Vitamin B12 Coenzyme Models: Perspectives on Recent Developments in the Chemistry of the Cobaloximes and Related Models

Abstract

Discoveries on B12 models made since 1989 are assessed in the light of the advances in structural and spectroscopic methodologies. Further studies emanating in part from these advances have confirmed, often definitively, previously identified principles describing the properties of the classic simple models (cobaloximes and iminocobaloximes) and have established some new principles defining the properties of the axial Co-C and Co-N bonds; the latter are clearly relevant to enzymatic processes. Some new simple models have been proposed and studied in relation to the classic ones and to the more complicated natural cobalamins. In several cases, the influence of the steric and electronic factors have been established, sometimes in semi-quantitative terms, also with the help of studies on the rhodium analogues of cobaloximes. New spectroscopic techniques have been introduced, which have been found useful in the study of the natural cobalamins. Recent structural analyses of the binding site in some B12-based enzymes have shown that the B12 cofactors bind in the base-off form, with displacement of the benzimidazole residue from cobalt and coordination of a histidine residue of the protein chain. Such observations have stimulated new experiments aimed at defining the mechanism of the Co-C homolytic cleavage in isomerases and mutases or at testing the recently proposed mechanism for the Co-C heterolytic cleavage in methionine synthase. As a consequence, the information now available on models and on cobalamins (e.g., on the nature of the Co-S bond) is much broader in scope, and these advances have prompted this new analysis of models. The experimental aspects have advanced much more quickly than our theoretical understanding, and hence further calculations, possibly based on more sophisticated approaches, are clearly required.