Which of the following TCA cycle intermediate is a part of heme metabolism?
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 (Monopyrrole)2. Synthesis of Uroporphyrinogen (Tetrapyrrole)3. Conversion of Uroporphyrinogen to Protoporphyrin4. Formation of Heme by incorporation iron.1. Synthesis of Porphobilinogen (Monopyrrole)ALA 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.
Alpha ketoglutarate
Fumarate
Succinyl CoA
Malate
Proteins and Amino Acids