Metal Ions as Cofactors for the Binding of Inhibitors to Methionine Aminopeptidase: A Critical View of the Relevance of In Vitro Metalloenzyme Assays

Thiabendazole is a potent inhibitor of E. coli methionine aminopeptidase (MetAP) in vitro. Crystallographic structures of MetAP complexed with this and two other inhibitors show that binding is mediated by an auxiliary metal ion (see picture). This effect results from the high concentration of metal ions under in vitro conditions, and should be taken into account in assays for inhibitors of metal-dependent enzymes.