Clues to dimetallohydrolase mechanisms from studies on pyrazolate-based bioinspired dizinc complexes - Experimental evidence for a functional Zn-O2H3-Zn motif

Various hydrolytic metalloenzymes contain two adjacent zinc ions within their active site that work synergistically during substrate turnover. While structural biology, biochemical investigations, and quantum chemical calculations have provided much insight into those cocatalytic sites, crucial details of the catalytic mechanisms have remained under debate. Valuable contributions to further our understanding of the functional role of the zinc ions in a specific coordination environment can be obtained from the study of simple biomimetic synthetic complexes that emulate features of the natural systems. To this end, a series of highly preorganized pyrazolate-based dizinc complexes has been developed, which are particularly amenable to fine-tuning of the dimetallic core. These bioinspired dizinc complexes have made possible the investigation of systematic effects of factors such as the zinc-zinc separation on hydrolytic activity and substrate binding. The present microreview summarizes findings relevant to dimetallohydrolases that have been obtained from studies of the pyrazolate-based synthetic analogues, including experimental support for a functional role of the Zn-O2H3-Zn motif and clues to the binding and hydrolytic cleavage of phosphodiester and beta-lactain substrates.