Enzymic Reaction Selectivity by Negative Catalysis or How Do Enzymes Deal with Highly Reactive Intermediates?

Abstract

Our current understanding of enzyme catalysis is dominated by the hypothesis of transition‐state binding launched by Linus Pauling in 1946. Transition‐state binding and the interplay of properly positioned, catalytically active functional groups can largely explain both the acceleration and specificities of many enzymic reactions for which chemical analogy exists. Here it is postulated that, for chemically “difficult” or “improbable” reactions, enzymes may resort to an additional device. Using cofactors of potentially high energy (such as coenzyme B 12), stabilized radicals, or light, they can transform the bound substrate into a highly reactive (i.e., unstable) intermediate. Selectivity is now achieved by negative catalysis, that is, by preventing the “hot” intermediate from undergoing reactions that would occur in solution or in the gas phase and thus prolonging its lifetime. The highly reactive intermediate may then undergo reactions whose activation energy is relatively high and which would therefore be suppressed without negative catalysis. Reaction selectivity is thus achieved by preventing undesired reactions rather than by facilitating the target ones. The high reactivity may be transferred reversibly if its source is, for instance, coenzyme B 12 or irreversibly if it is generated by light or ATP. Highly reactive intermediates are often radicals but can also be other unstable species. In this article a number of enzymic reactions are discussed that seem to support the above postulate.