Figure: heme synthesis

Epidemiology: - heme is produced in virtually all mammalian tissues 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 Pathology: - derangements of porphyrin* synthesis are known clinically as porphyrias * porphyrins are intermediates in heme synthesis

References

Textbook of Biochemistry with Clinical Correlations, 3rd ed., TM Devlin (ed), Wiley-Liss, NY 1992 pg 1009