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Biosynthesis and degradation of porphyrin and heme
- 1. Submitted by T.Soundarya I- M.Scbiochemistry P19BC004 BIOSYNTHESIS AND DEGRADATION OF PORPHYRIN AND HEME
- 2. SYNOPSIS : Introduction Biomedical importance Porphyrin Biosynthesis of heme formation of heme Degradation heme Conclusion References
- 3. INTRODUCTION : Theheme speaks about: “ I am the red of blood, responsible for respiration ;
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- 6. • Heme isthemost important porphyrin containing compound. • It isprimarily synthesized in the liver &the erythrocyte- producing cells of bone marrow (erythroidc ells). • Heme synthesis also occursto some extent in other tissues. • Mature erythrocytes lacking mitochondria are a notable exception.
- 7. 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 CoAto form δ – aminolevulinate (ALA). • Catalysed by a PLPdependent δ – aminolevulinate synthase occursin the mitochondria. • It isa rate-controlling step in porphyrin synthesis
- 8. 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 issensitive to inhibition by heavy metals suchas lead.
- 9. Formation of porphyrinring •Porphyrin synthesis occursby condensation of four molecules of porphobilinogen (PBG). • Thefour pyrrole rings in porphyrin are interconnected by methylene (-CH2)bridges derived from α- carbon of glycine. • Theinteraction of two enzymes-namely uroporphyrinogen I synthase &uroporphyrinogen lll cosynthase-results in condensation of porphobilinogen followed by ring closure & isomerization to produce uroporphyrinogen lll.
- 10. 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
- 11. • Protoporphyrinogen oxidaseoxidizes methylene groups (-CH2-) interconnecting pyrrole rings to methenyl groups (=CH-). • Thisleads to the synthesis of protoporphyrin lX.
- 12. Synthesisof heme fromprotoporphyrin lX • The incorporation of ferrous iron (Fe2+) into protoporphyrin IX iscatalysed by the enzyme ferrochelatase or heme synthetase. • Thisenzyme can be inhibited by lead.
- 14. Effect of drugson ALAsynthase activity • The activity of ALAsynthase ismarkedly 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.
- 15. Heme oxygenase A complexmicrosomal enzyme, heme oxygenase utilizes NADPH &O2 and cleaves the methenyl bridges between the two pyrrole rings (A and B) to form biliverdin. Simultaneously, ferrous iron (Fe2+) isoxidized to ferric form (Fe3+) & released.
- 16. Biliverdin's methenylbridges (between the pyrrole rings Cand D) are reduced to methylene group to form bilirubin yellow pigment). Catalysed by an NADPH dependent soluble enzyme, biliverdin reductase
- 18. Transport of bilirubinto liver Bilirubin is lipophilic &therefore insoluble in aqueous solution. Bilirubin is transported in the plasma in a bound (non-covalently) form to albumin. Albumin has two binding sites for bilirubin-a high affinity site &a low affinitysite.
- 19. Text bookof Biochemistry – U Satyanarayana Text book of Biochemistry – DM Vasudevan Text book of Biochemistry – MN Chatterjea Text book of Biochemistry – harper illustrated