Zinc hydrolases are ubiquitous, and their overexpression and hyperactivity leads to a number of deleterious conditions. The development of tight-binding and selective inhibitors has been hampered by the lack of easily observable spectroscopic properties. Cobalt-substitution offers rich spectroscopy, but requires validation by comparison with the native Zn enzymes. We present here a series of studies aimed at identification and characterization of zinc-binding moieties that can be used in place of more fluxional acetohydroxamates. An integrated spectroscopic approach, using X-ray absorption spectroscopy to compare Zn- and Co-substiuted enzymes to obtain coordination numbers and metal-ligand bond lengths, optical spectroscopy to obtain binding kinetics, and paramagnetic resonance (multi-frequency EPR, ENDOR and NMR) to determine finer structural details. Results of these studies will be compared with those from structurally characterized model compounds, in an effort to determine the number and nature of relevant binding modes for each zinc-binding group.

Spectroscopic studies of Zn-hydrolase inhibitor complexes and related models

245th National Meeting (2013)

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