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Abstract

Our understanding of enzyme catalysis is dominated by transition state theory. According to this concept, an enzymatic reaction is guided along a desired reaction coordinate through the stabilization of favorable transition state. But how much is the outcome of an enzyme reaction controlled by the destabilization of unwanted transition states? Here, we revive and critically review the hypothesis that the active site of enzymes also features elements of 'negative catalysis'. We provide examples that show that enzyme catalysis can be achieved by the combined action of positive and negative constraints at the active site of an enzyme. This integrated view of enzyme catalysis has direct consequences for our studies on the catalytic landscape of enzymes, as well as current efforts in enzyme engineering and the de novo-design of enzymes.