BMB401 ANGELA Review-1

BMB401 ANGELA Review-1 - LECTURE 11 Heme Synthesis...

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LECTURE 11 Heme Synthesis Formation of protoporhyrin IX o Asymmetric ring structure o Requres chelation of iron Requires o 4 mitochondrial enzymes o 4 cytosolic enzymes Reaction1: Condensation between succinyl CoA and Glycine occurring in mitochondrial matrix Enzyme: α- Aminolevulinate Synthase (ALA) Happens in the mitochondrial matrix Atleast one of the reactants is activated (liberation of CoA and CO 2 helps drive it forward o Regulation primarily by negative feedback (most highly regulated step) Transport of α -ALA into the mitochondrion is blocked by high heme concentration. ALA synthase is synthesized in cytosol, block the entry from cytosol to matrix you can block the action Transcription of D-ALA synthase Messenter stability Translation: Negative feedback by heme reduces translation of α -ALA mRNA **it degrades quickly so it goes away quickly Reaction 2: Dehydration Synthesis Transport to cytosol 2 molecules of α- ALA condenses to form each porphobilinogen molecule **It takes 8 molecules of for 4 porphobilinogen Reaction 3: Condensation Link 4 molecules of porphobilinogen head to tail to form a linear tetrapyrrole molecule o Releases 1 ammonium ion for each methylene bridge made Enzyme: Porphobilinogen Deaminase
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Reaction 4: Cyclization Synthesis of an asymmetric ring (Uroporphyrinogen III) Enzyme: Uroporphyrinogen III synthase o Also called Uroporphyrinogen III cosynthase because it requires a cosynthase to form the asymmetric ring o Cosynthase flips one pyrool (APAPA PPA ) o Formation of uroporphynogen 1 leads to build up of byproducts in tissues Next Few Reactions Form methyl and vinyl side chains, and alter saturation of ring constituents, finally ending with protporphyrin IX. o Takes place in mitochondrion on the innermembrane Finally ferrous Iron, Fe 2+ is chelated o Enzyme: Ferrochelatase o (PP IX is transported to matrix where iron is chlated) Where does iron come from? Free iron is toxic because it can donate and accept electrons and acts as catalyst in O 2 Iron must be sequestered o In a molecule called ferritin that acts as intracellular iron storage o 24 subunits organisms make into ball like structure with (hollow core) o In the hollow core is where iron is localized o Localization of iron in ferritin protein allows it to be kept in a soluble easily accessed form Comes from diet on the protein Transferrin o Can only carry 2 o Binds to transferring receptor (endocytosed into the cell in endosytic vesicle and through the pathway. Vessel is acidified and iron is dropped.) o Transferrin is recycled by transporting it through the exocytic pathway through the cell. Porphyrias:
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BMB401 ANGELA Review-1 - LECTURE 11 Heme Synthesis...

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