Isomerization of isopentenyl diphosphate, a homoallylic diphosphate ester, to dimethylallyl diphosphate, an allylic diphosphate ester, is a required step in the isoprenoid biosynthetic pathway. Two forms of isopentenyl diphosphate isomerase have evolved convergently to catalyze this reaction. While convergent evolution of enzymes to catalyze similar reactions is common, for example the diverse collection of enzymes that hydrolyze amide bonds, it is unusual for such an event to produce enzymes that catalyze identical reactions for the same substrate. One of the isomerase enzymes is a metalloprotein with zinc as a cofactor, while the other requires flavin, normally a cofactor for redox reactions, thus raising the unusual possibility that the two enzymes catalyze the same reaction by different chemical mechanisms.
The chemical mechanisms for the reactions catalyzed by both enzymes were studied using substrate analogs, mechanism-based active site directed irreversible inhibitors, and crystal structures. A new role for flavin as a cofactor is proposed.
