Specificity distorted: Chemical induction of biological paracatalysis

We define paracatalysis as the acceleration of a reaction that appears abnormal or nonphysiological. With the high specificity of enzymes, side reactivity of this kind is typically negligible. However, enzyme paracatalysis can be amplified to levels that are biologically significant through interactions with a special class of small molecule “antagonist”, here termed a paracatalytic inducer. Compounds with this unusual mode of action tend to be natural products, identified by chance through phenotypic screens. In this Perspective, we suggest two general types of paracatalytic inducer. The first type promotes substrate ambiguity, where the enzyme’s ground state selectivity is compromised, enabling the transformation of non-native substrates. The second type involves transition state ambiguity, where the paracatalytic inducer changes the enzyme’s interactions with the activated substrate, giving rise to nonnative bond making. Although they are unusual, small molecules that induce paracatalysis have established value as hypothesis-generating probes and a few substances, i.e., aspirin and the aminoglycosides, have proven to be translatable as medicines.