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16. porphyrins
 

16. porphyrins

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    16. porphyrins 16. porphyrins Presentation Transcript

    • PORPHYRINS HEME SYNTHESIS AND DEGRADATION
    • Heme
    • 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)
    • PORPHYRINS HC CH HC CH N H Pyrrole ring  Porphyrin: Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges
    • PORPHYRIN SIDE CHAINS  M = Methyl (-CH3)  V = Vinyl (-CH=CH2)  P = Propionyl (-CH2-CH2-COO-)  A = Acetyl (-CH2-COO-)
    • HEME  One ferrous (Fe2+) atom in the center of the tetrapyrrole ring of Protoporphyrin IX  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
    • Heme Protoporphyrin III prefix or suffix urocoproproto-porphyrinogen -porphyrin ring substituents acetate, propionate methyl, propionate methyl, propionate, vinyl --- between rings --methylene methene
    • BIOSYNTHESIS OF HEME  Synthesized  Liver in every human cell (15%):  Bone Marrow (80%)
    • All Carbon and Nitrogen atoms provided by 2 building blocks: COOH CH2 SUCCINYL CoA CH2 COSCoA CH2 NH2 COOH GLYCINE
    • COOH CH2 SUCCINYL CoA CH2 COSCoA CH2 NH2 COOH - CO2 GLYCINE is Decarboxylated δ AMINOLEVULINIC ACID SYNTHASE IN MITOCHONDRIA
    • COOH CH2 CH2 C=O CH2 NH2 Condense to form: δ AMINOLEVULINIC ACID (δALA) MOVES OUT OF THE MITOCHONDRION
    • COOH CH2 COOH CH2 CH2 C=O CH2 CH2 NH2 -2 H2O C=O CH2 NH2 2 Molecules dehydrated by δALA DEHYDRATASE
    • COOH CH2 COOH CH2 CH2 C C C NH C CH2 NH2 To form Porphobilinogen (PBG)
    • COOH Propionate CH2CH2COO- CH2 Acetate CH2COO- COOH CH2 CH2 N H CH2 NH2 Porphobilinogen (PBG)
    • A CH2 P N H NH2 Porphobilinogen (PBG)
    • H2 N A H2 C N H 2 CH 2 NH 2 CH NH 2 N P A H P N H H P N A A H2 C H2 N P
    • HYDROXYMETHYLBILANE SYNTHASE & UROPORPHYRINOGEN III SYNTHASE  Four PBG molecules condense  Ring closure  Isomerization
    • P A A B A NH P HN Uroporphyrinogen III NH A D P HN C P A
    • COOH CH2 CH2 COOH CH2 -CH2-CH2-COOH HOOC-H2CNH HN Uroporphyrinogen III NH HN -CH2-COOH HOOC-H2CCH2 CH2 COOH CH2 CH2 COOH
    • 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 
    • CH=CH2 CH3 -CH=CH2 H3CNH N Protoporphyrin IX N HN -CH3 H3CCH2 CH2 COOH CH2 CH2 COOH
    • HEME Fe2+ chelated by Protoporphyrin IX Assisted by Ferrochelatase CH3-
    • REACTIONS FOR PROTOPORPHYRI N IX
    • REGULATION OF HEME SYNTHESIS
    • δ AMINOLEVULINIC ACID SYNTHASE Two tissue-specific isozymes  Coded on separate genes  In Liver, heme represses synthesis and activity of δALAS   Heme attack  can be used for treatment of acute porphyric In RBC heme synthesis regulation is more complex  Coordinated with globin synthesis
    • IN MITOCHONDRIA COOH CH2 CH2 COSCoA CH2 NH2 C=O CH2 COOH GLYCINE CH2 CH2 SUCCINYL CoA COOH NH2 δALA δAMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS
    • Bonkovsky ASH Education Book December 2005
    • DISORDERS OF HEME SYNTHESIS  Acquired: Lead poisoning  Congenital: Porphyrias Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.) 
    • LEAD TOXICITY Symptoms • • • • Irritibility Lethargy Sleeplessness Headaches • Poor appetite • Abdominal pain (with or without vomiting) • Constipation Pathophysoiology • Binds to any compound with a sulfhydryl group • Inhibits multiple enzyme reactions including those involved in heme biosynthesis (ALA dehydratase & ferrochelatase)
    • δALA moves out of the mitochondrion COOH CH2 COOH CH2 CH2 C=O CH2 CH2 NH2 C=O CH2 NH2 A -2 H2O CH2 NH2 P N H PBG δALA DEHYDRATASE Inhibited by Heavy Metal: LEAD POISONING
    • Lead Poisoning
    • Lead Poisoning Lead Poisoning δALAD and Ferrochelatase Are particularly sensitive to Lead inhibition Ferrochelatase Fe + PPIX Heme
    • 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
    • Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001.
    • 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)
    • 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
    • HEME DEGRADATION
    • NS FIG. 44.8
    • Heme oxygenase Biliverdin reductase Serum albumin Bilirubin UDP-glucuronyl transferase Spleen Macrophages Blood Liver
    • HEME DEGRADATION Features  Reactions  Jaundice   hemolytic  obstructive  Neonate kernicterus  liver disease  Gilbert’s disease •Blood Proteins –serum albumin –haptoglobin –hemopexin