HEME SYNTHESIS

HEME SYNTHESIS

• 1.
  Heme Synthesis Gandham.Rajeev
• 2.
  • Heme isthe most important porphyrin containing compound. • It is primarily synthesized in the liver & the erythrocyte-producing cells of bone marrow (erythroidc ells). • Heme synthesis also occurs to some extent in other tissues. • Mature erythrocytes lacking mitochondria are a notable exception.
• 3.
  Formation of δ-aminolevulinate • Glycine, a non-essential amino acid & succinyl CoA, an intermediate in the citric acid cycle, are the starting materials for porphyrin synthesis. • Glycine combines with succinyl CoA to form δ – aminolevulinate (ALA). • Catalysed by a PLP dependent δ –aminolevulinate synthase occurs in the mitochondria. • It is a rate-controlling step in porphyrin synthesis
• 4.
  Synthesis of porphobilinogen • Two molecules of δ -aminolevulinate condense to form porphobilinogen (PBG) in the cytosol. • Catalysed by a Zn-containing enzyme ALA dehydratase. • It is sensitive to inhibition by heavy metals such as lead.
• 5.
  Formation of porphyrinring • Porphyrin synthesis occurs by condensation of four molecules of porphobilinogen (PBG). • The four pyrrole rings in porphyrin are interconnected by methylene (-CH2) bridges derived from α- carbon of glycine. • The interaction of two enzymes-namely uroporphyrinogen I synthase & uroporphyrinogen lll cosynthase-results in condensation of porphobilinogen followed by ring closure & isomerization to produce uroporphyrinogen lll.
• 6.
  Conversion of uroporphyrinogenlll to protoporphyrin lX • Uroporphyrinogen decarboxylase decarboxylates all the four acetate (A) side chains to form methyl groups (M), to produce coproporphyrinogen. • Coproporphyrinogen oxidase converts (oxidative decarboxylation) two of the propionate side chains (P) to vinyl groups (V) & results in the formation of protoporphyrinogen
• 7.
  • Protoporphyrinogen oxidaseoxidizes methylene groups (-CH2-) interconnecting pyrrole rings to methenyl groups (=CH-). • This leads to the synthesis of protoporphyrin lX.
• 8.
  Synthesis of hemefrom protoporphyrin lX • The incorporation of ferrous iron (Fe2+) into protoporphyrin IX is catalysed by the enzyme ferrochelatase or heme synthetase. • This enzyme can be inhibited by lead.
• 10.
  Regulation of hemesynthesis • Heme production in the liver is required for the formation of hemoproteins (e.g. Cytochrome P450 involved in detoxification) while in the erythroid cells, it is necessary for the synthesis of hemoglobin. • Two different mechanisms exist for the regulation of heme biosynthesis in the liver & the erythroid cells
• 11.
  Regulation in theliver • The first committed step in heme biosynthesis catalysed by δ-aminolevulinate (ALA) synthase is regulatory. • Heme or its oxidized product hemin (Fe3+) controls this enzyme activity by three mechanisms • Feedback inhibition • Repression of ALA synthatase • Inhibition of transport of ALA synthase from cytosol to mitochondria (the site of action).
• 12.
  Effect of drugson ALA synthase activity • The activity of ALA synthase is markedly increased by the administration of a large number of drugs e.g. phenobarbital, insecticides, carcinogens etc. • These compounds are mostly metabolized by a heme containing protein, cytochrome P450 • On administration of drugs, cellular levels of heme are depleted due to its increased incorporation into cytochrome P450.
• 13.
  • The reducedheme concentration increases the synthesis (derepression) of ALA synthase to meet the cellular demands. • Regulation in the erythroid cells: • The enzyme ALA synthase does not appear to control the heme synthesis in the erythroid cells. • Uroporphyrinogen synthase & ferrochelatse mostly regulate heme formation in these cells
• 14.
  Thank you