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HEMOGLOBIN SYNTHESIS
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HEMOGLOBIN SYNTHESIS

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HEMOGLOBIN SYNTHESIS HEMOGLOBIN SYNTHESIS Presentation Transcript

  • HAEME SYNTHESIS ANDHAEME SYNTHESIS AND CATABOLISMCATABOLISM BYBY DR MUHAMMAD MUSTANSARDR MUHAMMAD MUSTANSAR
  • Majority of amino acids used for de novo protein synthesis (80%) derives from the degradation of existing proteins Only 30 g (6%) used for synthesis of specialized products Amino Acid Pools are in Steady State
  • Only 70 g (14%) of total amino acid utilization is used for energy or stored as glycogen/fatty acids in the well-fed state (nitrogen balance)
  • • Heme is the most important porphyrin containing compound. • Heme is a derivative of the porphyrin. • Porphyrins are cyclic compounds formed by fusion of 4 pyrrole rings linked by methenyl (=CH-) bridges. HEME SYNTHESIS
  • Hemoglobin
  • HC HC N H CH CH Pyrrole ring • Porphyrin: Cyclic molecule formed by linkage of four pyrrole rings through methenyl bridges PORPHYRINS
  • NH NH HN HN A B CD A A P A P P P A Uroporphyrinogen III
  • NH NH HN HN HOOC-H2C- HOOC-H2C- -CH2-CH2-COOH -CH2-COOH CH2 CH2 COOH CH2 CH2 COOH COOH CH2 CH2 COOH CH2 Uroporphyrinogen III
  • NH N HN N H3C- H3C- -CH=CH2 -CH3 CH2 CH2 COOH CH2 CH2 COOH CH3 Protoporphyrin IX CH=CH2
  • HEME Fe2+ chelated by Protoporphyrin IX Assisted by Ferrochelatase CH3-
  • • Metal ions can bind with nitrogen atoms of pyrrole rings to form complexes. • Since an atom of iron is present, heme is a ferroprotoporphyrin. • The pyrrole rings are named as l, ll, lll, lV and the bridges as alpha, beta, gamma and delta.
  • HEME-CONTAINING PROTEINS • Hemoglobin • Myoglobin • Cytochromes • Catalase • Some peroxidases
  • Heme structure Heme is a metaloporphyrine (cyclic tetrapyrrole) •Heme contains:  conjugated system of double bonds → red colour  4 nitrogen (N) atoms  1 iron cation (Fe2+ ) → bound in the middle of tetrapyrrole skelet by coordination covalent bonds methine bridge pyrrole ring
  • • Hb is a spherical molecule consisting of 4 peptide subunits (globins) = quartenary structure • Hb of adults (Hb A) is a tetramer consisting of 2 - and 2 β-globins → each globin contains 1 heme group with a central Fe2+ ion (ferrous ion) Structure of hemoglobin
  • COOH CH2 CH2 COSCoA CH2 NH2 COOH SUCCINYL CoA GLYCINE IN MITOCHONDRIA δAMINOLEVULINIC ACID SYNTHASE RATE-CONTROLLING STEP IN HEPATIC HEME SYNTHESIS COOH CH2 CH2 C=O CH2 NH2 δALA
  • REACTIONS FOR PROTOPORPHYRIN IX
  • Biosynthesis of Heme • Heme can be synthesised by almost all the tissues in the body. • Heme is primarily synthesised in the liver and the erythrocyte-producing cells of bone marrow (erythroid cells). • Heme is synthesised in the normoblasts, but not in the matured ones.
  • • The pathway is partly cytoplasmic and partly mitochondrial. Step 1: ALA synthesis • The synthesis starts with the condensation of succinyl CoA and glycine in the presence of pyridoxal phosphate to form delta amino levulinic acid (ALA).
  • • The enzyme ALA synthase is located in the mitochondria and is the rate-limiting enzyme of the pathway.
  • Iron atom is co-ordinately linked with 5 nitrogen atoms (4 nitrogen of pyrrole rings of protoporphyrin and 1st nitrogen atom of a histidine residue of globin).
  • SUMMARY OF HEME SYNTHESIS
  • STRUCTURE OF HEME Ferrous iron (Fe2+) Protoporphyrin IX: contains 4 pyrrole rings linked together by methenyl bridges
  • Heme is the prosthetic group of hemoglobin, myoglobin, & cytochromes. Heme is an asymmetric molecule. E.g., note the positions of methyl side chains around the ring system.
  • Heme 8 8 Succinyl CoA Glycine** ** Amino acid (building blocks of protein) synthesized in your body HEME SYNTHESIS
  • •The liver is the main non-RBC source of heme synthesis •Heme produced in the liver is used mainly for the synthesis of the cytochrome P450 class of enzymes that are involved in detoxification Regulated at level of ALA synthase: Formation of 5- ALA is the rate-limiting step in heme synthesis in the liver HEME SYNTHESIS: Liver
  • HEME SYNTHESIS: Red blood cells •85% of total heme synthesis occurs in red blood cells (RBC) •Ceases when RBC’s mature •Heme stimulates protein synthesis in reticulocytes Synthesis is regulated at the level of the enzymes ferrochelatase* and porphobilinogen deaminase**
  • Simplified scheme of the formation of erythrocytes
  • 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 and acetate. It was later determined that the labeled acetate enters Krebs Cycle as acetyl-CoA, and the labeled carbon becomes incorporated into succinyl-CoA, the more immediate precursor of heme.
  • Heme synthesis begins with condensation of glycine & succinyl-CoA, with decarboxylation, to form d- aminolevulinic acid (ALA).
  • Pyridoxal phosphate (PLP) serves as coenzyme for d-Aminolevulinate Synthase (ALA Synthase), an enzyme evolutionarily related to transaminases.
  • Condensation with succinyl-CoA takes place while the amino group of glycine is in Schiff base linkage to the PLP aldehyde. CoA & the glycine carboxyl are lost following the condensation.
  • Uroporphyrinogen I Coproporphyrinogen I Overview of Heme SynthesisOverview of Heme Synthesis Succinyl CoA + Glycine δ-aminolevulinic acid δ-aminolevulinic acid Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III Coproporphyrinogen III Protoporphyrinogen IX Protoporphyrin IX Heme ALA synthase cytoplasmmitochondrial matrix
  • Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow.
  • ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway. Regulation occurs through control of gene transcription. Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells.
  • A variant of ALA Synthase expressed only in developing erythrocytes is regulated instead by availability of iron in the form of iron-sulfur clusters.
  • • Acquired: Lead poisoning • Congenital: Porphyrias • Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.) Disorders of Heme Synthesis
  • • 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 PORPHYRIAS
  • • 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
  • • Caused by hereditary or acquired defects in heme synthesis • - Accumulation and increased excretion of metabolic • precursors (each unique) • - Most porphyrias show a prevalent autosomal dominant pattern, except congenital eythropoietic porphyria, which is recessive Porphyrias
  • • Can be hepatic or erythropoietic, reflecting the two major locations of heme synthesis • - hepatic can be acute or chronic
  • • Those with tetrapyrrole intermediates show photosensitivity due to extended conjugated double bonds • - Formation of superoxide radicals • - Skin blisters, itches (pruritis) • - Skin may darken, grow hair (hypertrichosis)
  • Lead poisoning - inhibition of ferrochelatase and ALA dehydratase - displaces Zn+2 at enzyme active site Acquired Porphyrias
  • Children • - developmental defects • - drop in IQ • - hyperactivity • - insomnia • - many other health problems
  • Adults • - severe abdominal pain • - mental confusion • - many other symptoms
  • Skin eruptions in a patient with porphyria cutanea tarda.
  • Urine from a patient with porphyria cutanea tarda (right) and from a patient with normal porphyrin excretion (left).
  • Most heme from RBCs (85%) - rest from turnover of cytochromes, p450s, immature erythrocytes. RBCs last 120 days, degraded by reticuloendothelial (RE) system [liver and spleen].
  • Microsomal heme oxygenase hydroxylates methenyl bridge carbon and oxidizes Fe2+ to Fe3+. Second reaction open ring and release methenyl carbon as CO. The resulting biliverdin is poorly soluble due to ring stacking and aggregation. Serum albumin carries bilirubin in circulation, ligandin in hepatocytes.
  • Phototherapy in neonatal jaundice
  • Types of Jaundice Hemolytic 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, urobilinogen is increased in blood, urine - unconjugated bilirubin in blood increases = jaundice
  • Obstructive jaundice - Obstruction of the bile duct - tumor or bile stones - gastrointestinal pain - nausea - pale, clay-colored stools - can lead to liver damage and increased unconjugated bilirubin
  • Hepatocellular jaundice - Liver damage (cirrhosis or hepatitis) cause increased bilirubin levels in blood due to decreased conjugation - Conjugated bilirubin not efficiently exported to bile so diffuses into blood
  • - Decreased urobilinogen in enterohepatic circulation so urine is darker and stool is pale, clay-colored - AST and ALT levels are elevated due to hepatic damage - Nausea and anorexia
  • Jaundice in Newborns Premature babies often accumulate bilirubin due to late 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 bilirubin glucuronyltransferase