Heme Synthesis

Hemes are cyclic tetrapyrroles that contain iron and are commonly found as the prosthetic group of hemoglobin, myoglobin and the cytochromes.

Location of Heme Synthesis

Heme synthesis takes place in the cytosol and mitochondria of cells of the liver and bone marrow.

  • Substrates: Succinyl A CoA; glycine; Fe2+
  • Product: Heme.

Overview of the Pathway

Heme Synthesis Pathway

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  1. Succinyl CoA and glycine are combined by ALA synthase to form aminolevulinic acid.
  2. Aminolevulinic acid is subsequently dehydrated by ALA dehydrase to form porphobilinogens.
  3. Porphobilinogen deaminase catalyzes the condensation of four porphobilinogens to form a linear tetrapyrrole.
  4. This compound then cyclizes to form uroporphyrinogen III, the precursor of hemes, chlorophylls and vitamin B12.
  5. Other modifications to groups attached to the outside of the ring structure, in the cytosol of the cell results in the transformation of porphobilinogen to protoporphyrinogen IX, which is subsequently transferred back into the mitochondria of the cell.
  6. In the mitochondria of the cell, protoporphyrinogen IX is converted to protoporphyrin IX.
  7. Iron is added to protoporphyrin IX by the enzyme, ferrochelatase, to form heme.


ALA synthase, the primary regulating enzyme of heme synthesis, is inhibited by high levels of hemin (a heme derivative).


  • Hemes are a diverse group of tetrapyrrole pigments, being present as the prosthetic group of both the globins (hemoglobin and myoglobin).
  • They are present in the cytochromes (including those involved in respiratory and photosynthetic electron transport) and the cytochrome P450s that are used in detoxification reactions.
  • Some enzymes, including the catalases and peroxidases, contain heme.
  • In all these hemoproteins the function of the heme is either to bind and release a ligand to its central iron atom, or for the iron atom to undergo a change in oxidation state, releasing or accepting an electron for participation in a redox reaction.

Diseases and toxicities

  • Deficiencies in any of the heme synthesis enzymes lead to a porphyria.
  • Lead inhibits ferrochelatase and ALA dehydrase, leading to deficient heme synthesis with resulting anemia and other symptoms of lead poisoning.
  • Barbiturates and other drugs that induce the cytochrome P-450 system can lead to the activation of ALA synthase.
  • Activation of the cytochrome P-450 system leads to decreased heme levels, which results in enhanced ALA synthase activity. Use of these drugs can precipitate the clinical manifestations of porphyrias.


  1. David Hames and Nigel Hooper (2005). Biochemistry. Third ed. Taylor & Francis Group: New York.
  2. Smith, C. M., Marks, A. D., Lieberman, M. A., Marks, D. B., & Marks, D. B. (2005). Marks’ basic medical biochemistry: A clinical approach. Philadelphia: Lippincott Williams & Wilkins.
  3. John W. Pelley, Edward F. Goljan (2011). Biochemistry. Third edition. Philadelphia: USA.

About Author

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Sagar Aryal

Sagar Aryal is a microbiologist and a scientific blogger. He is currently doing his Ph.D. from the Central Department of Microbiology, Tribhuvan University in collaboration with Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany. He did his M.Sc. in Microbiology and B.Sc. in Microbiology from St. Xavier’s College, Kathmandu, Nepal. He worked as a Lecturer at St. Xavier’s College, Maitighar, Kathmandu, Nepal, from March 2017 to June 2019. He is interested in research on actinobacteria, myxobacteria, and natural products. He has published more than 15 research articles and book chapters in international journals and well-renowned publishers.

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