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10 Cards in this Set
- Front
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Porphyrins |
- Compounds that chelate metal ions tightly (ex.: heme) - Formed by the linkage of 4 pyrrole rings (via methenyl bridges); double bonds conjugated (-> colors) => prosthetic group - Each ring - 2 side chains - 3 types (physiologically important in humans: III) - Central pocket can be occupied by a metal ion -- Fe2+ -> heme -- Co2+ -> cobaltamine (vit B12) -- Mg2+ -> chlorophyll |
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Physiological roles of hemes |
- Mito cytochromes - ETC (-> H gradient; cyanide poisoning -| Cyt a3) - Hemoglobin & myoglobin - O2 transport in blood & muscle - Cytochrome P450 (CYP): metabolism of fat-soluble compounds, drugs (liver) - Catalase - antioxidant enzyme hydrolyzing H2O2 |
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Heme biosynthesis |
- in liver, bone marrow (Pb -|) - different isozymes - Gly + succinyl-CoA -> ALA synthase, irr., RLS1 -> δ-aminolevulinic acid (ALA) [-fb: ALAs mRNA |-- heme, G] - 2ALA -> ALA dehydrase -> porphobilinogen (PBG = pyrrole) - 4PBG -> Hydroxymethylbilane synthase, RLS2 -> hydroxymethylbilane -> Uroporphyrinogen synthase -> uroporphyrinogen I (symmetrical ring) -> Uroporphyrinogen III cosynthase -> uroporphyrinogen III (assymetry) ->> protoporphyrin IX [purple & fluorescent] -> ferrochelatase -> heme ->> CYP (liver), hemoglobin (blood), etc. |
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Uroporphyrinogen III |
Common precursor for chlorophyll, cobalamine, heme |
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Acute porphyrias |
Blockage of early RLSs in liver (mostly genetic) -| heme production
Ex.: Acute Intermittent Porphyria (AIP) - drug (As = inducers) ingestion -> CYP enzyme production -| heme => heme shortage -> ↑ALA synthase -> accumulation of ALA & PBG (in liver; GABA antagonist) -> abdominal pain, neuro symptoms - excess PBG in urine -> oxidation -> purple - treatment: IV hemin / G |
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Non-acute porphyrias |
Blockage beyond hydroxymethylbilane (2' to liver dmg - acquired) -> accumulation of abnormal porphyrin derivatives (uroporphyrins) -> liver dmg, photosensitive rashes (no neuro) Heme & ALA lvls normal (compensation by -fb) Expose urine to air -> oxidation -> turns red Ex.: Porphyria Cutanea Tarda (most common) - ↓uroporhyrinogen decarboxylase activity -> ↑uroporphyrins - treatment: phlebotomy (drawing a lot of blood); avoid liver toxins & sun |
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Lead poisoning |
Pb -| ALA dehydrase & ferrochelatase in both liver & blood Symptoms: AIP (abdominal pain, neuro symptoms) + anemia (↓ BM heme synthesis) Basophilic stippling of RBC's on blood smear |
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Iron-deficiency anemia |
Enzymes in BM regulated differently than the ones in liver: ++ Fe -> (erythroid) ALA synthase mRNA transcript: IRE (Iron Response Element) binds IRP in absence of Fe -| translation (mRNA lvls same) |
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Degradation of heme |
Macrophage (spleen): Heme -> Heme oxygenase, NADPH, O2 ->> biliverdin (green), Fe -> Billiverdin reductase, NADPH -> bilirubin (fat-soluble, yellow-red) -> liver -> Bilirubin glucuronyltransferase, 2 glucuronic A -> bilirubin diglucuronide (H2O-soluble) -> bile, intestine (bacteria) -> urobilinogen -> -- ox. -> stercobilin (brown) -- reabsorbed, blood -> kidney -> urobilin (yellow) |
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Jaundice |
Result of ↑ bilirubin in blood (also -> BBB => encephalopathy, coma) van den Bergh rxn = biochemical assay (solubility test in met/H2O) -> lvl of total/conjugated bilirubin in blood Types of jaundice: Hemolytic (RBC lysis -> sickle cell anemia) -> ↑ unconjugated b. (liver enzymes can't keep up) Obstructive (bile duct blockage by gallstones) -> ↑ conjugated b. Hepatocellular (hepatitis, inability to synthesize/excrete) -> ↑ liver enzymes AST, ALT in blood (both un/conjugated accumulate) Neonatal -> ↓ lvls of bilirubin glucuronyltransferase -> cannot conjugate billirubin (treated by blue fluorescent light => bilirubin -> H2O-soluble metabolytes) |
