The porphobilinogen synthase (PBGS) family of enzymes catalyzes the first c
ommon step in the biosynthesis of the essential tetrapyrroles such as chlor
ophyll and porphyrin, Although PBGSs are highly conserved at ail four level
s of protein structure, there is considerable diversity in the use of dival
ent cations for the catalytically essential and allosteric roles. Assumptio
ns regarding commonalities among the PBGS proteins coupled with the diversi
ty of usage of metal ions has led to a confused literature. The recent publ
ication of crystal structures for three PBGS proteins coupled with more tha
n 50 individual PBGS sequences allows an evaluation of these assumptions. T
his topical review focuses on the usage of metals by the PBGS family of pro
teins. It raises doubt concerning a dogma that there has been an evolutiona
ry shift between Zn-II and Mg-II at one or more of the divalent metal-bindi
ng sites. It also raises the possibility that there may be up to four speci
fic divalent metal ion-binding sites, each serving a unique function that c
an be alternatively filled by amino acids in some of the PBGSs.