metallohydrolases

Metallohydrolases are enzymes that catalyze the hydrolysis of chemical bonds in substrates by using metal ions in their active sites. The metal cofactors are most commonly zinc (Zn2+), but manganese (Mn2+), iron (Fe2+/3+), cobalt (Co2+), and nickel (Ni2+) also occur. Some metallohydrolases use a single metal ion, while others feature dinuclear or multinuclear centers that cooperate during catalysis. The bound metal often functions to polarize the substrate and to generate a reactive hydroxide or water molecule that attacks the target bond, such as amide, ester, phosphate, or glycosidic bonds.

Active-site features typically include coordinating residues—often histidines, aspartates, and glutamates—that bind the metal and help position a metal-bound hydroxide. The catalytic mechanism usually involves deprotonation of bound water to form a nucleophilic hydroxide, with the metal ion lowering the pKa and stabilizing transition states. The geometry and charge of the metal center help stabilize intermediates and control selectivity.

Notable examples of metallohydrolases include zinc-dependent metalloproteases (such as matrix metalloproteinases), zinc-dependent beta-lactamases that hydrolyze antibiotic rings, carbonic anhydrases that catalyze CO2 hydration, alkaline phosphatases that remove phosphate groups, and ureases that hydrolyze urea using nickel. Other families include metallo-beta-lactamases, phosphodiesterases, and lactonases.

Biologically, metallohydrolases participate in digestion, metabolism, signaling, tissue remodeling, and metal homeostasis. They are important biomedical targets (for example, metalloprotease and beta-lactamase inhibitors) and have wide applications in biotechnology and environmental remediation as versatile biocatalysts operating under mild conditions.