Heme synthesis and disorders

• Heme


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


  Cyclic compounds that readily bind metal ions, usually Fe2+
• Proteins that include heme molecule

  • Hemoglobin
  • Myoglobin
  • Cytochromes
  • Catalase
  • Tryptophan pyrrolase
• Heme


  • A derivative of the porphyrin
  • Porphyrins are cyclic molecules formed by the linkage of four pyrrole rings by methenyl (=CH–) bridges
  • An atom of iron is present, so heme is a ferroprotoporphyrin
  • Only Type III porphyrins, which contain an asymmetric substitution on 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
• Heme biosynthesis


  1. Initial reaction and last three steps occur in mitochondria

  2. Intermediate steps occur in the cytosol
• Heme synthesis


  Heme can be synthesized by almost all tissues in the body, but not in mature red blood cells which lack mitochondria
• Two main steps in heme biosynthesis

  1. Formation of delta-aminolevulinic acid (ALA)

  2. Formation of Heme
• Step 1: Formation of aminolevulinic acid (ALA)

  1. Glycine and succinyl CoA condense to form ALA, catalyzed by ALA synthase

  2. This is the rate controlling step in hepatic porphyrin biosynthesis

  3. The coenzyme is B6 vitamin
• Step 2: Formation of PBG

  1. Two molecules of ALA are condensed to form porphobilinogen (PBG), catalyzed by ALA dehydratase

  2. Porphobilinogen is a monopyrrole

  3. The enzyme contains zinc and is inhibited by lead
• Step 3: Formation of UPG (uroporphyrinogen)

  1. Condensation of 4 molecules of porphobilinogen results in the formation of uroporphyrinogen (UPG)

  2. Uroporphyrinogen III Synthase produces the asymmetric uroporphyrinogen III
• Step 4: Formation of CPG-III

  Uroporphyrinogen III undergoes decarboxylation of its acetate groups, generating coproporphyrinogen III
• Step 5: Synthesis of PPG (Protoporphyrinogen)

  Coproporphyrinogen is oxidized to protoporphyrinogen (PPG-IX) by coproporphyrinogen oxidase, which acts only on type III series
• Step 6: Generation of PP (Protoporphyrin)


  Protoporphyrinogen-IX is oxidized by protoporphyrinogen oxidase to protoporphyrin-IX (PP-IX) in the mitochondria
• Step 7: Generation of Heme

  Ferrous iron is attached to the protoporphyrin by the enzyme heme synthase or ferrochelatase, also located in mitochondria
• Porphyrias are a group of inborn errors of metabolism associated with the biosynthesis of heme
• Classification of porphyrias


  • Hepatic porphyrias (chronic or acute)
  • Erythropoietic porphyrias
  • Porphyrias with both erythropoietic and hepatic abnormalities
• Porphyrias


  • 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


  Characterized by acute attacks of gastrointestinal, neuropsychiatric, and motor symptoms that may be accompanied by photosensitivity
• Porphyria cutanea tarda


  • The most common porphyria, a chronic disease of the liver associated with a deficiency in uroporphyrinogen decarboxylase
  • Porphyrin accumulation leads to cutaneous symptoms and urine that is brown in natural light and pink to red in fluorescent light
• Erythropoietic porphyrias


  Characterized by skin rashes and blisters that appear in early childhood, 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
• Heme


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


  Cyclic compounds that readily bind metal ions, usually Fe2+
• Proteins that include heme molecule

  • Hemoglobin
  • Myoglobin
  • Cytochromes
  • Catalase
  • Tryptophan pyrrolase
• Heme


  • A derivative of the porphyrin
  • Porphyrins are cyclic molecules formed by the linkage of four pyrrole rings by methenyl (=CH–) bridges
  • An atom of iron is present, so heme is a ferroprotoporphyrin
  • Only Type III porphyrins, which contain an asymmetric substitution on 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
• Heme biosynthesis


  1. Initial reaction and last three steps occur in mitochondria

  2. Intermediate steps occur in the cytosol
• Heme synthesis


  Heme can be synthesized by almost all tissues in the body, but not in mature red blood cells which lack mitochondria
• Heme biosynthesis


  1. Formation of delta-aminolevulinic acid (ALA)

  2. Formation of Heme
• Formation of ALA


  1. Glycine and succinyl CoA condense to form ALA, catalyzed by ALA synthase

  2. This is the rate controlling step in hepatic porphyrin biosynthesis
• Formation of PBG


  Two molecules of ALA are condensed to form porphobilinogen (PBG), catalyzed by ALA dehydratase
• Formation of UPG


  Condensation of 4 molecules of PBG results in the formation of uroporphyrinogen (UPG)
• Formation of CPG-III


  UPG-III is converted to coproporphyrinogen (CPG-III) by decarboxylation, catalyzed by uroporphyrinogen decarboxylase
• Synthesis of PPG


  CPG is oxidized to protoporphyrinogen (PPG-IX) by coproporphyrinogen oxidase
• Generation of PP


  Protoporphyrinogen-IX is oxidized by protoporphyrinogen oxidase to protoporphyrin-IX (PP-IX)
• Generation of Heme


  Ferrous iron is attached to protoporphyrin by the enzyme ferrochelatase (heme synthase)
• Porphyrias are a group of inborn errors of metabolism associated with the biosynthesis of heme
• Classification of porphyrias


  • Hepatic porphyrias (chronic or acute)
  • Erythropoietic porphyrias
  • Porphyrias with both erythropoietic and hepatic abnormalities
• Porphyrias


  • 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