Figure: heme synthesis

Epidemiology

• heme is produced in virtually all mammalian tissues

Pathology

• derangements of porphyrin* synthesis are known clinically as porphyrias

* porphyrins are intermediates in heme synthesis

Biochemistry

• its synthesis is most pronounced in the bone marrow & liver because of the requirements for incorporation of heme into hemoglobin & cytochromes, respectively
• the initial & final 3 enzymatic steps of heme synthesis occur in the mitochondrial matrix, whereas intermediate steps take place in the cytoplasm
• formation of aminolevulinic acid (ALA) is rate-limiting in all tissues
• the organic part of heme is derived from 8 molecules each of glycine & succinyl-CoA
• porphyrins are intermediates in heme synthesis

biosynthetic pathway

• heme synthesis 1
  • enzyme: aminolevulinic acid synthetase
  • substrate: glycine + succinyl-CoA
  • product: aminolevulinic_acid
  • occurs in mitochondrial matrix releasing aminolevulinic acid into cytoplasm
• heme synthesis 2
  • substrate: aminolevulinic acid
  • product: aminolevulinic acid
  • occurs in cytoplasm
• heme synthesis 3
  • enzyme: aminolevulinic acid dehydratase
  • substrate: aminolevulinic acid
  • product: porphobilinogen
  • occurs in cytoplasm
• heme synthesis 4
  • enzyme: uroporphyrinogen III synthase
  • substrate: porphobilinogen
  • product: uroporphyrinogen III
  • occurs in cytoplasm
• heme synthesis 5
  • enzyme: uroporphyrinogen decarboxylase
  • substrate: uroporphyrinogen III
  • product: coproporphyrinogen III
  • occurs in cytoplasm
• heme synthesis 6
  • substrate: coproporphyrinogen III
  • product: coproporphyrinogen III
  • translocation of coproporphyrinogen III from cytoplasm to mitochondrial matrix
• heme synthesis 7
  • enzyme: coproporphyrinogen oxidase
  • substrate: coproporphyrinogen III
  • product: protoporphyrinogen IX
  • occurs in mitochondrial matrix
• heme synthesis 8
  • enzyme: protoporphyrinogen oxidase
  • substrate: protoporphyrinogen IX
  • product: protoporphyrin IX
  • occurs in mitochondrial matrix
• heme synthesis 9
  • enzyme: ferrochelatase
  • substrate: protoporphyrin IX
  • product: heme
  • occurs in mitochondrial matrix releasing heme into cytoplasm

alternative pathway from porphobilinogen

• heme synthesis 10
  • enzyme: uroporphyrinogen I synthase
  • substrate: porphobilinogen
  • product: uroporphyrinogen I
  • occurs in cytoplasm
• heme synthesis 11
  • enzyme: uroporphyrinogen decarboxylase
  • substrate: uroporphyrinogen I
  • product: coproporphyrinogen I
  • occurs in cytoplasm