Haem synthesis

Haem consists of a protoporphyrin ring with an iron atom at its centre. Haem is synthesized from the precursors succinyl CoA and glycine, which condense to form S-aminolaevulinic acid (ALA) under the action of ALA synthase (ALAS), with pyridoxal phosphate as a coenzyme (p. 19). 'Housekeeping' ALAS (ALAS1) is coded by a gene on chromosome 3, but, in erythroid cells erythroid-specific ALAS2 predominates and is coded on the X chromosome. ALA can be utilized for the formation of both purines and haem. Four molecules of porphobilinogen condense under the influence of porphobilinogen deaminase (PBGD) and uroporphyrinogen cosynthase to form the tetrapyrrole ring compound uroporphyrinogen III. The latter is converted to protoporphyrin IX. Finally, iron in the ferrous form is incorporated under the influence of the enzyme ferrochelatase. Iron in haem has six coordinating valencies: four link the iron to nitrogen atoms in each pyrrole ring, whereas the remaining two link haem to histidine residues in the globin chain, the distal bond being unstable and easily replaced by oxygen to form oxyhaemoglobin.

The mitochondria play a major role in haem synthesis as they contain ALAS, coproporphyrinogen oxidase and ferrochelatase, the enzyme sequence from ALA to coproporphyrinogen being situated in the cytoplasm. The mitochondria are also the site of the citric acid cycle, which supplies succinate. The mature red cell, which lacks mitochondria, is therefore unable to synthesize haem.

A number of porphyrins are formed by side reactions during the synthesis of protoporphyrin. In the porphyrias (p. 39), many of these compounds accumulate in the major sites of haem synthesis, the liver and the red cells.

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