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16. porphyrins

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2. Heme 3. PORPHYRINS Cyclic compounds that bind metal ions Chlorphyll (Mg2+) Central to solar energy utilizationHeme (Fe2+) Mostprevalent metalloporphyrin in humans Central to oxygen sensing and utilization Cobalamin (Cobalt) 4. PORPHYRINSHCCHHCCH N HPyrrole ring Porphyrin:Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges 5. PORPHYRIN SIDE CHAINS M = Methyl (-CH3)V = Vinyl (-CH=CH2)P = Propionyl (-CH2-CH2-COO-)A = Acetyl (-CH2-COO-) 6. HEME Oneferrous (Fe2+) atom in the center of the tetrapyrrole ring of Protoporphyrin IX Prosthetic group for Hemoglobinand Myoglobin The Cytochromes Catalase and Tryptophan pyrrolase Nitric Oxide Synthase Turnoverof Hemeproteins (Hemoglobin, etc) is coordinated with synthesis and degradation of porphyrins Bound iron is recycled 7. HemeProtoporphyrin III prefix or suffix urocoproproto-porphyrinogen -porphyrinring substituents acetate, propionate methyl, propionate methyl, propionate, vinyl ---between rings --methylene methene 8. BIOSYNTHESIS OF HEME Synthesized Liverin every human cell(15%): Bone Marrow (80%) 9. All Carbon and Nitrogen atoms provided by 2 building blocks: COOH CH2SUCCINYL CoACH2 COSCoA CH2 NH2 COOHGLYCINE 10. COOH CH2SUCCINYL CoACH2 COSCoA CH2 NH2 COOH- CO2GLYCINE is Decarboxylated AMINOLEVULINIC ACID SYNTHASE IN MITOCHONDRIA 11. COOH CH2 CH2 C=O CH2 NH2 Condense to form: AMINOLEVULINIC ACID (ALA) MOVES OUT OF THE MITOCHONDRION 12. COOH CH2COOHCH2CH2C=O CH2CH2NH2-2 H2OC=O CH2NH2 2 Molecules dehydrated by ALA DEHYDRATASE 13. COOH CH2COOHCH2CH2C CCNHC CH2 NH2To form Porphobilinogen (PBG) 14. COOHPropionate CH2CH2COO- CH2Acetate CH2COO-COOH CH2CH2N HCH2 NH2Porphobilinogen (PBG) 15. ACH2PN HNH2Porphobilinogen (PBG) 16. H2 NAH2 C NH2CH2NH2CHNH 2NPAHPN HHPNAAH2 C H2 NP 17. HYDROXYMETHYLBILANE SYNTHASE & UROPORPHYRINOGEN III SYNTHASE FourPBG molecules condense Ring closure Isomerization 18. P AABA NHPHNUroporphyrinogen III NHAD PHNC PA 19. COOH CH2 CH2COOH CH2-CH2-CH2-COOHHOOC-H2CNHHNUroporphyrinogen III NHHN-CH2-COOHHOOC-H2CCH2 CH2 COOHCH2 CH2 COOH 20. 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 21. CH=CH2CH3-CH=CH2H3CNHNProtoporphyrin IX NHN-CH3H3CCH2 CH2 COOHCH2 CH2 COOH 22. HEME Fe2+ chelated by Protoporphyrin IX Assisted by FerrochelataseCH3- 23. REACTIONS FOR PROTOPORPHYRI N IX 24. REGULATION OF HEME SYNTHESIS 25. AMINOLEVULINIC ACID SYNTHASE Two tissue-specific isozymes Coded on separate genes In Liver, heme represses synthesis and activity of ALAS Hemeattackcan be used for treatment of acute porphyricIn RBC heme synthesis regulation is more complex Coordinatedwith globin synthesis 26. IN MITOCHONDRIA COOHCH2 CH2COSCoA CH2 NH2C=O CH2COOHGLYCINECH2 CH2SUCCINYL CoACOOHNH2ALAAMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS 27. Bonkovsky ASH Education Book December 2005 28. DISORDERS OF HEME SYNTHESISAcquired: Lead poisoningCongenital: PorphyriasDeficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.) 29. LEAD TOXICITY Symptoms Irritibility Lethargy Sleeplessness Headaches Poor appetite Abdominal pain (with or without vomiting) ConstipationPathophysoiology Binds to any compound with a sulfhydryl group Inhibits multiple enzyme reactions including those involved in heme biosynthesis (ALA dehydratase & ferrochelatase) 30. ALA moves out of the mitochondrion COOH CH2COOHCH2CH2C=O CH2CH2NH2C=O CH2 NH2A-2 H2OCH2 NH2PN HPBGALA DEHYDRATASE Inhibited by Heavy Metal: LEAD POISONING 31. Lead Poisoning 32. Lead PoisoningLead Poisoning ALAD and Ferrochelatase Are particularly sensitive to Lead inhibitionFerrochelatase Fe + PPIXHeme 33. PORPHYRIAS A group of rare disorders caused by deficiencies of enzymes of the heme biosynthetic pathway The majority of the porphyrias are inherited in a autosomal dominant fashion - thus, affected individuals have 50% normal levels of the enzymes, and can still synthesize some heme Affected individuals have an accumulation of heme precursors (porphyrins), which are toxic at high concentrations Attacks of the disease are triggered by certain drugs, chemicals, and foods, and also by exposure to sun Treatment involves administration of hemin, which provides negative feedback for the heme biosynthetic pathway, and therefore, prevents accumulation of heme precursors 34. Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001. 35. ACUTE INTERMITTENT PORPHYRIA Hepatic, autosomal dominant Caused by a deficiency in porphobilinogen deaminase, which is involved in the conversion of porphobilinogen (PBG) to uroporphyrinogen III PBG, uroprophryin, and 5-ALA accumulate in the plasma and the urine Patients have neuropyschiatric symptoms and abdominal pain (neurovisceral) 36. PORPHYRIA CUTANEA TARDA Most common porphyria Hepatic, autosomal dominant Disease is caused by a deficiency in uroporphyrinogen decarboxylase, which is involved in the conversion of uroporphyrinogen III to coproporphyrinogen III Uroporphyrinogen accumulates in urine Patients are photosensitive (cutaneous photosensitivity) Accumulation of porphyrinogens results in their conversion to porphyrins by light Porphyrins react with molecular oxygen to form oxygen radicals Oxygen radicals can cause severe damage to the skin 37. HEME DEGRADATION 38. NS FIG. 44.8 39. Heme oxygenase Biliverdin reductase Serum albumin Bilirubin UDP-glucuronyl transferaseSpleen Macrophages Blood Liver 40. HEME DEGRADATION Features Reactions Jaundice hemolytic obstructive Neonatekernicterus liver disease Gilberts diseaseBlood Proteinsserum albumin haptoglobin hemopexin

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