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Porphyrin Metabolism

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Content :-
What is porphyrin?
Biosynthesis of porphyrin (heme)
Site
Reactions
Regulation
Degradation of heme
Site
Reactions
Reference

What is Porphyrin?
Porphyrins are cyclic compound formed by the linkage of four pyrrole rings through methyne(=HC-)bridges.

Structure of hemoglobin & chlorophyll
Examples of some important human and animal hemoproteins.
Biosynthesis of heme



Site of biosynthesis:-

-Liver (hepatocyte) & Bone Marrow
( erythryoid producing cells )










2) ALA dehydratase :-

The substrates are two molecules of ALA.

The product is porphobilinogen, the first pyrrole.

ALA dehydratase is a -SH containing enzyme.

It is very susceptible to inhibition by lead.


3) Uroporphyrinogen I synthase and uroporphyrinogen IIIcosynthase

Production of uroporphyrinogen III requires two enzymes.The substrates are four molecules of porphobilinogen.


4) Uroporphyrinogen decarboxylase:-
Decarboxylates the acetic acid groups, converting them to methyl groups.


5) Coproporphyrinogen III oxidase:-
Catalyzes the conversion of two propionic acid groups to vinyl groups


6) Protoporphyrinogen IX oxidase:-
Protoporphyrinogen IX oxidase converts the methylene bridges between the pyrrole rings to methenyl bridges.



7) Ferrochelatase:-

Ferrochelatase adds Fe++ to protoporphyrin IX, forming heme.
• The enzyme requires Fe++, ascorbic acid and cysteine (reducing agents).
• Ferrochelatase is inhibited by lead.
Regulation of heme synthesis
Feedback regulation:- heme is a feedback inhibitor of ALA synthase. ALA synthase occurs in both hepatic (ALAS 1) and erythroid (ALAS 2) forms.

Effects of drugs and steroids:- Certain drugs and steroids can increase heme synthesis via increased production of the ratelimiting enzyme, ALA synthase

Substrate availability:- Fe++ must be available for ferrochelatase.


Degradation of heme

Site of Degradation :-

- cells of the reticulo endothelial system in spleen, liver and bone marrow


Heme Degradation
Most of the heme which is degraded comes from hemoglobin in red blood cells, which have a life span of about 120 days.
There is thus a turnover of about 6 g/day of hemoglobin.
Normally , senescent red blood cells and heme from other sources are engulfed by cells of the reticuloendothelial system.
The globin is recycled or converted into amino acids, which in turn are recycled or catabolized as required.
Heme is oxidized.

Microsomal heme oxygenase system
Transport of bilirubin in Plasma
Bilirubin on release from macrophages circulates as unconjugated bilirubin in plasma tightly bound to albumin.










HARPER’S ILLUSTRATED BIOCHEMISTRY (28TH EDITION) by robert murray,david A.bender,peter j kennekky,victor w rodwell,p.antony weil.(page No-271)

Biochemistry Lippincott’s Illustrated Reviews by Richard Harvey& Denise Ferrier



Porphyrin Metabolism

  1. 1. BY:-
  2. 2. • What is porphyrin? • Biosynthesis of porphyrin (heme)  Site  Reactions  Regulation • Degradation of heme  Site  Reactions • Reference
  3. 3. • Porphyrins are cyclic compound formed by the linkage of four pyrrole rings through methyne(=HC-)bridges.
  4. 4. Examples of some important human and animal hemoproteins.
  5. 5. Site of biosynthesis:- -Liver (hepatocyte) & Bone Marrow ( erythryoid producing cells )
  6. 6. (Linear tetrapyrrole)
  7. 7. 1) Delta-aminolevulinic acid synthase (ALA synthase) :- • The substrates are succinyl-CoA and glycine The product is delta aminolevulinic acid (ALA),An essential cofactor is pyridoxal phosphate (vit B-6). • This is the rate-limiting reaction of heme synthesis in all tissues, and it is therefore tightly regulated.
  8. 8. 2) ALA dehydratase :- • The substrates are two molecules of ALA. • The product is porphobilinogen, the first pyrrole. • ALA dehydratase is a -SH containing enzyme. • It is very susceptible to inhibition by lead.
  9. 9. 3) Uroporphyrinogen I synthase and uroporphyrinogen IIIcosynthase • Production of uroporphyrinogen III requires two enzymes.The substrates are four molecules of porphobilinogen.
  10. 10. 4) Uroporphyrinogen decarboxylase:- • Decarboxylates the acetic acid groups, converting them to methyl groups.
  11. 11. 5) Coproporphyrinogen III oxidase:- • Catalyzes the conversion of two propionic acid groups to vinyl groups
  12. 12. 6) Protoporphyrinogen IX oxidase:- • Protoporphyrinogen IX oxidase converts the methylene bridges between the pyrrole rings to methenyl bridges.
  13. 13. 7) Ferrochelatase:- • Ferrochelatase adds Fe++ to protoporphyrin IX, forming heme. • The enzyme requires Fe++, ascorbic acid and cysteine (reducing agents). • Ferrochelatase is inhibited by lead.
  14. 14. • Feedback regulation:- heme is a feedback inhibitor of ALA synthase. ALA synthase occurs in both hepatic (ALAS 1) and erythroid (ALAS 2) forms. • Effects of drugs and steroids:- Certain drugs and steroids can increase heme synthesis via increased production of the ratelimiting enzyme, ALA synthase • Substrate availability:- Fe++ must be available for ferrochelatase.
  15. 15. Site of Degradation :- - cells of the reticulo endothelial system in spleen, liver and bone marrow
  16. 16. • Most of the heme which is degraded comes from hemoglobin in red blood cells, which have a life span of about 120 days. • There is thus a turnover of about 6 g/day of hemoglobin. • Normally , senescent red blood cells and heme from other sources are engulfed by cells of the reticuloendothelial system. • The globin is recycled or converted into amino acids, which in turn are recycled or catabolized as required. • Heme is oxidized.
  17. 17. 1) Conversion of heme to bilirubin:- (cells of the reticuloendothelial system in spleen, liver and bone marrow) • Heme ring is cleaved by a microsomal heme oxygenase between the I and II pyrrole rings. • Biliverdin reductase reduces the central methene bridge of biliverdin, producing bilirubin.
  18. 18. Microsomal heme oxygenase system
  19. 19. • Bilirubin on release from macrophages circulates as unconjugated bilirubin in plasma tightly bound to albumin. Albumin + free Bilirubin Bilirubin ~ Albumin Complex unconjugated bilirubinWhy bound to albumin? Significance: ★Increase the solubility of whole molecule ★ Prevent unconjugated bilirubin freely come into other tissue, cause damage.
  20. 20. 2) Conjugation of bilirubin with glucuronic acid: (hepatocytes) • Conjugation is accomplished by attaching two molecules of glucuronic acid to it in a two step process by UDP glucuronyl transferase. •The reaction is a transfer of two glucuronic acid groups sequentially to the propionic acid groups of the bilirubin. •The major product is bilirubin diglucuronide .
  21. 21. • HARPER’S ILLUSTRATED BIOCHEMISTRY (28TH EDITION) by robert murray,david A.bender,peter j kennekky,victor w rodwell,p.antony weil.(page No-271) • Biochemistry Lippincott’s Illustrated Reviews by Richard Harvey& Denise Ferrier

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