Heme Synthesis

• Heme

  One of the hemoproteins found in the body, produced by the combination of iron with porphyrin rings
• Porphyrins


  Cyclic compounds that readily bind metal ions, usually Fe2+
• Only Type III porphyrins, containing an asymmetric substitution on the ring, are physiologically important in humans
• Side chains of porphyrins

  • Uroporphyrin contains acetate and propionate side chains
  • Coproporphyrin contains methyl and propionate groups
  • Protoporphyrin IX (heme) contains vinyl, methyl, and propionate groups
• The methyl and vinyl groups in heme are produced by decarboxylation of acetate and propionate side chains, respectively
• Heme Biosynthesis

  1. The major sites are liver and erythrocytes-producing cells of the bone marrow

  2. Initial reaction and last three steps occur in mitochondria, intermediate steps occur in the cytosol
• Heme can be synthesized by almost all tissues in the body, except matured erythrocytes
• Mature red blood cells lack mitochondria and are unable to synthesize heme
• All carbon and nitrogen atoms of the porphyrin molecule are provided by glycine and succinyl CoA
• Two Main Steps in Heme Biosynthesis

  1. Formation of delta-aminolevulinic acid (ALA)

  2. Formation of Heme
• Disorders of heme synthesis
• Mitochondria are unable to synthesize heme
• Carbon and nitrogen providers for the porphyrin molecule

  • Glycine
  • Succinyl CoA
• Porphyrias are a group of inborn errors of metabolism associated with the biosynthesis of heme
• Most of the porphyrias are inherited as autosomal dominant traits
• Types of Porphyrias

  • Hepatic porphyrias (can be further classified as chronic or acute)
  • Erythropoietic porphyrias
  • Porphyrias with both erythropoietic and hepatic abnormalities
• Porphyrias are rare, inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors
• Individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuro-psychiatric signs
• Individuals with enzyme defects leading to the accumulation of tetrapyrrole intermediates show photosensitivity
• Acute hepatic porphyrias are characterized by acute attacks of gastrointestinal, neuropsychiatric, and motor symptoms that may be accompanied by photosensitivity
• Porphyria cutanea tarda is a chronic disease of the liver associated with a deficiency in uroporphyrinogen decarboxylase
• Porphyrin accumulation in Porphyria cutanea tarda leads to cutaneous symptoms and urine that is brown in natural light and pink to red in fluorescent light
• The erythropoietic porphyrias are characterized by skin rashes and blisters that appear in early childhood and are complicated by cholestatic liver cirrhosis and progressive hepatic failure
• Enzymes involved in heme biosynthesis

  • Ferrochelatase
  • PRP oxidase
  • CRP oxidase
  • URP decarboxylase
  • URP III synthase
  • ALA synthase
  • HMB Synthase
  • ALA dehydratase