Haeme Biosynthesis

Abstract

Haeme is a cofactor required for the function of many key haemoproteins in living organisms. The pathway for haeme synthesis consists of eight enzymes and their substrates and products. Pathway intermediates include an amino acid, a pyrrole and a series of porphyrins that undergo decarboxylations followed by insertion of iron to form haeme (iron protoporphyrin IX). When activities of enzymes in the haeme biosynthetic pathway are altered by mutations or inhibitors, pathway intermediates may accumulate and cause skin photosensitivity and neurological dysfunction, as found in the porphyrias. Closely related pathways in plants and bacteria provide chlorophylls and other tetrapyrrolic pigments important for harvesting energy from light.

Key Concepts

  • Haeme is essential as a cofactor for proteins involved in key biological processes such as oxidations, oxygen transport and storage and electron transport.
  • The haeme biosynthetic pathway consists of eight enzymes, which have been characterised and their genes sequenced in many species including humans.
  • Closely related pathways in plants and bacteria synthesise chlorophyll and other light‐harvesting pigments.
  • Key stages in haeme biosynthesis are the synthesis of the precursor amino acid ALA, formation of the cyclic tetrapyrroles uroporphyrinogen III, decarboxylation to form protoporphyrinogen IX, oxidation to protoporphyrin IX and insertion of iron to complete haeme synthesis.
  • ALA is synthesised from glycine and succinyl‐coenzyme A in animals, yeast and some bacteria, but from glutamate in plants, algae, archaea and some other bacteria.
  • In mammals, the tissues that are most active in haeme synthesis are the bone marrow, where haeme is used primarily for haemoglobin; and the liver, which synthesises large amounts of cytochrome P450 enzymes and smaller amounts of many other haemoproteins.
  • The initial enzyme ALAS1 is rate limiting for haeme biosynthesis in mammalian liver, and this enzyme is downregulated by the endproduct haeme.
  • Synthesis of pathway enzymes in the marrow is coordinated by erythroid‐specific transcription factors and iron.

Keywords: haeme; porphyrins; porphobilinogen; porphyrias; chlorophyll; bilanes

Figure 1. Enzymes and intermediates of the haeme biosynthetic pathway and their mitochondrial and cytosolic locations. The pathway is regulated, especially in the liver by the end‐product, haeme, mainly by feedback repression (dashed arrow).
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Further Reading

Beale SI (2007) Biosynthesis of Open‐Chain Tetrapyrroles in Plants, Algae, and Cyanobacteria. In: Chadwick DJ and Ackrill K (eds) Ciba Foundation Symposium 180–The Biosynthesis of the Tetrapyrrole Pigments. John Wiley & Sons, Ltd., Chichester, UK. DOI: 10.1002/9780470514535.ch9.

Bonkovsky HL, Guo J‐T, Hou W, et al. (2013) Porphyrin and heme metabolism and the porphyrias. Comprehensive Physiology 3: 365–401.

Brzezowski P, Richter AS and Grimm B (2015) Regulation and function of tetrapyrrole biosynthesis in plants and algae. Biochimica et Biophysica Acta 1847 (9): 968–985.

Dailey HA (ed) (1990) Biosynthesis of Heme and Chlorophylls. New York: McGraw‐Hill.

Layer G, Reichelt J, Jahn D and Heinz DW (2010) Structure and function of enzymes in heme biosynthesis. Protein Science 19 (6): 1137–1161.

Phillips JD and Anderson KE (2016) The porphyrias (Chapter 58). In: Kaushansky K, Lichtman MA, Prchal JT, et al. (eds) Williams. Hematology, 9th edn, pp. 839–863. New York: McGraw‐Hill.

Sachar M, Anderson KE and Ma X (2016) Protoporphyrin IX: the good, the bad, and the ugly. Journal of Pharmacology and Experimental Therapeutics 356 (2): 267–275. DOI: 10.1124/jpet.115.228130.

Tanaka R and Tanaka A (2007) Tetrapyrrole biosynthesis in higher plants. Annual Review of Plant Biology 58: 321–346.

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Moghe, Akshata, Phillips, John D, and Anderson, Karl E(Sep 2016) Haeme Biosynthesis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000556.pub2]