There's more to enzyme antagonism than inhibition

Abstract

A native enzyme's usual assurance in recognizing their physiological substrate(s) at the ground state and on going to the transition state can be undermined by interactions with selected small molecule antagonists, leading to the generation of abnormal products. We classify this mode of enzyme antagonism resulting in the gain-of-nonnative-function as paracatalytic induction. Enzymes bound by paracatalytic inducers exhibit new or enhanced activity toward transformations that appear aberrant or erroneous. The enzyme/ paracatalytic inducer complex may take up native substrate but then bring about a transformation that is chemically distinct from the normal reaction. Alternatively, the enzyme / paracatalytic inducer complex may exhibit abnormal ground state selectivity, preferentially interacting with and transforming a molecule outside the physiological substrate scope. Paracatalytic inducers can be cytotoxic, while in other cases they divert enzyme activity toward transformations that appear adaptive and even therapeutically useful. In this perspective, we highlight two noteworthy examples from recent literature.

Keywords: Antagonism; DNA repair; Enzyme; HTS; Kinase; Nonnative activity; Paracatalysis.