A STRUCTURAL BASIS FOR ENANTIOSELECTIVE INHIBITION OF CANDIDA-RUGOSA LIPASE BY LONG-CHAIN ALIPHATIC-ALCOHOLS

Molecular modeling showed that the enantiomers of heptyl 2-methyldecan oate are productively bound to the active site of Candida rugosa lipas e in quite different conformations. The fast-reacting S-enantiomer may well occupy the previously identified acyl-binding tunnel in the acti ve site of the lipase. By contrast, the slow-reacting R-enantiomer mus t be bound to the active site, leaving the tunnel empty to allow the f ormation of two catalytically essential hydrogen bonds between His 449 of the catalytic triad and the transition state of the catalyzed reac tion. This information enables us to propose a molecular mechanism exp laining how long-chain aliphatic alcohols act as enantioselective inhi bitors of this lipase in the resolution of 2-methyldecanoic acid. Long -chain aliphatic alcohols may coordinate to the acyl-binding tunnel of the C. rugosa lipase, thereby selectively inhibiting the turnover of the fast-reacting S-enantiomer, thus resulting in a lowered enantiosel ectivity in the resolution.