Dr. Shumaila Asim Lecture # 2

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Presentation transcript:

Dr. Shumaila Asim Lecture # 2 Heme Synthesis Dr. Shumaila Asim Lecture # 2

Overview of Heme Synthesis 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.

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

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

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

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, repressing transcription of the ALA Synthase gene in most cells.

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

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.

Uroporphyrinogen III Synthase converts the linear tetrapyrrole hydroxymethylbilane to the macrocyclic uroporphyrinogen III.

All 4 acetyl side chains are decarboxylated to methyl groups (catalyzed by Uroporphyrinogen Decarboxylase) Oxidative decarboxylation converts 2 of 4 propionyl side chains to vinyl groups (catalyzed by Coproporphyrinogen Oxidase) Oxidation adds double bonds (Protoporphyrinogen Oxidase).

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

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.

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