1) Glucose --> 30-32 molecules of ATP
2) Fat metabolism --> 106 ATP (C16)
3) Proteins --> TCA or Ketone Bodies
Where is cholesterol synthesized?
By most tissues
- Highest in liver, Adrenal Cortex, reproductive
- Tissues and intestines
- Cytosolic and membrane of ER
What is Cholesterol made from?
1) Fat oxidation
2) Ketogenic amino acid
What is the rate-limiting reaction of cholesterol synthesis?
target for anti-cholesterol medication
integral protein of ER membrane
What is needed to make 3-Hydroxy-3methylglutaryl CoA (HMG CoA)?
(3) acetyl-CoA + HMG-CoA Synthase
(cytosolic, HMG-CoA reductase) - CHOLESTEROL synthesis
(mitochondrial, HMG-CoA lyase) - Ketone body synthesis
HMG-CoA Reductase (integral protein of endoplasmic reticulum membrane)
Rate limiting for cholesterol synthesis
Target of Drug therapy
HMG CoA --> (HMG CoA reductase + 2 NADPH) releases CoA --> Mevalonic Acid
Regulation of HMG-CoA Reductase
1. Regulation of Gene Expression (Sterol-Dependent; Cholesterol)
- Cholesterol "sensing"
2. Protein Degradation (Proteolysis)
- Increase in cholesterol --> INCREASE in UBIQUITIN-labelling and degradation of HMG-CoA
Increase in cholesterol --> decrease liver HMG-CoA reductase enzyme
3. Covalent modification via PHOSPHORYLATION
- (UNDER LOW ENERGY, AMPK- AMP-activated protein Kinase) --> Inactivates HMG-CoA reductase + Acetyl-CoA carboxylase
Allows for acetyl-CoA to feed into TCA for energy
4. Hormonal regulation (Sterol-Indepenedent)
- Insulin (+) HMG-CoA expression
- Glucagon (-) HMG-CoA
Competitive Inhibitor of HMG-CoA Reductase
- Lipitor - Atorvastatin
- Zocor - Simvastatin
- Vytorin: Simvastatin + Ezemtimibe (NOT only blocks production of cholesterol but inhibits absorptions as well)
Genetic Deficiency in Cholesterol Synthesis
- craniofacial anomalies, delayed myelination, cleft palates, genital malformations, congenital heart defects
Mutations in DHCR7 gene: 7-dehydrocholesterol reductase; final step in cholesterol synthesis
-Most common in Caucasians from Slovakia and Czech Republic
Composed of: Lecithin, BILE Salts, Bilirubin
Synthesized - Liver and secreted OR
Bile Salts stored in Gallbladder until needed, sent to intestines via duct
Common Bile Acids (Primary)
Made by the Liver
1) Cholic Acid
2) Chenodeoxycholic Acid
Common Bile Acids (Secondary)
Intestinal Flora or bacteria
1) Deoxycholic Acid
2) Lithocholic Acid
Conjugation of acids --> Salts
- Cholic acid + Glycine
- Chenodeoxycholic acid + Taurine
-Made from cholesterol
- Detergent properties
Only significant way to remove CHOLESTEROL from body is via Bile Salts
Gallbladder stores and concentrates bile: releases it when signaled by CHOLECYSTOKININ
Regulation of Bile Acid Synthesis
Maintain cholesterol homeostasis
(+) Cholesterol; substrate
(-) Cholic; product
What are the Functions of Bile Acids and Salts
2) Solubilization of fats
3) Absorption and Transport of fat-soluble vitamins (A, E, K)
Enterohepatic Circulation of Bile Salts and Acids
1. >95% of bile acids and salts reabsorbed via portal blood
2. Bile Acids carried by ALBUMIN in blood back to liver
3. Removed by Liver parenchymal
4. Intestinal Flora
- Remove glycine and taurine --> bile acids
- Primary --> Secondary Bile Acids
Absorbed in Ileum as Bile Acids
too much cholesterol in bile w/out enough lecithin or bile salts for solubilization --> Precipitation in GALLBLADDER
Cholesterol Gallstones - MOST COMMON
- Bilirubin gallstones
Bile Acid Sequestrates
Colestipol & Colesevelam( also showed to lowered blood glucose)
- MORE CHOLESTEROL is used to produce BILE SALTS and serum cholesterol is LOWERED; lower LDL Cholesterol levels
What is a Lipoprotein Composed of?
Lipids + Apoproteins
CORE - (TG) triacylglycerols and (CE) Choesteryl esters
Outer Shell -
1) Apoproteins (amphipathic)
3) Non-esterified cholesterol (-OH near outside)
Transport Lipids in serum
Keep lipids soluble in serum
Have 5 major groups: A thru E
1) Provides RECOGNITION sites for cell-surface receptors
- (B-100) for LDL
2) ACTIVATES ENZYMES activity
- (C-2) for lipoprotein lipase
- (A-I) for LCAT (lecithi: cholesterol acyltransferase)
Synthesized on RER
Order of Lipoproteins Size and Density
1. Chylomicrons (Largest and Least Dense)
4. HDL (smallest and Most Dense: Highest amount of Apoproteins)
Lipoproteins: Electrophoretic Mobility (Origin -> Anode (+))
Origin - 1) Chylomicrons
2) Beta: LDL
3) pre-Beta: VLDL, Lipo (a)
ANODE (+) - 4) HDL (Alpha-Lipoprotein)
carries DIETARY lipids to peripheral tissues (peripheral = anything that is not the liver)
- assembled INTESTINES
- 90% TAG
- ApoB-48 (synthesized in intestines)
- Apo C-2 (activates Lipoprotein lipase)
- Apo E3 (needed for RECOGNITION by receptor - LIVER; E3/4)
carries HEPATIC lipids to peripheral (extrahepatic) tissues --> LDL
- produced by the LIVER
- ApoB-100 (synthesized in Liver)
- Apo C-2 (activates Lipoprotein Lipase)
- Apo E (Liver Recognition)
**TAG are exchanged with HDL for CE via (CETP -> IDL)
HTGL further hydrolyzes TAG from IDL which now has concentrated CE --> LDL
carries CHOLESTEROL to peripheral tissues (LDL-C)
VLDL remnant (IDL) --> LDL
REMOVES free cholesterol from extrahepatic tissues (HDL-C)
- formed in BLOOD
- Reservoir of ApoC-2 and ApoE for chylomicrons and VLDL
- Apo A-1 (made in liver and intestines)
- ABCA1 draws free cholesterol to HDL3 (unesterified cholesterol)
- PCAT/LCAT activated by ApoA-1 which esterifies cholesterol (making HDL 2)
HDL 2 recognized by LIVER receptor SR-B1
What does the presence of ApoE4 isozyme mean?
Predisposing genetic risk factor for late-onset Alzheimer's
ApoB Gene RNA editing in Intestines
ApoB- 100 and ApoB-48 made from same gene
- Intestine changes mRNA to a stop codon --> 48% of translation: ApoB-48
CETP (cholesterol Ester Transfer Protein)
Transfers CE from HDL --> VLDL
Increases (CE) in VLDL
Transfers TAG from VLDL --> HDL
CETP in plasma
Hepatic Steatosis (fatty liver)
- Imbalance between TG synthesis and VLDL secretion
- Seen in Obesity, IDDM (insulin dependent diabetes mellitus), and alcoholics
HDL3 vs. HDL2
HDL3 (discoidal unesterified cholesterol) vs
HDL2 (spherical - MATURE)
LCAT (PCAT) Reaction
Lecithin/Cholesterol Acyl Transferase activated by A-1 --> Cholesterol remains in HDL
Low HDL? Avg? Amount needed to protect against heart disease?
Low HDL * At risk for HEART disease
1) Men <40mg/dL
2) Women <50mg/dL
1) Men (40-50mg/dL)
2) Woman (50-60mg/dL)
Protection against Heart disease >60mg/dL
CHOLESTEROL transport to extrahepatic tissues
- CE, C >> TAG
- 40% carried to extrahepatic tissue for lipid synthesis
1) Steroid synthesis
2) Vitamin D synthesis
3) Membrane synthesis
- 60% taken up by liver
ApoB-100 on LDL for receptor recog. (ApoB-100/E-receptor)
- Stored in liver as cholesterol ester
LDL uptake (LDL receptor)
Glycoproteins (Neg. Charge) clustered at CLATHRIN coated pits on cell surface
- Integral protein: recognizes ApoB-100/E
LDL Uptake (After internalization)
1) As pH falls (H+ ATPase) LDL receptor recycles back to membrane
2) Hydrolysis by lysosomal enzymes
- Amino acids
- Fatty Acids
- Cholesterol (esterified by ACAT); gets stored in the liver
Esterification of Cholesterol
cholesterol esterified for storage in the cell
Enzyme (ACAT) Acetyl CoA:Cholesterol Acyltransferase
What are the three ways that Cellular Cholesterol Homeostasis is regulated?
- Under HIGH cholesterol --> HMG-CoA reductase DECREASED, no new cholesterol synthesis
- Under HIGH cholesterol --> LDL receptors (DOWN regulated) *
2) Inhibition of Cholesterol
- Under HIGH cholesterol --> HMG-CoA reductase DECREASED
3) Esterified of Cholesterol for storage
- Under HIGH cholesterol --> INCREASES ACAT activity
What things oxidize LDL --> oxLDL
2) Nitric Oxide
3) Hydrogen Peroxide
4) Other oxidants
What are antioxidants?
1) Vitamin E
2) Ascorbic Acid
4) Other antioxidants
Why are macrophages able to uptake oxidized LDL?
Contain "scavenger receptors": SR-A
SR-A is NOT down-regulated by cholesterol as seen in LDLreceptors
**Oxidation or other modifications of LDL are CHEMOTACTIC for monocytes, induce migration, initiate inflammatory responses, ALTER the ENDOTHELIUM (INJURY)
What is the process of forming an Atherosclerotic plaque?
OxLDL cholesterol esters accumulate in macrophages --> FOAM cells --> Fatty streak --> Atherosclerotic plaque
What symptoms are precursors for Plaque Development?
2) Elevated LDL, chylomicron remnants
3) Low HDL
4) Cigarette smoking
5) High glucose
What does Aspirin effect to reduce plaque development?
Reduces the synthesis of Thromboxane (platelet activator) --> can reduce heart attacks
Total Blood Cholesterol should be?
Optimal LDL level? Optimal for person w/ history of heart disease?
Optimal LDL - Under 100mg/dL
Optimal for person w/ history of heart disease - Under 70mg/dL
Borderline High? High? Very High LDL?
Borderline High - (130-159mg/dL)
High - (160-189mg/dL)
Very High - (>190mg/dL)
Low HDL level for Men? Women?
Men - (< 40mg/dL)
Women - (< 50mg/dL)
Low HDL Cholesterol - MAJOR factor for heart disease
What is High HDL that will protect against Heart Disease?
60mg/dL and above
Exercise INCREASES HDL levels
Total Cholesterol- (<200mg/dL)
LDL (Bad) - (<100mg/dL)
HDL (Good) - ( >40mg/dL)
Triglycerides - (<150mg/dL)
Lipoprotein (a) **Little a is a marker for?
Major risk factor in Cardiovascular disease and plaque formation
consists of a LDL-like particle
Type 1 Hyperlipoproteinemia
Familial LIPOPROTEIN LIPASE deficiency
Accumulation of CHYLOMICRONS in plasma
Serum appears MILKY
- NO lipid deposits (no xanthomas)
**"Familial - Genetic"
Type 2a Hyperlipidemia
Familial Hypercholestrolemia (FH)
Deficiency in functioning LDL receptors
ELEVATED LDL and plasma cholesterol
XANTHOMAS- cholesterol deposits
BLOCKAGE IN RIGHT CORONARY ARTERY
Type 3 Hyperlipoproteinemia
Familial Dysbetalipoproteinemia or remnants disease
- Homozygous for ApoE2: low affinity binding
- Hypercholesterolemia and premature atherosclerosis
-"Broad Beta Disease"
Lipid deposits primarily located in PALMAR CREASES
HyperLipidemia Type 4
Overproduction and decreased clearance of VLDL
- Characterized by HIGH blood triglyceride levels and obesity, usually with mild diabetes (>200mg/dL)
Associated with an increased risk for coronary atherosclerosis
Hyperlipidemia Type 5
Increase VLDL production AND Decrease LPL production
- Hypertriglyceridemia and Hyperchylomicronemia
Chylmicrons and VLDL elevated
- Defective ABCA1 transporters (used to transport cholesterol out of cells)
Tonsils appear orange-yellow and are ENLARGED due to cholesterol deposits
- Marked REDUCED levels of HDL
- Inability to esterify cholesterol
Total FREE CHOLESTEROL increased in tissues
- Diffuse corneal opacities (FISH-EYE DISEASE; Partial LCAT deficiency)
- Hepatomegaly, Splenomegaly, Hemolytic Anemia, Renal Failure
PCAT or LCAT
Lecithin Cholesterol Acyl Transferase
- Esterifies cholesterol on surface of HDL
Cholesterol Ester Transfer Protein
- Transfer of cholesterol to HDL from VLDL and LDL in exchange for TG
Acyl cholesterol acyl transferase
- Esterifies cholesterol w/in the Liver
ATP-binding cassette protein: transports cholesterol out of peripheral tissues
Simplest structure - Phosphatidic Acid (PA)
Formed from - PA + an Alcohol (OH)
1) 2 FA (hydrophobic tail)
2) Glycerol (backbone)
3) Phosphodiester link
4) Polar head
Examples of Glycerophohspholipids
1) Serine + PA --> phosphatidylserine
2) Ethanolamine + PA --> phosphatidylethanolamine (PE)
3) Phasphatidylcholine (PC)
4) Phosphatidylinositol (PI)
5) Phosphatidylglycerol (PG)
Cardiolipin is elevated in what type of infection?
Syphillis (Trep. Pallidum)
- two phosphatidic acids (1,2) esterified through phosphate to and additional molecule of glycerol (3)
ONLY ANTIGENIC glycerophospholipid
- Important component of inner Mt. membrane and bacterial membrane
Sphingophospholipids are different from glycerophospholipids because?
Sphingosine backbone (rather than glycerol) --> an amino alcohol
myelin - surrounds nervous tissue
Ceramide + Choline via Phosphate
- (Ceramide = FA + sphingosine linked by amide bond)
Phosphatidic acid Synthesis
- 2 FA's are esterified to the activated glycerol
(Intermediate in TAG synthesis in liver, adipocytes, mammary glands, intestines)
How are ethanolamine and choline obtained?
From diet or from recycling pathways
- PE and PC (most abundant phospholipids)
- Choline phosphate or ethanolamine phosphate is transferred from the CDP to DAG
DPPC (dipalmitoyl-PhosphatidylCholine) = Lecithin
- Palmitate at carbons #1 and 2 of glycerol
- Maintains surface tension in lung alveoli to prevent collapse (ATELECTASIS)
Respiratory Disease Syndrome (RDS)
"Hyaline Membrane Disease"
- Insufficient amount of DPPC
- Lecithin-to-sphingomylein (L/S ratio)
*(L/S) ratio < 2 = potential risk of RDS
Risk = 75-80% when (L/S) ratio is 1.5
presence of (PG) phosphatidyglycerol indicates fetal lung maturity
What is phosphatidylinositol (PI) used for?
Membrane signal transmission
Phospholipase C degrades --> IP3 and DAG (Protein Kinase C)
- Sphingomyelinase deficiency
- Autosomal recessive
- Lysosomal storage disease
A) Increase sphingomyelin, FOAM cells, CNS issues, early death
B) Less sever variant; chronic
C) Hepatosplenomegaly, MUTANT membrane transporter in lysosomal system, Increase cholesterol and glycolipid deposits
1) Antiphospholipid Antibody Syndrome
2) Leiden Variant
Antiphospholipid Antibody Syndrome
thrombosis in artery and Vein (with LUPUS)
- autoimmune antibodies (ANTICARDIOLIPIN and LUPUS anticoagulant)
- associated with decreased prostacyclin --> INCREASED platelet clumping
Leidan variant of clotting factor V --> cannot be turned off --> THROMBOPHILIA (only veins)
Don't give birth control to women with leidan variant
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