* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download USMLE STEP 1 Review: Week 3, Biochemistry
Survey
Document related concepts
Butyric acid wikipedia , lookup
Biosynthesis wikipedia , lookup
Lactate dehydrogenase wikipedia , lookup
Plant nutrition wikipedia , lookup
Fatty acid synthesis wikipedia , lookup
Amino acid synthesis wikipedia , lookup
Evolution of metal ions in biological systems wikipedia , lookup
Citric acid cycle wikipedia , lookup
Fatty acid metabolism wikipedia , lookup
Glyceroneogenesis wikipedia , lookup
Transcript
Chase Findley, MSIV Vitamins, Fat Soluble, 94 Vitamins A, D, E, K Absorption dependent on ileum and pancreas Accumulate in body fat, more potential for toxicity Fat malabsorption conditions may cause deficiency ○ Cystic fibrosis, celiac sprue, mineral oil intake Vitamins, Fat Soluble, 94 Vitamin A (Retinol) Found: liver, leafy vegetables Functions: antioxidant, constituent of retinal visual pigment Deficiency: night blindness, dry skin Excess: head ache, arthralgias, fatigue, skin changes, sore throat, alopecia Teratogenic: cleft palate, cardiac problems Remember bear hunter who eats liver! Vitamins, Fat Soluble, 97 Vitamin D Found: Fortified milk Function: Increases intestinal absorption of calcium and phosphate, bone resorption Deficiency: Rickets (children), osteomalacia (adults), hypocalcemic tetany Excess: Hypercalcemia, hypercalciuria, loss of appetite, stupor. (Seen in sarcoidosis) Vitamins, Fat Soluble, 97 Vitamin D, continued D2 ○ Found in plants, pharmacological form D3 ○ Found in milk, formed in sun exposed skin 25-OH D3 ○ Storage form 1,25-(OH)2D3 (Calcitriol) ○ Active form Vitamins, Fat Soluble, 97 Vitamin E Found: Vegetable oils, nuts, leafy vegetables Function: Antioxidant, protects RBC’s and membranes from free radical damage Deficiency: Increased fragility of RBC’s, muscle weakness, neurodysfunction Vitamins, Fat Soluble, 98 Vitamin K Found: Leafy vegetables, some fruits Function: Necessary for synthesis of clotting factors II, VII, IX, X, protein C and S, catalyzes γ-carboxylation of glutamic acid residues Deficiency: Hemorrhage with increased PT, PTT, normal bleeding time. ○ Neonatal hemorrhage, give Vitamin K at birth ○ Warfarin antagonizes Vitamin K Vitamins, Water Soluble, 94 Vitamins B1 (thiamine), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B6 pyridoxine, B12 (cobalamin), C (ascorbic acid, biotin, folate All except B12 and folate wash out from body, low risk of toxicity Vitamins, Water Soluble, 94 Vitamin B1 (thiamine) Function: Component of thiamine pyrophosphate, cofactor in: ○ Pyruvate dehydrogenase (glycolysis) ○ α-ketoglutarate dehydrogenase (TCA cycle) ○ Transketolase (HMP shunt) ○ Branched chain amino acid dehydrogenase Vitamins, Water Soluble, 95 Vitamin B1 (thiamine), continued Deficiency: ○ Wernike-Korsakoff syndrome Seen in malnutrition, alcoholism Confusion, ophthalmoplegia, confabulation ○ Beriberi (dry) Polyneuritis, symmetrical muscle wasting ○ Beriberi (wet) High-output cardiac failure (dilated cardiomyopathy) edema Vitamins, Water Soluble, 95 Vitamin B2 (riboflavin) Function: Cofactor in oxidation and reduction (FAD, FMN) B2=2 ATP Deficiency: Cheilosis, corneal vascularization Vitamins, Water Soluble, 95 Vitamin B3 (niacin) Function: Constituent of NAD, NADP, used in redox reactions, B3=3 ATP Derived from tryptophan, requires B6 for synthesis Deficiency: Pellagra (diarrhea, dermatitis, dementia), glossitis ○ Hartnup disease (decreased tryptophan absorption) ○ Malignant carcinoid syndrome (increased tryptophan metabolism ○ INH (anti-TB) (decreased B6) Vitamins, Water Soluble, 95 Vitamin B3 (niacin), continued Clinical use: Treatment of hyperlipidemia (decrease LDL, increase HDL) Excess: Facial flushing, treat with aspirin Vitamins, Water Soluble, 95 Vitamin B5 (pantothenate) Function: Component of CoA (cofactor in acyl transfers) and fatty acid synthase Deficiency: Dermatitis, enteritis, alopecia, adrenal insufficiency Vitamins, Water Soluble, 95 Vitamin B6 (pyridoxine) Function: Converted to pyridoxal, phosphate, cofactor in transamination (ALT/AST), decarboxylation reactions, glycogen phosphorylase, heme synthesis Required for synthesis of B3 (niacin) Deficiency: Convulsions, hyperirritability, peripheral neuropathy ○ May be induced by INH, OCP’s Vitamins, Water Soluble, 96 Vitamin B12 (cobalamin) Found: Only in animal products, synthesized by microorganisms (large reserves in liver) Function: Cofactor for homocysteine methyltransferase (transfers CH3 groups) and methylmalonyl-CoA mutase Vitamins, Water Soluble, 96 Vitamin B12 (cobalamin) Deficiency: ○ Macrocytic-megaloblastic anemia ○ Neurological symptoms Irreversible if prolonged Paresthesias Sub acute combined degeneration - Posterior and lateral spinal columns Vitamins, Water Soluble, 96 Vitamin B12 (cobalamin) Causes of deficiency ○ Intestinal malabsorption Sprue, enteritis, fish tapeworm ○ Lack of intrinsic factor Pernicious anemia ○ Absence of terminal ileum Crohn’s disease, surgical Schilling test to detect etiology of deficiency Vitamins, Water Soluble, 96 Folic Acid Function: Converted to tetrahydrofolate (THF), coenzyme used in 1-carbon transfer/methylation reaction. Used in synthesis of nitrogenous bases in DNA/RNA Deficiency: ○ Macrocytic-megaloblastic anemia Without neurological symptoms ○ Neural tube defects Prevent with prenatal supplements Vitamins, Water Soluble, 96 Folic acid, continued Deficiency ○ Much smaller liver stores than B12 ○ Most common US vitamin deficiency Especially in pregnancy, alcoholism ○ Can be caused by phenytoin, sulfonamides, methotrexate Vitamins, Water Soluble, 97 Biotin Function: Cofactor for carboxylation enzymes, pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase Avidin (raw egg whites) binds biotin and prevents absorption Deficiency: Dermatitis, alopecia, enteritis. ○ Antibiotic use or excessive raw eggs Vitamins, Water Soluble, 97 Vitamin C (ascorbic acid) Found: Fruits, vegetables Function: Antioxidant, also: ○ Facilitates iron absorption by keeping Fe in more absorbable Fe2+ ○ Necessary for hydroxylation of proline and lysine in collagen synthesis ○ Necessary for dopamine β-hydroxylase (converts dopamine to norepinephrine) Vitamins, Water Soluble, 97 Vitamin C (ascorbic acid) Deficiency: Scurvy ○ Swollen gums, bruising, anemia, poor wound healing Minerals, 98 Zinc Function: Involved in activity of 100+ enzymes. Important in zinc finger (transcription factor motif) Deficiency: Delayed wound healing, hypogonadism, decreased adult hair, predisposes to alcoholic cirrhosis Malnutrition, 98 Kwashiorkor Protein deficiency Skin lesions, liver malfunction (fatty change), edema, anemia Malnutrition, 98 Marasmus Total calorie deficiency Tissue and muscle wasting, loss of subcutaneous fat, edema Ethanol Metabolism, 98 Alcohol dehydrogenase operates via zero-order kinetics NAD+ is limiting reagent Fomepizole inhibits alcohol dehydrogenase Disulfiram inhibits acetaldehyde dehydrogenase Universal Electron Acceptors, 101 NAD+, NADP+ Require Vitamin B3 (niacin) for production NAD+ ○ Catabolic processes, carry reducing equivalents as NADH NADP+ ○ Anabolic processes, supply reducing equivalents as NADPH ○ NADPH also used in respiratory burst, P-450 FAD+ Requires Vitamin B2 (riboflavin) for production Metabolism, 101 ATP Production (Glycolysis) Hydrolysis drives energetically unfavorable reactions Aerobic metabolism ○ Produces 32 (heart/liver) 30 (muscle) ATP per glucose Anaerobic metabolism ○ Produces 2 ATP per glucose Hexokinase Vs. Glucokinase, 101 First step of glycolysis is glucose to G6P Reaction catalyzed by hexokinase or glucokinase, 1st regulation point Hexokinase Ubiquitous, high affinity (low Km), low capacity (low Vmax), feedback inhibited by product Glucokinase Liver and pancreas β-cells, low affinity (high Km) and high capacity (high Vmax) induced by insulin, sequesters excess glucose in liver. Hexokinase Vs. Glucokinase, 101 Glycolytic Enzyme Deficiency, 103 Deficiency of pyruvate kinase or phosphoglucose isomerase Inability to maintain Na+-K+ ATPase RBC swelling, lysis Hemolytic anemia RBC’s depend solely on glycolysis of glucose for metabolism Pyruvate dehydrogenase Deficiency, 103 Back up of substrate (pyruvate, alanine), leads to lactic acidosis Congenital and acquired (B1 deficiency) forms Neurologic deficits Treat by increasing intake of ketogenic nutrients (high fat, lysine, leucine) Pyruvate Metabolism, 103 Alanine carries AA to liver from muscle Oxaloacetate used to in TCA cycle or gluconeogenesis Transition from glycolysis to TCA cycle End of anaerobic glycolysis Cori Cycle, 103 Muscle and RBC’s generate lactate via anaerobic glycolysis Lactate sent to liver to be used in gluconeogenesis Glucose can then be sent back and used by muscle and RBC’s Loss of 4 ATP/Cycle HMP Shunt, 105 Produces NADPH for fatty acid and steroid synthesis, and glutathione reduction in RBC’s Oxidative (irreversible) and non-oxidative (reversible) phases Occurs in lactating mammary glands, liver, adrenal cortex, RBC’s Respiratory Burst, 105 Produces reactive oxygen (HOCl) species for immune response Occurs in neutrophils, macrophages Involves membrane-bound NADPH oxidase (deficient in chronic granulomatous disease) Glucose-6-Phosphate Dehydrogenase Deficiency, 106 G6PD produces NADPH, necessary to keep glutathione reduced, which detoxifies free radicals/peroxides Decreased NADPH leads to hemolytic anemia due to damage from oxidizing agents X-linked recessive, most common enzyme deficiency Glucose-6-Phosphate Dehydrogenase Deficiency, 106 Oxidizing agents include fava beans, sulfanamides, primaquine, anti-TB drugs Affected individuals have malarial resistance Heinz bodies Altered precipitated hemoglobin in RBC’s Bite Cells From phagocytic removal of Heinz bodies by spleen Glucose-6-Phoshate Dehydrogenase Deficiency, 106 Heinz bodies, bite cells Disorders of Fructose Metabolism, 106 Fructose intolerance Hereditary deficiency of aldolase B Autosomal recessive Fructose-1-phosphate accumulates, leading to decrease in available phosphate, inhibits glycogenolysis and gluconeogenesis Hypoglycemia, jaundice, cirrhosis, vomiting Decrease intake of fructose and sucrose Disorders of Fructose Metabolism, 106 Essential fructosuria Defect in fructokinase Autosomal recessive Benign, asymptomatic Fructose in blood and urine Disorders of Galactose Metabolism, 107 Classic galactosemia Absence of galactose-1-phosphate uridyltransferase. Autosomal recessive Toxic damage from galactitol Failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation Exclude galactose and lactose from diet Disorders of Galactose Metabolism, 107 Galactokinase deficiency Autosomal recessive Galactitol accumulates if galactose is present in diet Galactose appears in blood and urine, infantile cataracts, failure to track objects, lack of social smile Lactase Deficiency, 107 Age dependent or hereditary lactose intolerance due to loss of brush-border enzyme Bloating, cramps, osmotic diarrhea Avoid dairy products, lactase supplements Transport of alanine and glutamine, 108 Glucose in muscle is oxidized to pyruvate, producing energy Pyruvate is transaminated to alanine, travels to liver, providing nitrogen for urea cycle, and carbon for gluconeogenesis Hyperammonemia, 108 Acquired (liver disease) or hereditary (urea enzyme deficiencies) Results in excess NH4+, depletes αketoglutarate, inhibits TCA cycle Tremor, slurring speech, somnolence, vomiting, cerebral edema, blurred vision Treat with benzoate, phenylbutyrate Ornithine Transcarbamoylase Defiency, 108 Most common urea cycle disorder X-linked recessive Interferes with elimination of ammonia May present in first days of life Excess carbamoyl phosphate converted to orotic acid Orotic acid in blood and urine, decreased BUN, hyperammonemia Phenylketonuria, 109 Decreased phenylalanine hydroxylase or tetrahydrobiopterin cofactor. Tyrosine can not be synthesized, becomes essential Autosomal recessive Increased phenylalanine leads to excess phenylketones in urine. Phenylketonuria, 109 Mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor Treat by increased tyrosine and decreased phenylalanine in diet Maternal PKU, (deficiency in pregnancy) causes mental retardation, growth retardation, microcephaly, heart defects Alkaptonuria, 109 Congenital deficiency of homogentisic acid oxidase in degradative pathway of tyrosine Autosomal recessive Dark connective tissue, pigmented sclera, urine turns black on standing, arthralgias Albinism, 109 Congenital defect in either: Tyrosinase ○ Inability to synthesize melanin from tyrosine ○ Autosomal recessive Tyrosine transporters ○ Variable inheritance, locus heterogenity ○ Decreased availability of tyrosine for melanin synthesis Albinism, 109 Can result from lack of migration of neural crest cells. Increased risk of skin cancer Homocystinuria, 100 Autosomal recessive 3 forms, all result in excess homocysteine 1. Cystathionine synthase deficiency 2. Decreased affinity of cystathionine synthase for pyridoxal phosphate (treat with increased B6 in diet) 3. Homocysteine methyltransferase deficiency Homocystinuria, 110 Cystine becomes essential Increased homocysteine in urine, mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation, atherosclerosis (MI and stroke) Cystinuria, 110 Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, arginine in proximal convoluted tubule. Excess cystine in precipitates, forms cystine kidney stones. Autosomal recessive Treat with acetazolamide to alkalinize urine. Maple Syrup Disease, 110 Blocked degradation of branched amino acids (Ile, Leu, Val), due to decreased αketoacid dehydrogenase. Results in accumulation of α-ketoacids in blood Severe CNS defects, mental retardation, death. Urine smells like maple syrup Adenosine Deaminase Deficiency, 111 Excess ATP and dATP imbalances nucleotide pool (feedback inhibition of ribonucleotide reductase) Prevents DNA synthesis Decreased lymphocyte count Major cause of severe combined immunodeficiency disorder Lesch-Nyhan Syndrome, 111 Absence of HGPRT leads to defective purine salvage pathway Excess uric acid production X-linked recessive Mental retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis Orotic aciduria, 111 Inability to convert orotic acid UMP in de novo pyrimidine synthesis pathway Defect in orotic acid phosphoribosetransferase or orotidine 5’phosphate decarboxylase Autosomal recessive Increased orotic acid in urine, megaloblastic anemia, failure to thrive Treat with oral uridine Insulin, 112 Synthesized in pancreas β cells Released in response to ATP from glucose metabolism (depolarizing K+ channels) Anabolic effects: Increases glucose transport, glycogen synthesis and storage, triglyceride synthesis and storage, protein synthesis Increased Na+ retention, cellular K+ uptake Insulin, 112 Inhibits glucagon release by pancreas α cells Insulin dephosphorylates Serum C-peptide only present with endogenous protein Lack of C-peptide indicated exogenous insulin use Insulin, 112 Insulin moves glucose into cells Some cells do not need insulin, use a glucose transporter GLUT1: RBC’s, brain GLUT2: β islet cells, liver, kidney GLUT4: (insulin sensitive) adipose tissue, skeletal muscle Glycogen, 112 Branches: α (1,6) bonds Linkages: α (1,4) bonds Glycogen phosphorylates Skeletal muscle Glycogen undergoes glycogenolysis to form glucose, which is metabolized during exercise Hepatocytes Glycogen is stored and undergoes glycogenolysis to maintain blood glucose levels Glycogen Storage Disease, 113 All cause abnormal glycogen metabolism and accumulation within cells Disease Findings Deficient enzyme Von Gierke’s (I) Severe fasting hypoglycemia, increased glycogen in liver, increased blood lactate, hepatomegaly Glucose-6-phosphate Pompe’s (II) Cardiomegaly Lysosomal α-1,4 glucosidase (acid maltase) Cori’s (III) Milder type I, normal blood lactate levels Debranching enzyme McArdle’s (V) Increased glycogen in Skeletal muscle muscle, muscle glycogen cramps, myoglobinuria phosphorylase Ketone Bodies, 115 In liver, fatty acids and amino acids are metobolized to acetoacetate and βhydroxybutyrate for use in muscle and brain Produced in response to starvation, alcoholism Breath smells like acetone Metabolic Fuel Use, 116 Exercise 1st (seconds) Stored ATP, creatine phosphate, anaerobic glycolysis 2nd (minutes) +Oxidative phosphorylation 3rd (hours) Glycogen and FFA oxidation, glucose conserved Metabolic Fuel Use, 116 Fasting and starvation Preserve glucose for brain and RBC’s Days 1-3 ○ Hepatic glycogenolysis and glucose release ○ Adipose release of free fatty acids, used by muscle and liver (in place of glucose) ○ Hepatic gluconeogenesis from peripheral lactate and alanine, adipose tissue Metabolic Fuel Use, 116 Fasting and starvation After 3 days ○ Muscle protein used for hepatic formation of ketone bodies for brain and heart Several days ○ Ketone bodies become main energy source for brain ○ Survival time determined by fat stores Lipid Transport Enzymes, 117 Pancreatic lipase Degradation of dietary lipase in small intestine Lipoprotein lipase Degradation of TG in chylomicrons and VLDL Hepatic TG lipase Degradation of TG in IDL Hormone sensitive lipase Degradation of TG in adipocytes Cholesterol Synthesis, 116 Rate limiting step catalyzed by HMG-CoA reductase Enzyme inhibited by statins 2/3 plasma cholesterol is esterified by lecithincholesterol acyltransferase (LCAT) Cholesterol ester transport protein (CETP) mediates transfer of cholesterol esters to lipoprotein particles Essential Fatty Acids, 116 Can not be synthesized, must be in diet Linoleic and linolenic acids Arachidonic acid, if linoleic acid is absent Necessary for synthesis of eicosandoids Lipoprotein Functions, 118 Lipoproteins are composed of varying proportions of cholesterol, triglycerides, phospholipids LDL transports cholesterol from liver to tissues HDL transports cholesterol from tissues to liver Lipoprotein Functions, 118 Chylomicron Delivers dietary TG’s to tissue Delivers cholesterol to liver as chylomicron remnants (depleted of triacylglycerols) Secreted by intestinal epithelial cells B-48, A-IV, C-II, E Familial dyslipidemia I ○ Increased chylomicrons ○ Elevated TG, cholesterol ○ Lipoprotein lipase deficiency or altered apolipoprotein C-II Lipoprotein, 118 VLDL Delivers hepatic TG’s to tissue Secreted by liver B-100, C-II, E Hypertriglyceridemia ○ Increased VLDL ○ Elevated TG ○ Hepatic overproduction of VLDL IDL Formed by degradation of VLDL Delivers TG’s and cholesterol to liver, degraded to LDL’s B-100, E Lipoprotein Functions, 118 LDL Delivers hepatic cholesterol to tissues Formed by lipoprotein lipase modification of VLDL in tissue Taken up by target cells via receptor-mediated endocytosis B-100 Familial dyslipidemia IIa ○ Increased LDL ○ Elevated cholesterol ○ Autosomal dominant, absent/decreased LDL receptor Lipoprotein Functions, 118 HDL Mediates reverse cholesterol transport from tissues to liver. Repository of apoC and apoE Secreted from liver and intestine Abetalipoproteinemia, 118 Hereditary inability to synthesize lipoproteins, because of deficiency in apoB-100 and apoB-48 Autosomal recessive, appears early in life Failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness