Heme synthesis

Heme synthesis

• 1.
  Heme synthesis Radhakrishna GPillai
• 2.
  Heme –iron containingcompound • Gender-based difference in the total body iron content in adult humans; – approximately 50 mg/kg in men and 40 mg/kg in women • Due to the decreased mass of red cells, muscle and liver in women • Almost all iron in body is incorporated into heme-containing proteins, particularly hemoglobin, myoglobin and cytochromes • The unique properties of heme allows it to function both as an electron carrier and a catalyst for redox reactions • An iron molecule is coordinated within a tetrapyrrole ring
• 3.
  Heme synthesis • Biochemicalpathway with many steps, substrates, and enzymes • A deficiency in an enzyme or substrate leads to accumulation of intermediates of heme synthesis in blood, tissues, and urine • Leads to a group of disorders called porphyrias • Porphyrias are hepatic or erythropoietic • They can be acute or chronic • Cause neurologic dysfunction, mental disturbance or photosensitivity • Other symptoms: change in urine color, abdominal colic, highly agitated state, tachycardia, respiratory problems, nausea etc.
• 4.
  Heme synthesis • Hemesynthesis is through a highly conserved pathway • This involves both cytosolic and mitochondrial compartments • Protoporphyrin IX is generated • Protoporphyrin IX is an important compound in heme synthesis • All of the heme biosynthetic genes are nuclear-encoded and translated in the cytoplasm
• 5.
  Location of hemesynthesis • Most of the heme synthesis takes place in developing red cells in the marrow • About 15% of the daily production takes place in the liver for the formation of heme-containing enzymes • In the liver, heme biosynthetic enzymes are turned over rapidly, enabling the liver to respond to changing metabolic requirements • In erythroid progenitors the pathway is regulated to permit a high steady-state level of heme synthesis and • Regulation is tied to the availability of iron
• 6.
  Porphyrins • Large heterocyclicorganic ring structures • Composed of 4 modified pyrrole subunits connected by methine (=CH-) bridges • Heme is an example of naturally occurring porphyrin • Heme in biological system consists of Fe2+ ions complexed with 4N of porphyrin molecules Three structurally distinct hemes in human; heme a, b and c Heme is critical for biological functions of several enzymes – eg cytochromes of oxidative phosphorylation Cytochrome P450 family (CYP)
• 7.
  Heme synthesis • Firstreaction occurs in mitochondria • Condensation of one succinyl-coA & glycine by pyridoxal phosphate – requiring enzyme (vitamin B6) – δaminolevulinic acid synthase (ALAS) – forming δ aminolevulinic acid (5 aminoleuvinic acid) • This is the rate limiting reaction in heme synthesis • There are both “housekeeping” and erythroid genes for aminolevulinate synthase
• 8.
  Formation of Porphobilinogen •ALA is transported to cytosol • ALA dehydratase (porphobilinogen synthetase) dimerises 2 molcules of ALA • Forms Porphobilinogen
• 9.
  Heme synthesis • Head-tailcondensation of four molecules of porphobilinogen (PBG) form the tetrapyrrole, hydroxymethylbilane (HMB) • Enzyme for this condensation is porphobilinogen deaminase (PBG deaminase) • Hydroxymethylbilane has two fates • One due to enzymatic action • Other due to non-enzymatic action
• 10.
  Heme synthesis • Hydroxymethylbilaneis enzymatically converted to uroporphyrinogen III • Mediated by the enzyme uroporphyrinogen III synthase • Uroporphyrinogen III is decarboxylated by uroporphyrinogen decarboxylase • Forms coproporphyrinogens • Coproporphyrinogen III is most important in heme synthesis • Coproporphyrinogen III transported to the interior of the mitochondria
• 11.
  Formation of conjugatedring • Propionate residues of Coproporphyrinogen III are decarboxylated • Protoporphyrinogen IX formed • Catalysed by coproporphyrinogen-III oxidase • To protoporphyrin IX (PROTO IX)– By protoporphyrinogen IX oxidase • This oxidation requires oxygen as the terminal electron acceptor Protoporphyrinogen IX protoporphyrin IX Coproporphyrinogen-III oxidase
• 12.
  Insertion of Fe2+ •Ring system -Loss of 6 protons and 6 electrons – produce a completely conjugated ring • Final reaction in heme synthesis takes place on the inner surface of the inner mitochondrial membrane Insertion of Fe2+ into the ring system Enzyme involved is ferrochelatase Responsible for the red colour of heme
• 13.
  Thank you [email protected] 0091 9495554891