Porphobilinogen synthase, the first source of Heme's asymmetry

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Abstract
Porphobilinogen is the monopyrrole precursor of all biological tetrapyrroles. The biosynthesis of porphobilinogen involves the asymmetric condensation of two molecules of 5-aminolevulinate and is carried out by the enzyme porphobilinogen synthase (PBGS), also known as 5-aminolevulinate dehydratase. This review documents what is known about the mechanism of the PBGS-catalyzed reaction. The metal ion constitutents of PBGS are of particular interest because PBGS is a primary target for the environmental toxin lead. Mammalian PBGS contains two zinc ions at each active site. Bacterial and plant PBGS use a third metal ion, magnesium, as an allosteric activator. In addition, some bacterial and plant PBGS may use magnesium in place of one or both of the zinc ions of mammalian PBGS. These phylogenetic variations in metal ion usage are described along with a proposed rationale for the evolutionary divergence in metal ion usage. Finally, I describe what is known about the structure of PBGS, an enzyme which has as yet eluded crystal structure determination.