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Understanding Heme and Porphyrin: Functions, Synthesis, and Clinical Implications

This overview delves into the biology of heme and porphyrins, cyclic compounds vital for various physiological processes. Heme, the predominant metalloporphyrin in humans, plays a crucial role in oxygen transport and signaling, while porphyrins are key in solar energy utilization and enzymatic processes. The lecture outlines heme synthesis, regulation, and degradation, as well as iron metabolism and associated disorders, including porphyrias and anemia. Understanding these components can illuminate their significance in health and disease.

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Understanding Heme and Porphyrin: Functions, Synthesis, and Clinical Implications

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  1. Porphyrins David Hart Dec 12, 2006

  2. Heme

  3. Porphyrins • Cyclic compounds that bind metal ions • Chlorphyll (Mg2+) • Central to solar energy utilization • Heme (Fe2+) • Most prevalent metalloporphyrin in humans • Central to oxygen sensing and utilization • Cobalamin (Cobalt) Bacterial Coenzyme F430 (Nickel)

  4. The Heme Pocket in Hemoglobin

  5. Heme • One ferrous (Fe2+) atom in the center of the tetrapyrrole ring of ProtoporphyrinIX • Prosthetic group for • Hemoglobin and Myoglobin • The Cytochromes • Catalase and Tryptophan pyrrolase • Nitric Oxide Synthase • Turnover of Hemeproteins (Hemoglobin, etc) is coordinated with synthesis and degradation of porphyrins • Bound iron is recycled

  6. Lecture Outline • Heme function • Heme synthesis and regulation • Iron metabolism • Porphyrias • Heme degradation

  7. Heme Function • Oxygen sensing (heme and hemoproteins) • Oxygen transport (hemoglobin) • Oxygen storage (myoglobin) • Electron transport (cytochromes) • Oxidation (cyrochrome p450, tryptophan pyrrolase, guanylate cyclase …) • Decomposition and activation of H2O2 (catalase and peroxidase) • Nitric Oxide Synthesis • Regulation of cellular processes • Effector of apoptosis

  8. Porphyrin: Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges B A N HN NH N C D

  9. Porphyrin Side Chains • M = Methyl (-CH3) • V = Vinyl (-CH=CH2) • P = Propionyl (-CH2-CH2-COO-) • A = Acetyl (-CH2-COO-)

  10. Biosynthesis of Heme • Synthesized in every human cell • Liver (15%): • 65% Cytochrome P450 • Synthesis fluctuates greatly • Alterations in cellular heme pool • Bone Marrow (80%) • Erythrocyte precursors: Hemoglobin • Synthesis relatively constant • Matched to rate of globin synthesis • Largely unaffected by other factors

  11. All Carbon and Nitrogen atoms provided by 2 building blocks: COOH CH2 CH2 COSCoA SUCCINYL CoA CH2 NH2 COOH GLYCINE

  12. COOH CH2 CH2 COSCoA SUCCINYL CoA CH2 NH2 COOH GLYCINE is Decarboxylated - CO2  AMINOLEVULINIC ACID SYNTHASE IN MITOCHONDRIA

  13. COOH CH2 CH2 C=O CH2 NH2 Condense to form:  AMINOLEVULINIC ACID (ALA) MOVES OUT OF THE MITOCHONDRION

  14. COOH CH2 CH2 C=O COOH CH2 CH2 C=O -2 H2O CH2 NH2 CH2 NH2 2 Molecules dehydrated by • ALA DEHYDRATASE

  15. COOH CH2 CH2 C COOH CH2 C C C NH CH2 NH2 To form Porphobilinogen (PBG)

  16. COOH CH2 CH2 Acetate CH2COO- Propionate CH2CH2COO- COOH CH2 N H CH2 NH2 Porphobilinogen (PBG)

  17. A P N H CH2 NH2 Porphobilinogen (PBG)

  18. A A A A P P P P N H N H N H N H CH2 NH2 CH2 NH2 CH2 NH2 CH2 NH2

  19. Hydroxymethylbilane synthase& Uroporphyrinogen III synthase • Four PBG molecules condense • Ring closure • Isomerization

  20. P A B A A P NH HN Uroporphyrinogen III NH HN A C D A P P

  21. COOH CH2 CH2 COOH CH2 -CH2-CH2-COOH HOOC-H2C- NH HN Uroporphyrinogen III NH HN -CH2-COOH HOOC-H2C- CH2 CH2 COOH CH2 CH2 COOH

  22. Series of decarboxylations & oxidations • Porphyrinogens: • Chemically reduced • Colorless intermediates • Porphyrins: • Intensely colored • Fluorescent • Uroporphyrinogen III • Coproporphyrinogen III Moves back into Mitochondrion • Protoporphyrinogen IX • Protoporphyrin IX

  23. CH=CH2 CH3 -CH=CH2 H3C- NH N Protoporphyrin IX N HN -CH3 H3C- CH2 CH2 COOH CH2 CH2 COOH

  24. HEME Fe2+ chelated by Protoporphyrin IX Assisted by Ferrochelatase CH3-

  25. Regulation of Heme Synthesis

  26. AMINOLEVULINIC ACID SYNTHASE • Two tissue-specific isozymes • Coded on separate genes • InLiver, heme represses synthesis and activity of ALAS • Heme can be used for treatment of acute porphyric attack • In RBC heme synthesis regulation is more complex • Coordinated with globin synthesis

  27. IN MITOCHONDRIA COOH CH2 CH2 COSCoA COOH CH2 CH2 C=O SUCCINYL CoA ALA CH2 NH2 COOH CH2 NH2 GLYCINE • AMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS

  28. Bonkovsky ASH Education Book December 2005

  29. Disorders of Heme Synthesis • X-linked Sideroblastic Anemia • Lead Poisoning • Iron Deficiency Anemia • The Porphyrias

  30. X-linked Sideroblastic Anemia ALAS Requires Pyridoxal Phosphate as Coenzyme Some Sideroblastic Anemias improve with Pyridoxine (B6)

  31. ALA moves out of the mitochondrion COOH CH2 CH2 C=O COOH CH2 CH2 C=O A P -2 H2O N H CH2 NH2 CH2 NH2 PBG CH2 NH2 • ALA DEHYDRATASE Inhibited by Heavy Metal: LEAD POISONING

  32. Lead Poisoning

  33. Lead Poisoning Lead Poisoning ALAD and Ferrochelatase Are particularly sensitive to Lead inhibition Ferrochelatase Heme Fe + PPIX

  34. Iron Metabolism • Reactive Transition Metal (Fe2+ Fe3+) • Normally present complexed with proteins that limit its reactivity • Both iron deficiency and iron overload cause cellular defects and disease • Most available iron generated by macrophages that recycle red cell iron • Dietary Fe3+ in duodenum converted to Fe2+ and absorbed by duodenal enterocyte

  35. Iron 35% of Earth’s mass nasa

  36. Hepatocyte Macrophage Erythroid Cell Blood Apical Duodenal Enterocyte GUT Contents Fe3+ Heme diFe3+ Transferrin Fe2+ Fe2+ Mitochondrial Heme Synthesis

  37. NEJM June 2004

  38. Blood Macrophage RBC Hemoglobin Haptoglobin Heme Hemopexin Fe2+ Fe2+

  39. ? Syed, Hemoglobin 2006

  40. http://walz.med.harvard.edu

  41. Hentze, Muckenthaler & Andrews Cell, Vol 117, 285-297, April 30, 2004 Hepcidin

  42. Hepcidin: 25 Amino Acids J Med Genet 2004

  43. Nemeth et al, Science, Dec 2004

  44. Beutler, Science Dec 2004

  45. Hentze, Muckenthaler & Andrews Cell, Vol 117, 285-297, April 30, 2004 Ferroportin

  46. Genetic HemochromatosisDisruption of Hepcidin / Ferroportin • Autosomal Recessive • HFE C282Y/C282Y • TfR2 • Hemojuvelin • Hepcidin • Autosomal Dominant • Ferroportin

  47. Normal Liver medlib.med.utah.edu

  48. Granular, Dark Reddish Brown Surface of Liver in Hemochromatosis www.med.niigata-u.ac.j

  49. Iron Accumulation in Chronic Disease http://eduserv.hscer.washington.edu

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