Proteins Enzymatic entries Enzyme

Currently, only a handful of examples of unique protein carboxylate-zinc interactions are available in the Brookhaven Protein Data Bank. Each of these entries, however, displays syn coordination stereochemistry, and two are bidentate (Christianson and Alexander, 1989) (Fig. 5). Other protein structures have been reported with iyw-oriented car-boxylate-zinc interactions, but full coordinate sets are not yet available [e.g., DNA polymerase (Ollis etal., 1985) and alkaline phosphatase (Kim and Wyckoff, 1989)]. A survey of all protein-metal ion interactions reveals that jyw-carboxylate—metal ion stereochemistry is preferred (Chakrabarti, 1990a). It is been suggested that potent zinc enzyme inhibition arises from syn-oriented interactions between inhibitor carboxylates and active-site zinc ions (Christianson and Lipscomb, 1988a see also Monzingo and Matthews, 1984), and the structures of such interactions may sample the reaction coordinate for enzymatic catalysis in certain systems (Christianson and Lipscomb, 1987). 

The known coenzyme Bi2-dependent enzymes all perform chemical transformations in enzymatic radical reactions that are difficult to achieve by typical organic reactions. Homolytic cleavage of the Co bond of the protein-bound coenzyme B12 (3) to a 5 -deoxy-5 -adenosyl radical (9) and cob(n)alamin (5) is the entry to reversible H-abstraction reactions involving the 5 -position of the radical (9). Indeed, homolysis of the Co bond is the thermally most easily achieved transformation of coenzyme B12 (3) in neutral aqueous solution (with a homolytic (Co-C)-BDE of about 30 kcal mol ). However, to be relevant for the observed rates of catalysis by the coenzyme B12-dependent enzymes, the homolysis of the Co-C bond of the protein-bound coenzyme (3) needs to be accelerated by a factor of about 10 , in the presence of a substrate. Coenzyme B12 might then be considered, first of aU, to be a structurally sophisticated, reversible source for an alkyl radical, whose Co bond is labihzed in the protein-bound state (Figure 8), and the first major task of the... 

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