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27 Cards in this Set
- Front
- Back
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describe an overview of synthesis and catabolism of heme
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-synthesized in cells where it is used- succinyl CoA from TCA reacts with glycine to produce ALA and in 8 steps ALA molecules are converted to heme, a tetrapyrrole that is a red chromophore
-catabolism in reticuloendothelial cells of spleen, liver and bone marrow- tetrapyrrole ring is cleaved to biliverdin which is a green chromophore (in vomit) biliverdin is converted to orange colored bilirubin -water insoluble unconjugated bilirubin and water soluble conjugated bilirubin -bilirubin ends up as urobilins in urine and stercobilin in feces |
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describe characteristics of heme
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-70% made in bone marrow to hemoglobin
-15 for liver cytochrome P450 enzymes present in ER and mitochondria present in ER and mitochondria; imp in drug clearance; cytochrome b5 imp in ER for desaturation of polyunsaturated fatty acids -rest in myoglobin in muscle cells, mitochodnrial cytochromes of all cell types, except RBC which do not contain mitochondria and catalases (H2O2 to water) -prophyrins such as heme are prosthetic groups. prosthetic group and apoprotein yields holoprotein such as hemoglonin and myoglobin |
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describe the basic ring structure of all mature porphyrins
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-tetrapyrrole ring with conjugated double bonds making it a chromophore and giving red color
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describe rate limiting step
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-succinyl coa and glycine to ALA via ALA synthase
-requires pyridoxal phosphate PLP made from vit B6 -heme Fe2+ -hemin Fe3+, cannot function as oxygen carrier -both repress and allosterically inhibit ALA synthase -rxn decarboxylates glycine and adds it to succinyl coa -driven by high energy thioester of coenzyme A that is released |
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describe the anaplerotic rxns required for porphyrin synthesis
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-in TCA
-citrate from food sources -glutamate to a-ketoglutarate -met, val, ile to succinyl CoA |
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describe ALA dehydrase characteristics
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-contains functionally imp sulfhydryl groups, linked by zinc
-lead is a powerful inhibitor because it replaces zinc but inc concentrations of zinc will displace the lead -dietary zinc deficiency will impair this enzyme leading to anemia -takes 2 ALA molecules and forms porphobilinogen which contains pyrrole ring with acetate and propionate side chains -ALA and porphobilinogen are neurotoxins |
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describe charcteristics of porphobilinogen deaminase
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-takes 4 porphobilinogens
-forms a linear tetrapyrrole with symmetric side chains apapapap and 4 NH4+ |
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describe uroporphyrinogen synthase rxn
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-forms tetrapyrrole ring uroporphyrinogen 3 which is colorless as double bonds are not conjugated; abundant in nature
asymmetry APAPAPPA |
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describe uroporphyrinogen 3 rxn
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-synthesis requires uroporphyrinogen synthase
-genetic defect n uroporphyrinogen synthase, uroporphyrinogen 1 is formed spontaneously- it is symmetrical and useless; some intermediates will form but have no function |
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describe coproporphyrinogen 3 synthesis
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-uroporhyrinogen decarboxylase forms coproporhyrinogen and in process side chain acetyl groups are converted to methyl groups
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describe protoporphyrin 9 synthesis
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-couple of rxns to convert
-decarboxylation of side chains and oxidation of ring -2 acidic propionate groups are converted to uncharged vinyl groups -oxidation rxns result in conjugated ring system carried out by cytochrome P450 enzymes -still no iron, now fewer charged groups |
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describe heme synthesis
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-ferrous ion Fe2+ forms 6 bonds in heme
--histadine, oxygen and 4-N |
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what are eg of other metaloporphyrins
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-cobalamin Vit B12
--corrin ring with cobalt and cyanide group cyanocobalamin- commercial vitamin form -cobalmin coenzyme- in us -dimethylbenzimidazole |
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describe locations of heme synthesis
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-ALA transported out of mitochondria
-coproporphyrinogen 3 transported back in |
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describe regulation of heme synthesis
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-heme and hemin repress biosynthesis of ALA synthase by retarding synthesis of its precursor
-heme adn hemin inhibit transport of ALA precursor into mitochondrion where post translational modification occurs -both allosterically inhibit ALA synthase |
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describe lead poisoning
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-lacks clear symptoms
-in adults, may manifest as fatigue, abdominal pain and or arthralgia -in kids, can cause rofound encephalopathic crisis -biochemical effects leading to anemia- inactivates ALA dehydrate, inactivates ferrochelatase resulting in formation of zinc protoporphyrin |
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describe porphyrias
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-genetic defects in enzymes involved in heme synthesis with exception of ALA synthase
-induce photosensitivity -frequent symptoms include neuropsychiatric problems and abdominal pain -rare adn sometimes diagnosed incorrectly as psychiatric disorders |
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describe acute intermittent porphyria AIP
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-caused by defect in porphobilinogen deaminase
-ALA and porphobilinogen accumulate and at high concentrations are toxic to nervous system -urine contains porphobilinogen which can form porphyrins upon exposure to light leading to red colored urine -no photosensitivity -90% with genetic trait never have symptoms -elevated PBG and ala in urine as well as PBG deaminase in RBCs, no porphyrins would be elevated |
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how do drugs worsen AIP
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-treatment with certain drugs (when misdiagnosed) can be potentially fatal- barbiturates, phenytoin, tranquilizers, antipsychotics, hypnotics
-induce synthesis of cytochrome P450 apoproteins, the major mechanism for metabolizing drugs -inc in demand for heme can deplete teh heme pool which would inhibit ALA synthase allosterically and act as repressor of its synthesis -since PBG deaminase is defective, both ALA and PBG accumulate to toxic levels |
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describe treatment of AIP
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-withdraw offending drugs
-administer hematin (hemin) which represses and allosterically inhibits ALA synthase -carb rich diet to repress ALA sytnhase as well |
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-describe congenital erythropoietic porphyria
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-genetically defective uropophyrinogen synthase, 36 variants
-uroporphyrinogen 1 and its metabolites accumulate -hypersensitivity to sunlight; upon exposure to sunlight free radicals may be formed that attack lysosomes which release their contents consisting of many hydrolytic enzymes that destory teh cell -hemolytic anemia and enlargement of spleen -red wine colored urine |
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describe heme catabolism and transport
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-heme is catabolized in spleen, liver and bone marrow
-old RBCs are 70% of catabolized heme -first rxn by heme oxygenase uses O2 to crack ring and produce biliverdin, iron and CO -biliverdin reductase then reduces green biliverdin to orange bilirubin; uses NADPH -bilirubin is transported out of cell and transported by albumin to hepatocytes -in ER of hepatocytes, glucuronyl transferase conjugates bilirubin with glucuronic acid GlcUA using UDP-GlcUA -conjugated bilirubin (bilirubin diglucuronide) is water soluble and exported from hepatocyptes to liver canaliculus then to biliary system and into intestine for excretion -note Fe is recycled |
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describe characteristics of bilirubin
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-while bound to albumin, bilirubin can destroy 2 hydroxyperoxy radicals by donating 2 electrons and is oxidized back to biliverdin
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describe colors of bruises
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-red/purple heme
-green- biliverdin -orange- bilirubin |
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describe jaundice
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-in liver damage, conjugation of bilirubin may be imparied and water insoluble bilirubin accumulates because it cannot be excreted at sufficient rates. it collects in blood an fatty tissues such as subcutaenous fat
-jaundice means yellow skin -color may be yellow because of carotenoid pigments such as b-carotene and lycopene but do not usually color sclera of eye -3 types --prehepatic- usually due to excessive hemolysis, eg sickle cell anemia and drug induced hemolytic anemia; so much bilirubin that UDP-glucuronyltransferase cannot conjugate it fast enough to keep levels low --hepatic may be caused by defective transport, lack of UDP-glucuronyltransferase, liver dysfunction --posthepatic- caused by biliary obstruction, sometimes may be tumor eg pancreatic cancer can cause biliary obstruction simply because tumor can press against duct to shut off biliary flow -in neonates, hyperbilirubinemia commonly shows up 1-5 days post partum (60%) and more common in premature babies 80% -can cause brain damage (kernicterus) -usually caused by immature liver that is not yet producing all of its enzymes in sufficient quantities, usually UDP-glucuronyltransferase -phototherapy is treatment, light between wavelengths 425-450 n will convert bilirubin to harmless water-soluble isomers that can be excreted |
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describe direct and indirect bilirubin
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insoluble
- bilirubin- unconjugated bilirubin- indirect bilirubin soluble -bilirubin diglucuronide- conjugated bilirubin- direct bilirubin |
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describe the final fates of bilirubin
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-in large intestine, conjugated bilirubin is converted back to bilirubin and further metabolized to colorless urobiliogen UBG, some of which is recycled via enterohepatic circulation
-in liver some of UBG that has been recycle is exported to systemic circulation and oxidized -oxidized forms are filtered out by kidneys and appear in urine as urobilins including d and i-urobilin which give urine yellowish color -in large intestine UBG can be further oxidized to form stercobilin, the brown pigment in human feces |
