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313 Cards in this Set

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AA precursors of cathecolamines
Tyrosine, phenylalanine
AA precursor of serotonin
Tryptophan
What are the branched-chain AA
Valine, leucine, isoleucine
What are the acidic, negatively charrged AA
Aspartate, glutamate
What are the positively charged basic AA
Lysine arginine, histidine
AA used as site for O-linked glycosylation
Serine, threonine
AA used as site for N-linked glycosylation
Asparagine
Sulfur-containing AA
Cysteine, methionine
Essential AA
Arginine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine
What is Vmax?
The maximum rate possible to achieve with a given amount of enzyme
What is Km?
The substrate concentration required to produce half of Vmax
What does a high Km mean? Low Km?
High Km = low affinity; low Km = high affinity
What effect do competitive inhibitors have on Km?
Increase Km
What effect do noncompetitive inhibitors have on Vmax?
Decrease Vmax
What effect does increasing the enzyme concentration have on Vmax?
Increase Vmax
Mechanism of action: Gs receptor
1. Activates adenyl cyclase; 2. Increased cAMP; 3. Phosphorylation of protein kinase A and CREB
Mechanism of action: Gi receptor
1. Inhibits adenyl cyclase; 2. Decreases cAMP
Mechanism of action: Gq receptor
1. Activates phospholipase C; 2. Releases IP3 and DAG from membrane; 3. IP3 releases intracellular Ca+; DAG activates protein kinase C
Mechanism of action: tyrosine kinase receptor
1. Receptor binding by insulin, EGF, PDGF activates intrinsic tyrosine kinase on intracellular domain; 2. Insulin receptor substrate binds tyrosine kinase; 3. Activates SH2 domain proteins: PI-3 kinase (translocation of GLUT-4), p21RAS
Mechanism of action: 1,25 DHCC
Binds its zinc finger intracellular receptor in intestinal cells, which binds response elements in enhancer regions to induce synthesis of calcium binding proteins
Synthesis of vitamin D
1. UV light activates D3; 2. Liver 25 hydroxylase --> 25-HCC; 3. Kidney 1-a-hydroxylase induced by PTH --> 1,25 DDCC
Biochemistry of vision
1. When rhodopsin Gt receptor is not stimulated by light, there are high levels of GMP in the rod cell. GMP activates Na-gated channels which partially depolarize the rod, releasing inhibitor glutamate on bipolar cells of optic nerve. 2. Upon light stimulation, rhodopsin Gt receptor decreases GMP, hyperpolarizes the cell and stops glutamate inhibition of bipolar cells
Enzymatic action of y-glutamyl carboxylase
Introduces Ca+ binding sites by vitamin K-dependant carboxylation of glutamic acid
Mention the vitamin K-dependant factors
Factors II (prothrombin), VII, IX, X
Transport kinetics of GLUT-1
Low Km. At normal glucose concentrations GLUT-1 is at Vmax. Mediates glucose uptake in most tissues
Transport kinetics of GLUT-3
Low Km. At normal glucose concentrations GLUT-3 is at Vmax. Mediates glucose uptake in most tissues
Transport kinetics of GLUT-2
High Km. When glucose concentration drops below Km, the remainder glucose leaves the liver and enters the peripheral circulation. Located in hepatocytes and pancreatic beta cell.
Transport kinetics of GLUT-4
Insulin upregulatess expression of GLUT-4, increasing Vmax. Located in addipose tissue and muscle
Compare glucokinase Vs. Hexokinase
Both trap glucose into the cell by phosphorylation. Hexokinase is expressed by most tissues, has low Km, glucose-6-phosphate inhibits I (raises Km). Glucokinase is found in the liver and pancreas B-cell, high Km, induced by insulin in hepatocytes (increase Vmax)
Under which influence do phosphofructokinase inhibit the rate of glycolysis
Under the influence of glucagon (PFK-2) (increase cAMP/protein kinase A/phosphorylation) and ATP/citrate (PFK-1). Phosphorylated states noncompetitively inhibit PFK, lowering Vmax, lowering rate of glycolysis
PFKs are stimulated under the influence of what substances
Insulin-mediated dephosphorylation (PFK-2), AMP (PFK-q), fructose 2,6BP (PFK-1). Increase Vmax and rate of glycolysis
Rate-limiting enzyme in glycolysis
PFK-1, converts fructose-6P into fructose-1,6BP
What effect does increasing B-cell glucokinase Km have on glucose metabolism? Decrease Km?
An increased glucokinase Km (gene mutations), decreases production of insulin (MODY) and hyperglycemia because low glucose concentration in the cell (GLUT-2 has high Km) are not phosphorylated, thus cell doesn’t sense glucose and doesn’t produce insulin. A decreased glucokinase Km produces insulinemia and hypoglycemia.
Glyceraldehyde 3-P dehydrogenase
Oxidation of Glyceraldehyde-3P and reduction of NAD. Produces 1,3-BPG and NADH
3-PG kinase
Phosphorylates ADP using energy from 1,3-BPG. Produces ATP and 3-PG.
Pyruvate kinase
Substrate-level phosphorylation of ADP using energy from PEP. Produces pyruvate and ATP. Activated by fructose-1,6BP.
Lactate dehydrogenase
Oxidation of NADH producing lactate and NAD from pyruvate
Mention 3 irreversible reaction in glycolysis
1. Glucose + glucokinase/hexokinase --> glucose-6P; 2. Fructose-6P + PFK-1 + ATP --> Fructose-1,6BP; 3. PEP + pyruvate kinase --> pyruvate + ATP
Mention the 2 substrate-level phophorylations in glycolysis
1. 1,3BPG _ phosphoglycerate kinase --> 3PG + ATP; 2. PEP + pyruvate kinase --> pyruvate + ATP
Reactions in the malate shuttle
OAA + NADH (cytoplasm) --> malate + NAD; malate enters mitochondria
Reactions in the glycerol-3P shuttle
DHAP + NADH --> glycerol-3P + glycerol-P dehydrogenase + FAD --> FADH2 (inner membrane/ETC/CoQ)
Substrates used for substrate-level phosphorylations in glycolysis
1,3-BPG, PEP
Oxygen dissociation curve behavior in high altitude
Low PO2 produces hyperventilation and respiratory alkalosis which shifts curve to the left (lowers p50). Rate of glycolysis increases producing more 2,3-BPG (12-24 hours) shifting the curve to normal p50
Effect of pyruvate kinase deficiency on RBC
2,3-BPG and p50 increase, Hb may not be fully saturated in the lungs. Decrease in ATP stimulates PFK-1 in RBC and rate of glycolysis increaes. RBC looses biconcave shape and is hemolised by spleen. Na/K ATPase activity decreases causing osmotic fragility and lysis.
Metabolism of galactose
Lactose -- glucose + galactose + galactokinase --> galactose-1P + gal-1P-uridyl transferase --> glucose-1P
Pathophysiology of cataracts in galactosemia
Galactose is converted to galactiol by aldose reductase in the lens. In diabetes glucose is also converted to sorbitol by the same enzyme.
Pathophysiology of hyperbilirubinemia in galactosemia
If galactokinase is present, galactose-1P is trapped in hepatocyte causing cirrohsis
Deficiency of aldolase B
Fructose-1P (produced by fructokinase) gets trapped in hepatocyte and proximal tubule producing jaundice and renal failure
Pyruvate dehydrogenase
Converts pyruvate to acetyl-CoA in the mitochondria for citric acid cycle and fatty acid synthesis. Requires NAD, FAD, CoA and thiamine. Negative feedback by acetyl-CoA.
Thiamine deficiency
Impairs citric acid cycle/glucose oxidation in highly aerobic tissue first (brain and heart) because of decreased pyruvate dehydrogenase activity and alpha-ketoglutarate dehydrogenase. Ataxia, nystagmus, memory loss, confabulation psychosis, cerebral hemorhage
Rate-limiting enzyme of oxidative phosphorylation
Isocitrate dehydrogenase. Inhibited by NADH and ATP, activated by ADP.
Synthesis of alpha-ketoglutarate
Isocitrate + NAD + isocitrate DH --> a-ketoglutarate + NADH + CO2
Enzymes that require thiamine, lipoic acid, NAD, FAD, CoA
Pyruvate DH, a-ketoglutarate DH
Product of a-ketoglutarate DH
Succinyl CoA + NADH
Heme synthesis requires the product of this reaction
a-ketoglutarate + NAD + a-ketoglutarate DH --> succinyl CoA + NADH + CO2
Substrate-level phosphorylation reaction of oxidative phosphorylation
Succinyl CoA + GDP + succinyl CoA synthetase --> succinate + GTP
FADH2 is produced in this reaction of oxidative phosphorylation
Succinate + FAD + succinate DH (complex II) --> fumarate + FADH2
Substrate from oxidative phosphorylation used for fatty acid synthesis
Citrate (citrate shuttle)
Malate shuttle reaction in oxidative phosphorylation
Malate + NAD + malate DH --> OAA + NADH
Order of oxidative phosphorylation intermidiate synthesis
Citrate, isocitrate, a-ketoglutarate, succinyl CoA, succinate, fumarate, malate, OAA
High-energy intermediates that produce NADH in oxidative phosphorylation
Isocitrate, a-ketoglutarate, malate
Complex I of ETC. Activators and inhibitors.
NADH dehydrogenase. Activated by NADH, inhibited by barbiturates and rotenone.
Complex II of ETC
Succinate dehydrogenase
Electron donors to CoQ
Succinate DH (FADH2), glycerol-P shuttle (FADH2), fattyacyl CoA DH (FADH2), NADH dehydrogenase (electron)
Complex III of ETC
Cytochrome b/c1
Complex III passes electrons to this protein
Cytochrome C
Complex IV of ETC. inhibitors, cofactors.
Cytochrome oxidase (cyt a/a3). Inhibited by cyanide, CO. Requires Cu+.
Mechanism of action of ETC uncouplers
Increase permeability to H+ decreasing the proton gradient of inner mitochodrial membrane. Decreases ATP synthesis, increases O2 consumption and oxidation of NADH, releases heat.
Uncouplers
2,4-dinitrophenol, aspirin and salicylates, UCP (thermogenin) of brown adipose tissue.
Mechanism of ATP synthesis in ETC
Energy from a proton passing through Fo inner membrane channel is used by F1 component (ATP synthetase) to phosphorylate ADP. (Proton gradient has potential kinetic energy)
ATP yielded by NADH and FADH2
NADH yields 3 ATP. FADH2 yields 2 ATP.
ATP per glucose yielded by anaerobic glycolysis
2 ATP/glucose
ATP per glucose yielded by aerobic glycolysis via malate shuttle
Yields 8 ATP/glucose
ATP per glucose yielded by aerobic glycolysis via glycerol-P shuttle
Yields 6 ATP/glucose
Effect of tissue hypoxia on ETC and cell
Hypoxia decreases the rate of ETC and ATP production, leading to anaerobic glycolysis, lactic acidosis and cell membrane damage due to decreased ATPase activity
Outcome of ETC inhibition
1. Decreased oxygen consumption; 2. Increased intracellular NADH and FADH2; 3. Decreased ATP
Mechanism of action of cyanide inhibition of ETC
Cyanide irreversibly binds to cytochrome a/a3
What are sources of cyanide?
Burning polyurethane. Byproduct of nitroprusside (thiosulfate can be used to destroy cuanide).
Antidote for cyanide poisoning
Nitrites convert hemoglobin to methhemoglobin which binds cyanide in the blood before it reaches tissues
Mechanism of CO poisoning
Binds cytochrome oxidase and displaces oxygen from hemoglobin
Important reaction in oxidative stress
O2 + NADPH oxidase --> superoxide radical
superoxide radical + superoxide dismutase --> H2O2
H2O2 + catalse --> H2O + O2
H2O2 + Cl- + myeloperoxidase --> hypochlorite
How does cyanide poisoning inhibit glycolysis?
Complex Iv is inhibited, NADH acumulates and inhibits isocitrate DH, citrate acumulates and inhibits PFK-1
Name of the core glycogen protein
Glycogenin
Metabolic regulation of glycogen synthetase
Activated by glucose and insulin (in liver) and insulin (in muscle). Inhibited by glucagon and epinephrine (in liver) and epinephrine (muscle)
Activation of glucose
Glucose 1-P --> UDP-glucose. Irreversible reaction
Synthesis of glycogen
Linear chain of glucose residues with alpha 1,4 bonds created by glycogen syhtetase. Branches by branching enzyme hydrolization of alpha 1,4 bonds and attachment with alpha 1,6 bond
Metabolic regulation of glycogen phosphorylase
Activated by epinephrine and glucagon (in liver). Epinephrine, AMP and Ca+ (in muscle). Inhibited by insulin (liver), insulin and ATP (in muscle)
Reactions of glycogenolysis
Glycogen phosphorylase irreversibly hydrolizes alpha 1,4 bonds releasing glucose 1-P. Debranching enzyme hydrolizes alpha 1,4 bonds adjacent to branch and moves oligoglucose to main chain then hydrolizes the alpha 1,6 bond releasing a free glucose
Glucose 6 phosphatase
Converts glucose 1-P to glucose 6-P
In which condition is glycogen synthesis active in spite of high levels of glucagon and epinephrine?
Von Gierke disease. Profound hypoglycemia, so glucagon is high but glucose-6P stimulates glycogenesis.
Von Gierke disease
Deficiency of glucose 6 phosphatase. Severe hypoglycemia, lactic acidosis, hepatomegaly, hyperuricemia
McArdle's disease
Muscle glycogen phosphrylase deficiency. Exercise intolerance, muscle cramping, myoglubinuria.
Pompe disease
Lysosomal alpha 1,4 glucosidase deficiency. Cardiomegaly, glycogen inclusion bodies.
Substrates for gluconeogenesis
Lactate --> pyruvate
Alanine + ALT --> pyruvate
Glycerol 3P from triacylglycerol
Pyruvate carboxylase
Requires biotin. Activated by Acetyl-CoA. Produces OAA which leaves mitochondria via malate shuttle.
PEPCK
Induced by glucagon and cortisol. Converts OAA to PEP requiring ATP.
Fructose 1,6 biphosphatase
Hydrolizes phosphate from fructose 1,6BP. Activated by ATP, inhibited by AMP and fructose 2,6BP
Metabolic control of gluconeogenesis
Glucagon and cortisol induce PEPCK via GRE and CREB. Glucagon inhibits PFK-2, decreasing fructose 2,6BP a negative inhibitor of fructose 1,6 biphosphatse. Insulin activates PFK-2 increasing fructose 2,6BP which inhibits fructose 1,6, biphosphatase
Source of ATP for gluconeogenesis
From B-oxidation (gluconeogenesis depends on B-oxidation)
Regulation of pyruvate carboxylase and pyruvate DH by acetyl CoA
Acetyl CoA activates pyruvate carboxylase and deactivates PDH
Hypoglycemia induced by alcoholism
Alcohol metabolism produces excess NADH which interferes with gluconeogenesis by 1. favoring lactate formation from pyruvate; 2. Shifting the malate shuttle into the mitochondria; 3. Forming glycerol 3P from DHAP
Biochemistry of fatty liver in alcoholics
Fatty acids in the liver react with glycerol 3P to form triglycerides which get stored in the liver. The source of glycerol 3P is from impaired gluconeogenesis by NADH.
Why doesn't muscle produce blood glucose by gluconeogenesis?
It lacks glucose-6 phosphatase which is only in the liver
Reactions in alcohol metabolism
Alcohol + alcohol DH --> acetaldehyde + NADH + acetyldehyde DH --> acetate and NADH. Two NADH are released.
Rate-limiting enzyme of hexose-monophosphate shunt. Inhibitor and activators.
G6PDH. Induced by insulin, inhibited by NADPH, activated by NADP
Only thiamine-requiring enzyme in the red blood cell
Transketolase. Converts fructose 6P and glyceraldehyde into sugar intermidiates for nucleotide synthesis in hexose-monophosphate shunt
Functions of NADPH
Biosynthesis. Maintenance of reduced gluthathione pool to protect against ROS. Bactericidal activity in PMN
Gluthathione reductase
Reduces gluthathione using NADPH
Gluthathione peroxidase
Oxidizes H2O2 using reduced gluthathione
Heinz bodies formation
H2O2 acumulates and denatures Hb because of lack of G6PDH and reduced gluthathione
Pathophysiology of G6PDH deficiency
Inadequate production of NADPH decreases the activity of gluthathione peroxidase which degrades H2O2 which denatures Hb (Heinz bodies) and peroxidate membrane lipids (hemolisis)
Chronic granulomatous disease
No production of superoxide radical in PMN to destroy catalase-positive organisms due to NADPH oxidase deficiency. Negative nitroblue tetrazolium test is diagnostic.
Important fatty acids
Linoleic acid: C18:2(9,12); Linolenic acid: C18:3(9,12,15); Arachidonic acid C20:4(5,8,11,14); Palmitic acid: C16:0
Trans fatty acids
Unnatural trans-double bonds are introduced by partial hydrogenation of vegetable oils to make them solid at room temperature (margarine). Associated with atherosclerosis
Cardio protective effects of Omega 3 fatty acids
Replaces some arachidonic acid in platelet membrane, decreasing production of platelet aggregator thromboxane A2
Fatty acid activation
CoA is attached by fatty acylCoA synthetase. Requires ATP.
Digestion of lipids
1. Bile emulsifies lipids; 2. pancreatic lipase, colipase and cholesterol esterase degrade lipids to 2-monoglyceide, fatty acids and cholesterol; 3. Absorbed and re-esterified to TG and cholesterol esters; 4. Packaged with Apo-B48 into chylomicrons
Regualtion of fatty acid synthesis by insulin
Increases production of acetyl CoA in the liver: glucokinase (induced), PFK-2/PFK-1 (PFK-2 dephosphorylated); Pyruvate DH (dephosphorylated). Fatty acid synthesis: acetyl CoA carboxylse (dephosphorylated), fatty acid synthetase (induced)
Citrate shuttle
Acetyl CoA + OAA + citrate synthase --> citrate --> cytoplasm --> cytrate + citrate lyase --> acetyl CoA + OAA. Acetyl CoA for fatty acid and cholesterol syhnthesis. OAA to malate for malate shuttle or pyruvate via malic enzyme
Malic enzyme
Converts malate into pyruvate releasing NADPH in cytoplasm for FA synthesis
Acetyl CoA carboxylase
Acetyl CoA + CO2 --> malonyl CoA in cytoplasm. Requires biotin. Activated by insulin and citrate. Rate-limiting in FA synthesis. The CO2 is not incorporated into FA because its removed by FA synthase.
Fatty acid synthase
8 malonyl CoA + NADPH --> palmitate + 8CO2. Requires panthothenic acid. Induced by insulin in cytoplasm.
Cytochrome b5
Desaturation of fatty acids. Can't introduce double bonds past carbon 9 of FA.
How is acetyl coA activated for FA synthesis?
Its carboxylated to malonyl CoA by acetyl CoA carboxylase (activated by insulin)
Sources of glycerol 3P for triglyceride synthesis
Reduction of DHAP by glycerol 3P DH in adipose and liver; phosphorylation of glycerol by glycerol kinase in liver. Glycerol kinase works under insulin (VLDL metabolism) or glucagon (lypolysis glycerol) influence.
Glycerophospholipids
A glycerol with 2 FA and a water soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidylinositol). Source of reservoir for membrane-bound second messengers diacylglycerol, IP3, arachidonic acid. Needed for membrane synthesis
ApoB-48
Secreted by epithelial cells of intestine along with chylomicrons to allow their exit to lymph and tissues
Chylomicrons
Teansport dietary triglyceride and cholesterol from intestine to lymph to tissues. Have ApoB-48 plus ApoC-II and ApoE donated by HDL.
VLDL
Synthesized in liver to transport newly synthesized triglycerides to tissues. Have ApoB-100 and ApoC-II/ApoE donated by HDL
ApoC-II
Activates lipoprotein lipase. Donated to chylomicrons and VLDL by HDL
ApoE
Allows hepatocyte endocytosis of chylomicron and VLDL remnants
ApoA-1
Carried by HDL, activates LCAT and PCAT (blood enzymes) to hydrolize fatty streak cholesterol by attaching a fatty acid to it (esterification) so that it dissolves into HDL for reverse transport from tissues to hepatocyte
ApoB-100
Allows VLDL to exit from hepatocyte
Lipoprotein lipase
In the luminal surface of capillary endothelium. Releases fatty acids from triglycerides carried by chylomicrons and VLDL. Activated by ApoC-II and induced by insulin
IDL
VLDL remnant that is picked up by hepatocyte through ApoE receptor or aquire more cholesterol from HDL to become LDL
LDL
Delivers cholesterol to tissues for membrane and hormone synthesis. 80% picked up by hepatocytes to make bile acids. Clathrin endocytosis mediated by ApoB-100/LDL receptor
Cholesterol feedback loops
HMG-CoA reductase negative feedback. ACAT postive feedback. Represses expression of LDL receptor
HDL
Carry ApoA-1 which activates blood LCAT to esterize cholesterol and dissolve it into its core allowing reverse transport of cholesterol from the periphery to liver.
LCAT
Activated by ApoA-1from HDL. Binds a fatty acid to cholesterol to produce an ester that dissolves into the HDL for reverse transport to liver
CEPT
Transfers HDL cholesterol to IDL
SR-B1 receptors
Transfers HDL cholesterol into steroidgenic tissues ( ovaries, testes, adrenal, hepatocytes)
Pathophsysiology of atherosclerosis
1. Endothelial lesion produced by blood turbulence, elevated LDL, free radicals from cigarette smoke, homocystenemia, diabetes (glycolation of LDL) and hypertension.; 2. Inflamed endothelium recruits monocytes and macrophages and platelet adhesion; 3. Production of ROS by macropahges oxidizes LDL; 4. Macrophages become cholesterol-laden (foam cells) after phagocytosis of LDL, producing fatty streaks; 5. Fatty streak enlarges with necrotic debris, lipids, epitheloid and smooth muscle cells producing an advanced plaque and ocluding blood vessel with subsequent ischemia; 6 The plaque can rupture with subsequent thrombosis
Vitamin E
Only lipid-soluble antioxidant, protects LDL from oxidation and peroxidation of membranes by ROS
MCC of elevated tricglyceride and chylomicrons
Type IV hyperlipidemia in diabetics. Low insulin levels fail to induce lipoprotein lipase
Familial lipoprotein lipase or ApoC-II deficiency
Type I hypertriglyceridemia. Red-orange xanthomas, fatty liver, acute pancreatitis, abdominal pain
LDL receptor deficiency
Type IIa familial hypercholesterolemia. Autosomal dominant. Atherosclerosis and CAD, xanthomas of achilles tendon, tuberous xanthomas, xanthelasmas, corneal arcus.
MCC of hypolipidemia
Abetalipoproteinemia (deficiency of ApoB-48 and ApoB-100). No serum chylomicrons, triglycerides or cholesterol. ADEK vitamin deficiency, steatorrhea, ataxia, pigmentary degeneration of retina, acanthocytes, loss of night vision
DeNovo cholesterol synthesis
2 Aacetyl CoA provided by citrate shuttle + NADPH --> acetoacetyl CoA + HMG-CoA synthase --> HMG-CoA + HGM-CoA reductase --> mevalonate -->--> farnesyl ppi -->--> cholesterol.
Farnesyl ppi
Cholesterol synthesis intermediate important for synthesis of CoQ, dolichol ppi for N-linked glycosylation and prenylation
Rate-limiting enzyme in cholesterol synthesis
HMG-CoA reductase converts HMG-CoA to to mevalonate. Insulin activates it by dephosphorylation, gene expression repressed by cholesterol, competitively inhibted by statins
MOA of cholestyramine
Increases elimination of bile salts, lowering cholesterol levels in hepatocyte which increases LDL receptor expression and clearing of LDL from blood
MOA of statins and important side effects
Increase HMG-CoA reductase Km. Decreases denovo cholesterol synthesis in hepatocyte which increases LDL receptor expression and clears LDL from blood. Side effects: decreased farnesyl ppi decreases synthesis of CoQ, decreasing ATP production. Myopahty, rhabdomyolisis, mioglobimuria
Hormone-sensitive lipase
Hydrolizes triglycerides to glycerol and fatty acids in adipose tissue. Activated by decreased insulin, increased epinephrine and cortisol. Inhibited by niacin.
Fatty acyl CoA synthetase
On the outer mitochondrial membrane, activates fatty acids by attaching CoA
Carnitine shuttle
CAT-1 on outer mitochindrial membrane tranfers fattyacyl group of activated fatty acid to carnitine. Carnitine transporter shuttle fattyacyl-carnitine into inner mitochindrial matrix. CAT-2 on inner membrane transfers fattyacyl to CoA. CAT-1 Is inhibited by malonylCoA from fatty acid synthesis
Why don’t fatty acids enter mitochondria after FA synthesis?
Under influence of insulin, increased acetyl CoA carboxylase produces malonyl CoA which inhibits CAT-1
fatty acyl CoaA dehydrogenase
Enzyme of B-oxidation in mitochondrial matrix. Oxidizes activated fatty acids to acetyl CoA producing FADH2 (for CoQ) and NADH (for NADH DH). Also called LCAD and MCAD. Inhibited by Ackee fruit.
Myopathic CAT deficiency
No FA for B-oxidation. Muscle aches and weakness, rhabdomyolisis, myoglobinuria, elvated muscle TG
rhabdomyiolysis, mioglobinuria, muscle weakness
Can be produced by either farnesyl ppi deficiency from cholesterol intermediate which is needed for CoQ synthesis and ETC, or by CAT deficiency which inhibits carnitine shuttle and B-oxidation
Cause of non-ketotic hypoglycemia
MCAD deficiency. No B-oxidation, decereased ATP for gluconeogenesis, hypoglycemia, decreased acetyl CoA lowers pyruvate carboxylase activity and limits ketogenesis. Profound fasting non ketotic hypoglycemia, dicarboxilic acidemia, C8-C10 acyl carnitines in the blood
True or false: fatty acids cannot be converted to glucose
True with exception: Odd carbon FA produce propionyl CoA which is converted to succinyl CoA and leave as malate to cytoplasm for gluconeogenesis
Enzyme requires B12
Methylmalonyl CoA mutase converts methylmalonyl CoA into succinyl CoA in propionic acid pathway. Deficiency of B12 produces megaloblastic anemia and methylmalonic aciduria
Propionyl CoA carboxylase
Converts propionyl CoA from odd-carbon B-oxidation into methylmalonyl CoA
What are the ketone bodies and what tissues metabolize them?
Acetoacetate and B-hydroxybutirate metabolized by muscle, cardiac muscle and renal cortex. Brain metabolizes them after 1 week of fasting
Important intermediate of ketogenesis
HMG-CoA produced from acetyl CoA by HMG-CoA synthase
HMG-CoA lyase
Converts HMG-CoA into acetoacetate in ketogenesis
Why cant the liver metabolize ketones?
It lacks succinyl CoA-acetoacetyl CoA transferase (thiophorase)
Why and when does brain switch to ketogenolysis?
After one week of fasting acetyl CoA production from ketogenolysis inhibits pyruvate DH
Milestones in brain energy metabolism
12 hours: glucose from glycogen; 1 week: glucose from gluconeogenesis; beyond 1 wek: ketone bodies
Who develops ketoacidosis?
Type 1 and Type 2 diabetics and alcoholics
How does an infection triger ketoacidosis in diabetics?
Increased cortisol and epinephrine activate hormone-sensitive lipase and increases B-oxidation and ketogenesis
Pathophysiology of alcoholic ketoacidosis
Chronic hypoglycemia favors ketogenesis in liver but muscle would rather use acetate from alcohol metabolism which increases ketoacids in blood
Urinary nitroprusside test
Detects acetoacetate in urine which could underestimate B-hydroxybutirate in ketoacidosis
Signs and symptoms of ketoacidosis
Polyuria, polydypsia (hyperglycemia and osmotic diuresis), coma, depletion of K+ (masked by hyperkalemia), decreased HCO3 fruity odor
Cherry-red spots in macula, blindness, psychomotor retardation, death before 2 years
Tay SaXhH. Deficiency of Hexosaminidase A. Ganglioside acumulates
Hepatosplenomegaly, bone erosion, fractures, pancytopenia
Gaucher. Glucocerebroside deficiency. Glucocerebroside acumulates.
Cherry-red macula spots, hepatosplenomegaly, microcephaly, retardation
Nieman PickS: Sphingomyelinase deficiency. Sphingomyelin accumulates
Glutamine synthetase
Captures excess nitrogen by aminating glutamate to glutamine. Located in most tissues.
Glutaminase
Located in kidney and intestine. Deaminates glutamine releasing amonia. In kidney it's induced by chronic acidosis and amonia combines to form amonium and its excreted. In the intestine, amonia is sent to liver via portal blood where it enters the urea cycle
Amination of alpha-ketoglutarate
Produces glutamate and alpha-ketoacid by aminotransferase (requires B6)
Amination of pyruvate
Produces alanine and alpha-ketoglutarate. Amino group donated by glutamate. Alanine aminotransferase requires B6 and its in muscle and liver
Amination of OAA
Produces aspartate for urea cycle in liver and alpha-ketoglutarate. Amino group donated by glutamate. Requires B6
Donation of amino group by glutamate produces what?
Donation to pyruvate produces alanine. Donation to OAA produces aspartate. Deamination by glutamate DH produces free amonia in liver for urea cycle
Donators of amonia to urea cycle
Intestinal glutamine is deaminated by glutaminase and goes to portal blood. Glutamate is deaminated by glutamine DH releasing free amonia
How does muscle nitrogen in alanine enter urea cycle?
Alanine donate to alpha-ketoglutarate to form glutamate which donates to OAA to form aspartate (in liver)
Glutamate DH
Deaminates glutamate to release free amonia for urea cycle and alpha-ketoglutarate for citric acid cycle
Non-glucogenic AA
Leucine, lysine (ketogenic)
Ketogenic and glucogenic AA
Phe, Tyr, Try, Ile, Thr
Mitochondrial urea cycle enzymes
Carbamoyl phosphate synthetase I, ornithine transcarbamoylase
Citrulline
Produced in mitochondria by ornithine transcarbamoylase using carbamoyl phosphate and ornithine. Leaves mitochondria and combines with aspartate in cytoplasm
Blood findings if there is a defect of the urea cycle
Hyperamonemia, elevated blood glutamine, decreased BUN
Carbamoyl phosphate
Substrate for ornithine transcarbamoylase (urea cycle) and aspartate transcarbamoylase in pyrimidine synthesis. If it acumulates it increases uracil and orotic acid in blood and urine (pyrimidine synthesis intermidiates)
This substance acumulates in ornithine transcarbamoylase deficiency
Carbamoyl phosphate. Produces hyperamonemia, decreased BUN, elevated glutamine, uracil and orotic acid
Sodium benzoate, phenylpyruvate
Treatment of urea cycle enzyme deficiencies. Provides alternative rout for capturing and excreting excess nitrogen
Phenylketonuria
Phenylalanine hydroxylase deficiency. Mental retardation, microcephaly, pale skin, blonde hair, musty odor. Avoid aspartame, monitor pregnancy
Alkaptonuria
"Black Homo". Dark urine, ochronosis. Homogentisate oxidase deficiency.
Maple syrup urine
Branched-chain ketoacid dehydrogenase deficiency. Lethargy, alternating episodes of hypertonia and hypotonia, odor of maple syrup urine, ketosis, coma.
Neonatal ketoacidosis
Propionyl coa Carboxylase or methyl malonyl CoA mutase deficiency. Cant metabolizr val, met, ile, thr through propyonyl acid cycle
Methylmalonic acidura
Methylmalonyl CoA mutase deficiency in propionic acid pathway
Reactions that require methyl groups
Epinephrine synthesis, N-methylguanosine cap on mRNA, synthesis of purines and thymidine
Methyl donors (one-carbon units)
SAM (S-adenosylmethionine); tetrahydrofolate
Activation of folate
Folate --> dihydrofolate + dihydrofolate reductase --> THF + 1-carbon unit --> active folate
Homocystinemia and homocystinuria
Produced by cysthathione synthase deficiency or homocysteine-methyl THF methyltransferase deficiency or folate/B12 deficiency. Cardiovascular disease, atherosclerosis, DVT, thromboembolism, ectopic lens
B12 deficiency
Megaloblastic anemia, neuropathy, homocystinemia, methylmalonic aciduria. Needed by methylTHF-homocysteine methyl transferase and malonyl CoA mutase. Pernicious anemia, D. latum
Folate deficiency
Megaloblastic anemia, homocystinemia. Found in alcoholism and pregnancy
What is the folate storage pool and what enzyme acts upon it?
Stored as reduced methylTHF. MethylTHF-homocysteine methyl transferase transfers methyl group to homocysteine to form methionine which produces one-carbon unit donor SAM
Vitamin B1
Thiamine. Deficiency --> Wernicke-Korsakoff, wet and dry Beri Beri. Required by dehydrogenases
Biotin
Required by carboxylases. MCC of deficiency is due to consumption of raw eggs (avidin)
Vitamin B2
Riboflavin. Precursor of FAD.
Vitamin B3
Niacin. Precursor to NAD and NADPH used by dehydrogenases.
vitamin B5
Panthotenic acid. Deficiency results in dermatitis, enteritis, alopecia.
Vitamin B6
Pyridoxine. Required for heme synthesis and transaminations
Pantothenic acid
Vitamin B5 precursor of CoA
B2 deficiency
Riboflavin. Deficiency results in angular stomatitis (inflamation of oral mucous lining), cheilosis (inflammation of lips), corneal vascularization, glositis, keratitis
Pellagra
Niacin (B3) deficiency results in diarrhea, dermatitis, dementia and glositis.
Wet (adult) beri beri
B1/thiamine deficiency. Heart failure (dilated cardiomyopathy) and edema (wet)
Dry (infantile) beri beri
B1/Thiamine deficiency. Muscle wasting, neuropathy, can also have cardiomegaly
Base excision repair
Glycosylase tags defective bases; endonuclease and lyase cleave out defective bases; DNA polymerase synthesizes new bases; ligase reseals the DNA.
Types of DNA damage
Thymine dimers (UV light); depurination (spontaneous or chemicals); breaks and oxidative damage (ionizing radiation); Cross-linkage, intercalation, alkylation (chemical/drugs)
Important enzymes in heme synthesis
ALA synthase (requires B6, negative feedback by heme; stimulated by barbiturates and alcohol); ALA dehydrase (inhibited by lead); uroporphyrinogen synthase (deficiency leads to acute intermittent porphyria); ferrochelatase (inhibited by lead)
What is responsible for higher O2 affinity of HbF?
Presence of serine instead of histidine in the 2,3BPG binding sites of the beta chains. Serine decreaes 2,3BPG binding to beta chains and increases affinity.
Metabolism of homocysteine
Can be converted to cysthathione by cysthathione synthetase and then cysteine (requires B6). Or it can be converted into methionine (requires B12 and 5-methylTHF)
HbC versus HbS
HbS is formed by replacement of glutamic acid by valine (neutral); HbC is formed by replacement of glutamic acid by lysine (positively charged). Therfore HbC moves less than HbS in electrophoresis.
Thymidilate synthetase
Makes dTMP which is the deNovo precursor of DNA nucleotides. Requires methylTHF
Cofactors required by dehydrogenases
FAD, NAD, thiamine, CoA, lipoic acid. Deficiencies of these results in lactic acidosis (piruvate DH) and maple syrup urine (branched-chain ketoacid DH)
Components of the LAC operon
Inducer (lactose), repressor (decreased by lactose), activator protein (activated by cAMP/high glucose)
Which substance acumulates in lead poisoning?
delta-ALA (the substrate of delta-ALA dehydrase)
Bohr effect
High CO2 in tissues increases carbonic anhydrase synthesis of protons which bind to Hb and decrease affinity for oxygen (releasing it). In the lungs, high PO2 releases the protons from the ionizable histidine residues at N-terminals of alpha and beta chains
Enzymes that require biotin
Carboxylases. Biotin deficiency leads to increased pyruvate (pyruvate carboxylase) that is converted to lactate --> lactic acidosis
Gluconeogenic enzymes
Pyruvate carboxylase, Fructose 1-6 biphosphatase, PEPCK, glucose-6-phosphatase
Ketogenic enzymes
AcetoacetylCoA synthase, HMG-CoA synthase, HMG-CoA lyase
beta oxydation enzymes
CAT-1, CAT transporter, CAT-2, MCAD/LCAD (fattyacylCoA DH), fattyacylCoA synthase
Elastin
Responsible for lung recoil and elasticity of tissues. Composed of glycine, valine and alanine. Secreted as tropoelastin which crosslinks with fibrillin (needs lysyl oxidase). Elastase breaks down cross-links, alpha-1-antitrypsin inhibit elastases.
Receptors/second messengers used by cytochines
MAP/JAK/STATS (intrinsic tyrosine kinase activity)
Receptors/second messengers used by atrial natriuretic peptide
Guanylate cyclase pathway
Receptors/second messengers used by TSH, PTH, glucagon
Gs --> adenyl cyclase --> increase cAMP
Phosphodiesterase
Inactivates cAMP
Positively-charged AAs
Arginine, histidine, lysine (all essential)
Polar AAs
Ser, thr, cys, met, asn, gln
Aromatic AAs
Tyr, phe (essential), trp
N-acetylglutamate synthase
Makes N-acetyl glutamate which is the allosteric activator of carbamoyl phosphate synthase I
Cofactor for phenylalanine and tryptophan hydroxylases
Tetrahydropterin (BH4)
N-acetyl glutamate
allosteric activator of carbamoyl phosphate synthase I
Fructose metabolism
Bypases PFK-1 and therefore has the highest metabolic rate
Molecular defect in Marfan
Fibrillin defect. Fibrillin is necessary for elasticity of tissues and suspensory ligaments of the lens (ectopic lens)
Metabolism of branched-chain AAs
All require BCAA-DH. Val and Ile are metabolized via propionic acid path; Leu via acetyl CoA
Tyrosine
Needed for catecholamine and homogentisate synthesis
Vitamin A toxicity
Alopecia, dry skin, hepatomegaly, hyperlipidemia
AAs metabolized via propionic acid path
Val, Ile, Thr, Met
Zellweger syndrome
Peroxisome deficiency with lack of long-chain FA metabolism. Hypotonia, seizures, hepatomegaly, retardation.
Inducers and inhibitors of ALA dehydrase
Alcohol, barbiturates, hypoxia are activators; Heme inhibits it, lead denatures it
Hartnup disease
Defective intestinal/kidney reabosorption of Try which is essential and required precursor of niacin. Pellagra-like symptoms and basic aminoaciduria
Telomerase
Reverse transcriptase adds TTAGGG telomers to chromosomes of pluripotent and dividing cells
Proof-reading activity
DNA polymerases have 3'-5' exonuclease proof-reading activity
5'-3' exonuclease activity
Only DNA polymerase I (removes primers)
Cysthathione synthase deficiency
Homocystinemia. DVT, atherosclerosis, ectopic lens. Cysteine becomes essential AA. Rx.: B6 and cysteine supplements
Functions of vitamin A
Retinal pigments, differentiation of epithelial tissues
Propionic acidemia
Propionyl CoA carboxylase deficiency. Poor feeding, vomiting, hypotonia, lethargy, dehydration, acidosis
Stop and start codons
AUG (start, methionine); UAA, UAG, UGA are stop codons
Pyruvate DH deficiency
hypoxia-induced lactic acidosis
Acute intermitent porphyria
Abdominal pain, neurologic manifestations, no photosensitivity, coluria, increased ALA and PB
Regulators of ALA dehydrase
Alcohol, barbiturates and hypoxia activate it; heme inhibits it
Enzyme deficiencies that result in photosensitivity
Uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase
Enzymes that require B1
Branched-chain DH, alpha-ketglutarate DH, pyruvate DH, transketolase
Causes of pellagra
Niacin is made from tryptophan and requires B6 - therefore pellagra can be caused by Hartnup, malignant carcinoid (increases try metabolism), isoniazid (decreased B6)
Vitamin B6 deficiency
Induced by isoniazid and contraceptives - peripheral neuropathy, seizures
Vitamin D excess
Results in hypercalcemia, stupor; Seen in sarcoidosis due to macrophage conversion of vit D into active form
Vitamin K deficiency
Seen in neonates because intestine have no flora to synthesize it; results in neonatal hemorrhage with normal bleeding time and increased PT and PTT
Vitamin K dependant factors
II, VII, IX, X and proteins C and S
Limitting factor in ethanol metabolsm
NAD
Inhibitors of ethanol metabolism
Fomepizole (inhibits alcohol DH) and disulfram (inhibits acetaldehyde DH)
Kwashiorkor
Protein malnutrition --> edema, anemia, fatty liver
Marasmus
Total caloric malnutrition --> muscle wasting, loss of subcutaneous fat and edema
Bonds between purines and pyrimidines
G-C (3 H bonds) stronger than A-T bond (2 H bonds); increased G-C content --> increased melting temperature
Transition
Substituting pyrimidine for pyrimidine or purine for purine
Transversion
Substituting purine for pyrimidine or vice versa
Direction of replication and transcription
5'-3'. The incoming nucleotide bears the triphosphate in 5' that attaches to the 3' hydroxyl of nascent peptide
tRNA wobble
The third position of the codon may not be important for accurate base pairing
Energy requirements of translation
tRNA aminoacylation: ATP --> ADP; tRNA loading: GTP --> GDP; translocation: GTP --> GDP; total: 4 high-energy phosphate bonds
Enzyme regulation methods
Enzyme concentration alteration, covalent modification (phosphorylation), proteolytic activation, allosteric regulation, pH, temperature, transcriptional regulation
Permanent cells
Remain in G0, regenerate from stem cells; neurons, skeletal and cardiac muscle, RBCs
Stable quiescent cells
Enter G1 from G0 when stimulated; hepatocytes and lymphocytes
Labile cells
Never go to G0; bone marrow, gut epithelium, skin, hair follicles
Nissl bodies
RER of neurons
Dynein
ATPase that links peripheral 9 doublets to bend and slide cilium. Responsible for retrograde transport. Defective in Kartagener
Phosphatidylcholine (lecithin)
Component of RBC membranes, myelin, bile and surfactant. Used in sterification of cholesterol (LCAT)
Metabolic processes in the mitochondria
Beta oxydation, acetyl-CoA production, Krebs, ETC
Metabolic processes in the cytoplasm
Glycolysis, fatty acid synthesis, HMP shunt, protein synthesis (RER), steroid synthesis (SER)
Metabolic processes in mitochondria and cytoplasm
Heme synthesis, urea cycle, gluconeogenesis
Tissues that only carry anaerobic glycolysis
RBCs, leukocytes, kidney medulla, lens, testes, cornea
Gluconeogenic tissues
Liver, kidney, gut epithelium
Consequence of hyperammonemia
ornithinetranscarbamoyl synthase deficiency or liver disease --> hyperammonemia --> depletion of alpha-ketoglutarate --> inhibition of TCA cycle
Donators of NH2 and C to urea molecule
aspartate --> NH2; NH4+ --> NH2; CO2 --> C
Cystinuria
Defect of renal amino acid transporter for cysteine, lysine and arginine. Leads to cysteine stones. Rx.: acetazolamide
Adenosine deaminase deficiency
dATP accumulates which inhibits ribonucleotide reductase. Results in SCID due to decreased purine synthesis
Lesch Nyhan
Deficiency of HGPRT (hypoxanthine guanine phosphoribosyl pirophosphate transferase) which converts guanine to GMP and hypoxanthine to IMP. Hyperuricemia, retardation, self-mutilation, aggression, gout, choreoathetosis.
Pyrimidine synthesis
CO2 + glutamine + carbamoyl phosphate synthetase 2 --> carbamoyl phosphate + aspartate -->--> orotic acid + PRPP (from HMP shunt) --> UMP + ribonucleotide reductase --> dUMP + thymidylate synthase + THF --> dTMP + DHF
Dihydrofolate reductase
makes THF out of DHF for use of thymidylate synthase; inhibited by methotrexate (eukaryots) trimethorpim (prokaryotes)
Thymidylate synthase
makes dTMP out of dUMP in pyrimidine synthesis; inhibited by 5-fluoracil
Ribonucleotide reductase
Makes deoxyribonucletides from ribonucleotides. Inhibited by hydroxyurea
Carbamoyl phosphate synthase 2
Located in the cytoplasm. Makes carbamoyl phosphate from CO2 + glutamine in pyrimidine synthesis.
Pyrimidine synthesis major enzymes
Carbamoyl synthase 2, ribonucleotide reductase (inhibited by hydroxyurea), thymidylate synthase (inhibited by 5-FA), dihydrofolate reductase (inhibited by methotrexate and TMP)
Purine synthesis
Ribose-5-phosphate + PRPP synthase --> PRPP + PRPP amidotransferase --> 5-phosphoribosylamine + gly, asp, glu, THF -->-->--> IMP (contains hypoxanthine)
PRPP synthase
Makes PRPP from ribose-5-phosphate in purine synthesis.
PRPP amidotransferase
Makes 5-phosphoribosylamine from PRPP in purine synthesis. Inhibited by allopurinol and 6-mercaptupurine.
Why does Von Gierke and galactosemia produce hyperuricemia?
Excess consumption of Pi leads to accumulation of nucleosides that are degraded by xanthine oxidase
Enzymes of purine salvage pathway
Adenosine deaminase (deficient in SCID), xanthine oxidase, HPRT, HGPRT (deficient in Lesch Nyhan)
Heme synthesis
Glycine + succinyl CoA + ALA synthase --> δALA + ALA dehydrase --> porphobilinogen + uroporphyrinogen-I synthase --> uroporphyrinogen III -->-->--> protoporphyrin IX + Fe+ + ferrochelatase --> heme
Major enzymes of heme synthesis
ALA synthase (requires B6, negative feedback by heme; stimulated by barbiturates and alcohol); ALA dehydrase (inhibited by lead); uroporphyrinogen synthase (deficiency leads to acute intermittent porphyria); ferrochelatase (inhibited by lead)
Acute intermittent porphyria
Anxiety, confusion, paranoia, acute abdominal pain, no photosensitivity, coluria increased δ-ALA and porphobilinogen; due to uroporphyrinogen synthase deficiency; autosomal dominant, late onset, variable expression
↓protoporphyrin, ↓δ-ALA, ↑ferritin, ↑serum iron
Pyridoxine deficiency (isoniazid treatment)
↑protoporphyrin, δ-ALA normal, ↓ferritin, ↓serum iron
Iron deficiency anemia
↑protoporphyrin, ↑δ-ALA, ↑ferritin, ↑serum iron
Lead poisoning