Regulation of Heme Biosynthesis in Chick Embryo Liver Cells

  • G. S. Marks
  • J. E. Mackie
  • S. A. McCluskey
  • D. S. Riddick
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 271)


According to current evidence heme controls the heme biosynthetic pathway primarily by controlling translocation of inactive pre-ALA-S from the cytosol into the mitochondrion, where ALA-S is active. A secondary mechanism involves inhibition by heme of transcription of the ALA-S gene. Porphyrinogenic drugs act by lowering a regulatory “free heme pool” by three different mechanisms: (a) by mechanism-based inactivation of cytochrome P-450 resulting in N-alkylprotoporphyrin formation and ferrochelatase inhibition, (b) by mechanism-based inactivation of cytochrome P-450 resulting in continuous heme destruction, (c) by enhanced generation of active oxygen species which interact with an endogenous substrate to form an inhibitor of uroporphyrinogen decarboxylase. It is also possible that porphyrinogenic drugs may exert a direct effect on the nucleus to increase formation of ALA-S mRNA.

The rate-controlling enzyme of the heme biosynthetic pathway is δ-aminolevulinic acid synthase (ALA-S). This enzyme which is located in the mitochondrion catalyzes the condensation of succinyl-CoA and glycine to form δ-aminolevulinic acid (ALA). ALA passes out of the mitochondria into the cytoplasm where two molecules condense together to form the pyrrole, porphobilinogen (PBG). The enzyme involved in catalyzing this reaction is δ-aminolevulinic acid dehydratase (ALA-D). PBG is converted to a linear tetrapyrrole by the enzyme porphobilinogen deaminase. The linear tetrapyrrole is transformed into uroporphyrinogen III (URO'GEN III) by the enzyme URO'GEN III co-synthetase (Fig. 1) URO'GEN III is then sequentially decarboxylated by the enzyme uroporphyrinogen decarboxylase (UROG-D) to coproporphyrinogen III (COPRO’GEN III), in the process 7-carboxy, 6-carboxy, and 5-carboxy intermediates are formed. After passage into the mitochondrion two of the propionic acid substituents of COPRO’GEN are converted to vinyl groups, yielding protoporphyrinogen IX (PROTO’GEN IX). In the next step of the pathway six hydrogen atoms are removed from PROTO’GEN IX, with the formation of protoporphyrin IX (PROTO IX). Ferrochelatase catalyzes the final step in the pathway, viz. the insertion of ferrous iron into PROTO IX to form heme1. The heme is subsequently incorporated into several hemoproteins with cytochrome P-450 synthesis requiring more than half of the heme produced. Heme exerts feedback repression on the synthesis of ALA-S. Normally this pathway is well controlled and very little of the intermediate porphyrinogens accumulate.


Heme Biosynthesis Free Heme Heme Moiety Heme Biosynthetic Pathway Uroporphyrinogen Decarboxylase 
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Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • G. S. Marks
    • 1
  • J. E. Mackie
    • 1
  • S. A. McCluskey
    • 1
  • D. S. Riddick
    • 1
  1. 1.Department of Pharmacology and ToxicologyQueen's UniversityKingstonCanada

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