The aminopeptidase from Aeromonas proteolytica: structure and mechanism of co-catalytic metal centers involved in peptide hydrolysis

Abstract

Enzymes containing multi-metal active sites are central to numerous biological processes and, consequently, characterization of their structure and function is a problem of outstanding importance. One of the least-explored groups of enzymes is the hydrolases that contain dinuclear metal centers. These enzymes play key roles in carcinogenesis, tissue repair, and protein degradation processes. In addition, some of these enzymes can catalyze the hydrolysis of phosphorus(V) compounds found in nerve gases and agricultural neurotoxins. The determination of detailed reaction mechanisms for these enzymes is required for the design of highly potent, specific inhibitors that can function as potential pharmaceuticals. Hydrolytic enzymes that contain dinuclear centers can use every first row divalent transition metal ion from manganese to zinc, except copper. In order to understand the role of each metal ion in catalysis and the apparent non-selectivity of these enzymes towards divalent transition metal ions, it is critical that the reaction mechanism of a prototypical system be determined. The aminopeptidase from Aeromonas proteolytica (AAP) is one of the best mechanistically characterized hydrolytic enzymes that contains a dinuclear center and is, therefore, the focus of this review.