HAEME SYNTHESISHAEME SYNTHESISAND CATABOLISMAND CATABOLISMBYBYDR MUHAMMADDR MUHAMMADMUSTANSARMUSTANSAR
HEME-CONTAINING PROTEINS• Hemoglobin• Myoglobin• Cytochromes• Catalase• Some peroxidases
STRUCTURE OF HEMEFerrous iron (Fe2+)Protoporphyrin IX:contains 4 pyrrolerings linked togetherby methenyl bridges
Heme is the prosthetic group of hemoglobin, myoglobin, &cytochromes. Heme is an asymmetric molecule. E.g., notethe positio...
Heme88Succinyl CoAGlycine**HEME SYNTHESIS** Amino acid (building blocks of protein) synthesized in your body
HEME SYNTHESIS: LiverThe liver is the main non-RBC source of hemesynthesisHeme produced in the liver is used mainly for ...
HEME SYNTHESIS: Red blood cells85% of total heme synthesisoccurs in red blood cells (RBC)Ceases when RBC’s matureHeme s...
The heme ring system is synthesized from glycine& succinyl-CoA.Using isotopic tracers, it was initially found that N& C at...
Heme synthesis begins with condensation ofglycine & succinyl-CoA, withdecarboxylation, to form δ-aminolevulinicacid (ALA)....
Pyridoxal phosphate(PLP) serves as coenzymefor δ-AminolevulinateSynthase (ALA Synthase),an enzyme evolutionarilyrelated to...
Uroporphyrinogen I Coproporphyrinogen IOverview of Heme SynthesisOverview of Heme SynthesisHeme synthesis occurs in all ce...
ALA Synthase is the committed step of theheme synthesis pathway, & is usually rate-limiting for the overall pathway.Regula...
Disorders of Heme Synthesis Acquired: Lead poisoning Congenital: Porphyrias Deficiency of heme has far-reaching effects...
• A group of rare disorders caused by deficiencies of enzymes of the hemebiosynthetic pathway•The majority of the porphyri...
PorphyriasCaused by hereditary or acquired defects in heme synthesis- Accumulation and increased excretion of metabolicpre...
Acquired PorphyriasLead poisoning- inhibition of ferrochelatase and ALA dehydratase- displaces Zn+2at enzyme active siteCh...
Most heme from RBCs (85%) - rest from turnover ofcytochromes, p450s, immature erythrocytes.RBCs last 120 days, degraded by...
Types of JaundiceHemolytic jaundice- Liver can handle 3000 mg bilirubin/day - normal is 300- Massive hemolysis causes more...
Hepatocellular jaundice- Liver damage (cirrhosis or hepatitis) cause increasedbilirubin levels in blood due to decreased c...
Jaundice in NewbornsPremature babies often accumulate bilirubin due tolate onset of expression of bilirubin glucuronyltran...
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
HEME  METABOLISM  MUHAMMAD MUSTANSAR
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HEME METABOLISM MUHAMMAD MUSTANSAR

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HEME METABOLISM MUHAMMAD MUSTANSAR

  1. 1. HAEME SYNTHESISHAEME SYNTHESISAND CATABOLISMAND CATABOLISMBYBYDR MUHAMMADDR MUHAMMADMUSTANSARMUSTANSAR
  2. 2. HEME-CONTAINING PROTEINS• Hemoglobin• Myoglobin• Cytochromes• Catalase• Some peroxidases
  3. 3. STRUCTURE OF HEMEFerrous iron (Fe2+)Protoporphyrin IX:contains 4 pyrrolerings linked togetherby methenyl bridges
  4. 4. Heme is the prosthetic group of hemoglobin, myoglobin, &cytochromes. Heme is an asymmetric molecule. E.g., notethe positions of methyl side chains around the ring system.NNNNCH3 HCCH3S CH2CH3CH S CH2CH3CH2CH2COO−CH3H3CCH2CH2−OOCproteinproteinFeHeme c
  5. 5. Heme88Succinyl CoAGlycine**HEME SYNTHESIS** Amino acid (building blocks of protein) synthesized in your body
  6. 6. HEME SYNTHESIS: LiverThe liver is the main non-RBC source of hemesynthesisHeme produced in the liver is used mainly for thesynthesis of the cytochrome P450 class of enzymes thatare involved in detoxificationRegulated at level of ALA synthase: Formation of 5-ALAis the rate-limiting step in heme synthesis in the liver
  7. 7. HEME SYNTHESIS: Red blood cells85% of total heme synthesisoccurs in red blood cells (RBC)Ceases when RBC’s matureHeme stimulates proteinsynthesis in reticulocytesSynthesis is regulated at thelevel of the enzymesferrochelatase* andporphobilinogen deaminase**
  8. 8. The heme ring system is synthesized from glycine& succinyl-CoA.Using isotopic tracers, it was initially found that N& C atoms of heme are derived from glycine andacetate.It was later determined that the labeled acetateenters Krebs Cycle as acetyl-CoA, and the labeledcarbon becomes incorporated into succinyl-CoA,the more immediate precursor of heme.
  9. 9. Heme synthesis begins with condensation ofglycine & succinyl-CoA, withdecarboxylation, to form δ-aminolevulinicacid (ALA).−OOC CH2 CH2 C S-CoAO+ −OOC CH2 NH3+−OOC CH2 CH2 COCH2 NH3+CO2CoA-SHH+succinyl-CoA glycineδ-aminolevulinate (ALA)δ-AminolevulinicAcid Synthase
  10. 10. Pyridoxal phosphate(PLP) serves as coenzymefor δ-AminolevulinateSynthase (ALA Synthase),an enzyme evolutionarilyrelated to transaminases.Condensation withsuccinyl-CoA takes placewhile the amino group ofglycine is in Schiff baselinkage to the PLPaldehyde.CoA & the glycinecarboxyl are lost followingthe condensation.Pyridoxal phosphate (PLP)NHCOPO−OOOHCH3CH O−+H2NHCOPO−OOO−CH3HC−+H2NH2CH+COO−glycine-PLP Schiff base (aldimine)
  11. 11. Uroporphyrinogen I Coproporphyrinogen IOverview of Heme SynthesisOverview of Heme SynthesisHeme synthesis occurs in all cells due to the requirement for heme as a prostheticgroup on enzymes and electron transport chain. By weight, the major locations ofheme synthesis are the liver and the erythroid progenitor cells of the bone marrow.Succinyl CoA + Glycineδ-aminolevulinic acidδ-aminolevulinic acidPorphobilinogen Uroporphyrinogen III Coproporphyrinogen IIICoproporphyrinogen IIIProtoporphyrinogen IXProtoporphyrin IXHemeALA synthasecytoplasmmitochondrial matrix
  12. 12. ALA Synthase is the committed step of theheme synthesis pathway, & is usually rate-limiting for the overall pathway.Regulation occurs through control of genetranscription..
  13. 13. Disorders of Heme Synthesis Acquired: Lead poisoning Congenital: Porphyrias Deficiency of heme has far-reaching effects(hemoglobin, cytochromes, etc.)
  14. 14. • A group of rare disorders caused by deficiencies of enzymes of the hemebiosynthetic pathway•The majority of the porphyrias are inherited in a autosomal dominantfashion - 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, andfoods, and also by exposure to sun• Treatment involves administration of hemin, which provides negativefeedback for the heme biosynthetic pathway, and therefore, preventsaccumulation of heme precursors
  15. 15. PorphyriasCaused by hereditary or acquired defects in heme synthesis- Accumulation and increased excretion of metabolicprecursors (each unique)- Most porphyrias show a prevalent autosomal dominantpattern, except congenital eythropoietic porphyria, which isrecessiveCan be hepatic or erythropoietic, reflecting the two majorlocations of heme synthesis- hepatic can be acute or chronicThose with tetrapyrrole intermediates show photosensitivitydue to extended conjugated double bonds- Formation of superoxide radicals- Skin blisters, itches (pruritis)- Skin may darken, grow hair (hypertrichosis)
  16. 16. Acquired PorphyriasLead poisoning- inhibition of ferrochelatase and ALA dehydratase- displaces Zn+2at enzyme active siteChildren- developmental defects- drop in IQ- hyperactivity- insomnia- many other health problemsAdults- severe abdominal pain- mental confusion- many other symptoms
  17. 17. Most heme from RBCs (85%) - rest from turnover ofcytochromes, p450s, immature erythrocytes.RBCs last 120 days, degraded by reticuloendothelial(RE) system [liver and spleen].Microsomal heme oxygenase hydroxylates methenylbridge carbon and oxidizes Fe2+to Fe3+. Secondreaction open ring and release methenyl carbon asCO.The resulting biliverdin is poorly soluble due to ringstacking and aggregation.Serum albumin carries bilirubin in circulation, ligandinin hepatocytes.
  18. 18. Types of JaundiceHemolytic jaundice- Liver can handle 3000 mg bilirubin/day - normal is 300- Massive hemolysis causes more than can be processed- cannot be conjugated- increased bilirubin excreted into bile, urobilinogenis increased in blood, urine- unconjugated bilirubin in blood increases = jaundiceObstructive jaundice- Obstruction of the bile duct- tumor or bile stones- gastrointestinal pain - nausea- pale, clay-colored stools- can lead to liver damage and increased unconjugatedbilirubin
  19. 19. Hepatocellular jaundice- Liver damage (cirrhosis or hepatitis) cause increasedbilirubin levels in blood due to decreased conjugation- Conjugated bilirubin not efficiently exported to bileso diffuses into blood- Decreased urobilinogen in enterohepatic circulationso urine is darker and stool is pale, clay-colored- AST and ALT levels are elevated due to hepatic damage- Nausea and anorexia
  20. 20. Jaundice in NewbornsPremature babies often accumulate bilirubin due tolate onset of expression of bilirubin glucuronyltransferase- Maximum expression (adult level) at ~ 4 weeks- Excess bilirubin can cause toxic encephalopathy(kernicterus)- Treated with blue fluorescent light- converts bilirubin to more polar compound- can be excreted in bile without conjugation- Crigler-Najjar syndrome is deficiency in bilirubinglucuronyltransferase

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