<prompt> Which of the following TCA cycle intermediate is a part of heme metabolism?Alpha ketoglutarateFumarateSuccinyl CoAMalate  <response>: Ans. c Succinyl CoARef: Harpers Biochemistry 30th Ed; Page No- 325Steps of Synthesis of Heme To produce 1 molecule of heme, 8 molecules each of glycine and succinyl-CoA are required. It is divided into1. Synthesis of Porphobilinogen Monopyrrole2. Synthesis of Uroporphyrinogen Tetrapyrrole3. Conversion of Uroporphyrinogen to Protoporphyrin4. Formation of Heme by incorporation iron.1. Synthesis of Porphobilinogen MonopyrroleALA Synthase ALAS Catalyse condensation reaction between succinyl-CoA and glycine to form a-amino-ketoadipic acid, which is rapidly decarboxylated to form S-aminolevulinate ALA. Synthesis of ALA occurs in mitochondria. Two isoforms of ALAS ALAS-I the Hepatic Form is the Key regulatory enzyme ALAS-11 is the Erythropoietic formALA Dehydratase Two molecules of ALA are condensed by the enzyme ALA dehydratase to form two molecules of water and one of porphobilinogen PBG Takes place in the cytosol. ALA dehydratase is a zinc-containing enzyme This enzyme is sensitive to inhibition by lead, as can occur in lead poisoning. Thus the first precursor pyrrole is formed.2. Synthesis of Uroporphyrinogen Tetrapyrrole The formation of a cyclic tetrapyrrole-i.e. a porphyrin- occurs by condensation of four molecules of PBG.Uroporphyrinogen -I Synthase or HMB Synthase or PBG Deaminase Four molecules of PBG condense in a head-to-tail manner to form a linear tetrapyrrole, hydroxymethylbilane HMB. 4 moles of NH3 , is released Takes place in the cytosol. The reaction is catalyzed by uroporphyrinogen I synthase, also named PBG deaminase or HMB synthase.Uroporphyrinogen III synthase HMB is converted to Uroporphyrinogen III by Uroporphyrinogen III synthase. Uroporphyrinogen is thus the first porphyrin precursor formed. Under normal conditions, the uroporphyrinogen formed is almost exclusively the III isomer.But HMB cyclizes in certain porphyrias, spontaneously to form uroporphyrinogen I.3. Conversion of Uroporphyrinogen to Protoporphyrin Uroporphyrinogen decarboxylase Uroporphyrinogen II is converted to coproporphyrinogen III by decarboxylation of all of the acetate A groups, which changes them to methyl M substituents. The reaction is catalyzed by uroporphyrinogen decarboxylase. This is also capable of converting uroporphyrinogen I to coproporphyrinogen I This also takes place in the cytosol Coproporphyrinogen III then enters the mitochondria, where it is converted to protoporphyrinogen III. The mitochondrial enzyme coproporphyrinogen Oxidase catalyzes the decarboxylation and oxidation of two propionic side chains to form protoporphyrinogen. This enzyme is able to act only on type-III coproporphyrinogen, which would explain why type I protoporphyrins do not generally occur in nature. Protoporphyrinogen Oxidase The oxidation of protoporphyrinogen to protoporphyrin is catalyzed by another mitochondrial enzyme, protoporphyrinogen oxidase.4. Formation of Heme by incorporation of Iron This is the final step in heme synthesis. It involves the incorporation of ferrous iron into protoporphyrin in a reaction. This step is catalyzed by ferrochelatase heme synthase. Takes place in mitochondria. 