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36 Cards in this Set
- Front
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Committed, rate determining step in heme synth and how regulated |
ALA synthase: succinyl CoA + glycine --> ALA Regulated by feed back from heme/hemin |
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Basic structure of porphyrin molecule |
4 pyrrole rings linked by methenyl bridges with asymetetrical side chains, able to chelate metal ion |
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Rate limiting non committing step of heme synth |
Hydroxymethylbilane synthesis: 4x PBG --> hydroxymethylbilane (linear tetrapyrrole) |
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Acute intermittent porphyria |
Insufficiency in liver hydroxymethylbilane: build up of ALA and PBG in the liver AND low heme produced to feedback and slow pathway---> boughts of stomach pain and psychosis. Dx: PBG in urine Treat: hemin, avoiding alcohol/other things that require CYP450s, |
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physiological roles of heme |
- Electron transport - Oxygen transport - Drug detoxification (liver has a lot - cytochrome P450 enzymes) - Removal of H2O2 |
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What's chronic inability to make heme well? |
Porphyria Cutanea Tardea (PCT): insufficiency in uroporphyrinogen decarboxylase (not rate limiting step). Get enough heme made and no ALA/PBG back up, but back up of uroporphyrinogen, which is conjugated to uroporphyrins --> photosynthetic compounds in skin that react to sunlight and make blisters. Pee with also change color At risk: liver damage from alcohol, hep C etc Treat: stay out of sun and routine phlebotomy |
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Lead poisoning |
Lead blocks ALA dehydrase (ALA->PBG) and inhibits ferrochelatase (last step in making heme) --> heme levels down --> decrease in feedback --> sx overdrive --> ALA accumulation Sx: see anemia (because bone and liver isoforms affected), abx pain, psychosis |
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Iron deficiency anemia |
Not enough Fe --> no binding/inactivation of iron response protein --> Iron response elements on mRNA are not uncovered--> don't have translation of heme synth genes like ALA synthase --> little heme made --> anemic. Dx: thin rimmed, pale RBCs |
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Heme degradation critical steps |
1. Heme oxgenase in spleen macrophages: heme--> biliverdin 2. Biliverdin reductase: biliverdin --> bilirubin (fat soluble, transported to liver on albumin) 3. Bilirubin glucuronyl transferase in liver: bilirubin --> bilirubin diglucuronide (conjugated) 4. Congugated --> urobilinogen 5. Intestine convert to urobiligen --> sterocobalin = brown poop 6. Kidney: urobilinogen --> urobilinin = pee yellow |
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Thiamine B2 |
- Water soluble, co-enzyme for krebs cycle metabolizing enzymes - Brain, nerves, heart need a lot |
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Thiamine deficiency first world |
- Weinike's encephalopathy: not enough krebs cycle enzymes working --> impairs glucose metabolism in tissues like brain -Sx: confusion, nystagmus, bad motor control - At risk: alcoholics who don't eat well - Treat: glucose with thymine. No thymine and you'll make it work --> korsacoff's --> death |
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Thiamine deficiency third world |
Beriberi: dilated cardiomyopathy --> high output failure Sx: SOB, flushed with no fever, peripheral neuropathy (foot drop) treat: IV thiamine - can reverse |
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RiboflavinB2 |
Makes FAD Deficiency: dry mouth, striations around lips |
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Niacin B3 |
- Water soluble, Makes NAD and NAPH - Can also get them from tryptophan, but not if tryptophan is down cuz of chemo, etc |
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Niacin deficiency |
Pellegra: Sx: dark spots in reaction to sun, diarrhea, dementia, death At risk: carcinoid - tumor takes up all tryptophan, hartnup - diminish tryptophan uptake |
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Pyroxidine B6 / deficiency |
Water soluble, makes pyroxidine phosphate (PLP) that's cofactor for deaminases, decarboxylation Deficiency: rare, not fatal but get seizures, isoniazid = TB drug that binds it up |
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Biotin B7 |
Water soluble, cofactor for carboxylase enzymes Deficiency rare: see in body builders who eat raw eggs --> avidin protein binds up Sx: depression and dry skin |
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Folate |
- Water soluble B vitamin, important to one carbon metabolism that's needed for: aa synthesis, purine synthesis and thym-dine synthesis (key to DNA synthesis and cell replication/growth esp in fetus and blood) - |
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Folate deficiency |
- most common in the us esp pregers and on methotrexate (chemo drug) - Sx: megloblastic anemia - Methotrexate: shuts down all quickly dividing cells, often overshoot and rescue with THF (leukovorin) - Causes neural tube defects in babies - moms take supplement, enriched foods |
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Cobalamin B12 |
- Water soluble but can store for years and can't get from plants - Porphyrin chelated by cobalt - Absorption requires intrinsic factor from parietal cells - 2 forms 1) methylcobalin in blood, used for 1C transfer with folate. Deficiency causes megloblastic anemia too- treat with B12 or lots of folate 2) deoxyadenosylcobalamin: used by neurons to break up fat |
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Pernicious anemia |
- At risk: old ladies with autoimmune disease - Sx: anemia and peripheral neuropathy - Autoimmune degradation of parietal cells --> no IF --> no B12 absorbed and insufficient folate in diet --> megloblastic anemia and build up of fat in neurons - Treat: injected B12 |
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Subacute Combined Degeneration of spinal chord |
- Sx: sensory and motor neuropathy- clumsy and can't feel vibration - Autoimmune degradation of parietal cells --> no IF --> no B12 uptake BUT enough folate --> no anemia and just fat build up in brain --> irreversible damage - Treat: B12 injections |
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Vitamin C + deficiency |
- water soluble, aka ascorbic acid, needed for enzymes that make collagen - deficiency = scurvy: leg hairs curl, hemorrhages at hair follicles, gums swell and bleed, poor wound healing |
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Vitamin A/ deficiency |
- fat soluble, - Ingest as retinol and retinal: essential for repro, - Retinoic acid: essential for life, differentiation of epithelial cells - 11-cis-retinal: essential for rhodopsin in eyes - beta-carotene: in plants converted to retinal, heat stable, cleavage regulated so can't OD on vitA - Deficiency: night blindness, eye spots, corenal ulcerations, (major cause of blindness in world) |
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Vitamin D |
- D2: plants, D3: animals (can be made from plant D2 but requires UV light) - D3 converted to active calcitrol in liver/kidney --> increase Ca uptake by kidney/intestine |
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VitD deficiency |
- Osteomalacia: demineraization of bones after plates fuse, soft bones, from lack of diet D3 (no fortified milk)/ sunlight (dark skin in northern latitudes) - Rickets: deminieralization of bones before plates fuse, bowed legs - Treat: supplement calcitrol |
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Vitamin K/ deficiency |
- Fat soluble, made by intestinal bacteria, important in modifying clotting factors --> enable clotting - Coumadin inhibits action of vitamin K --> blood thinner for preventing stroke - Deficiency: rare, see in a) alcoholics (low nutrients and flora) b) lots of antibiotics/ baby on feeding tube - no gut flora - Sx: extended PT, babies: bleeding from venous puncture sites, hemorrhage (death) |
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What's main source of fuel for the heart? |
1) Fat metabolism 2) Lactate metabolism: lactate dehydrogenase turns to pyruvate --> krebs 3) glucose (low glycogen/glycolysis) favors oxidative pathways thus needs to have good perfusion always or wont get nutrients |
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How does AMPK increase ATP-generating processes? |
1) phorphorylate ACC --> down reg FA synth --> less malonyl CoA --> upreg FA oxidation 2) increase glut4 in muscle --> increase glucose uptake (insulin independent) |
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How do muscles upregulate glycolysis really fast when need quick source of ATP for exertion? |
- After blow through adenylate kinase and creatinine (10 sec) - Glycogen phosphorylase activated by AMP - Ca2+ activates phosphorylase kinase --> activates glycogen phosphoylase - Activate PFK: phosphate, AMP, NH3 - No PFK inhibition by ATP, creatinine-phosphate |
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how insulin affects FA balance in liver/adipocytes |
Liver: a) Activates ACC : more FA synth b) Breaks down cAMP, which is glucagon/epi second messenger in inhibiting ACC c) High ACC --> low CAT1 --> low Fa oxidation Adipocyte: a) upreg LPL for taking in FAs b) inhibit HSL - no FA breakdown d) doesn't make FFAs, but has ACC/CAT1 sx and down reg FA oxidation e) increase glucose uptake to make glycerol for TG synth |
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What neurons important in appetite |
- Arcuate hypothalamus: NPY = orexogenic, POMC = anorexogenic. - NPY sense high CAT1 levels --> hungry - Leptin activates POMC/ inactivates NPY --> not hungs - Ghrelin activates NPY |
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Thiazolidinedoines (TZDs) |
- Treat DMII by increasing insulin sensitivity - PPAR gamma analog: increase adipose fat storage capacity --> decrease stress on adipose --> less insulin resistance - Side effect = weight gain |
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Selective insulin resistance |
- Insulin does not cut down gluconeogenesis --> hyperglycemia - Insulin does activate lipogenesis --> fatty liver |
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Orlistat |
- only approved obesity drug: looks like a TG and binds up lipase in gut so that can't absorb - side effects: waxy stool, feel shitty, fat soluble vitamin deficiency |
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Sufuroneas |
- DMII drug for insulin sensitivity- inactivates K channel and increases Ca influx that releases insulin - side effects: weight gain - cheap and oral but not that effective |