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Overview of Heme Biosynthesis: Key Pathway Intermediates and Enzymes

This lecture provides an in-depth overview of the heme biosynthesis pathway, highlighting key substrates like succinyl-CoA and glycine, as well as important intermediates such as δ-aminolevulinic acid and porphobilinogen. The regulatory enzyme ALA synthase is discussed, along with the functions of other crucial enzymes in the pathway. The synthesis of heme starting in the mitochondria, regulatory mechanisms, and disorders affecting heme synthesis are also covered comprehensively.

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Overview of Heme Biosynthesis: Key Pathway Intermediates and Enzymes

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  1. Heme Synthesis Dr. Shumaila Asim Lecture # 2

  2. Overview of Heme Synthesis Heme Succinyl CoA + Glycine Protoporphyrin IX ALA synthase Protoporphyrinogen IX -aminolevulinic acid Coproporphyrinogen III mitochondrial matrix cytoplasm -aminolevulinic acid Uroporphyrinogen III Coproporphyrinogen III Porphobilinogen Uroporphyrinogen I Coproporphyrinogen I Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow.

  3. Heme biosynthesis • in bone marrow (85% of Hb) and liver (cytochromes) • cell location: mitochondria / cytoplasm / mitochondria • substrates: succinyl-CoA + glycine • important intermediates: • δ-aminolevulinic acid (= 5-aminolevulinic acid, ALA) • porphobilinogen (PBG = pyrrole derivate) • uroporphyrinogen III (= porphyrinogen – heme precursor) • protoporphyrin IX (= direct heme precursor) ● key regulatory enzyme: ALA synthase

  4. GLYCINE + SuccinylCoA ALA synthase d-aminolevulinic acid(ALA) ALA dehydratase Porphobilinogen(PBG) PBG deaminase hydroxymethylbilane Uroporphyrinogen III cosynthase uroporphyrinogen III Uroporphyrinogen decarboxylase coprophyrinogenIII Coproporphyrinogen oxidase Protoporphyrinogene IX Protoporphyrinogen oxidase protoporphyrin IX Ferrochelatase Heme

  5. δ-aminolevulinic acid (ALA) • synthesis of heme starts in mitochondria • succinyl-CoA and Gly undergo a condensation → ALA • reaction is catalyzed by enzyme ALA synthase

  6. ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway. Regulation occurs through control of gene transcription.  Heme functions as a feedback inhibitor, repressingtranscription of the ALA Synthase gene in most cells.

  7. Porphobilinogen (PBG) • ALA leaves the mitochondria → cytoplasm • 2x ALA condense together to form porphobilinogen • reaction is catalyzed by porphobilinogen synthase (ALA dehydratase)

  8. Porphobilinogen (PBG) is the first pathway intermediate that includes a pyrrole ring. The porphyrin ring is formed by condensation of 4 molecules of porphobilinogen.  Porphobilinogen Deaminase catalyzes successive PBG condensations, initiated in each case by elimination of the amino group.

  9. Uroporphyrinogen III Synthaseconverts the linear tetrapyrrolehydroxymethylbilane to the macrocyclicuroporphyrinogen III.

  10. All 4 acetyl side chains are decarboxylatedto methyl groups (catalyzed by UroporphyrinogenDecarboxylase) • Oxidative decarboxylation converts 2 of 4 propionyl side chains to vinyl groups (catalyzed by CoproporphyrinogenOxidase) • Oxidation adds double bonds (ProtoporphyrinogenOxidase).

  11. Fe++ is added to protoporphyrin IX via Ferrocheletase, a homodimeric enzyme containing 2 iron-sulfur clusters.

  12. Regulation of heme biosynthesis • ALA synthase is a key regulatory enzyme ● it is an allosteric enzyme that is inhibited by an end product - heme (feedback inhibition) ● requires pyridoxal phosphate as a coenzyme ● certain drugs and steroid hormones can increase heme synthesis • Porphobilinogen synthase is inhibited by lead ions Pb2+ in case of lead poisoning. • Ferrochelatase (heme synthase) can be also inhibited by Pb2+. Its activity is influenced by availability of Fe2+ and ascorbic acid.

  13. Disorders of Heme Synthesis • Acquired: Lead poisoning • Congenital: Porphyrias • Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)

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