Mechanisms of promiscuity among drug metabolizing enzymes and drug transporters

Detoxication, or ‘drug‐metabolizing’, enzymes and drug transporters exhibit remarkable substrate promiscuity and catalytic promiscuity. In contrast to substrate‐specific enzymes that participate in defined metabolic pathways, individual detoxication enzymes must cope with substrates of vast structural diversity, including previously unencountered environmental toxins. Presumably, evolution selects for a balance of ‘adequate’ k (cat)/K (M) values for a wide range of substrates, rather than optimizing k (cat)/K (M) for any individual substrate. However, the structural, energetic, and metabolic properties that achieve this balance, and hence optimize detoxication, are not well understood. Two features of detoxication enzymes that are frequently cited as contributions to promiscuity include the exploitation of highly reactive versatile cofactors, or cosubstrates, and a high degree of flexibility within the protein structure. This review examines these intuitive mechanisms in detail and clarifies the contributions of the classic ligand binding models ‘induced fit’ (IF) and ‘conformational selection’ (CS) to substrate promiscuity. The available literature data for drug metabolizing enzymes and transporters suggest that IF is exploited by these promiscuous detoxication enzymes, as it is with substrate‐specific enzymes, but the detoxication enzymes uniquely exploit ‘IFs’ to retain a wide range of substrates at their active sites. In contrast, whereas CS provides no catalytic advantage to substrate‐specific enzymes, promiscuous enzymes may uniquely exploit it to recruit a wide range of substrates. The combination of CS and IF, for recruitment and retention of substrates, can potentially optimize the promiscuity of drug metabolizing enzymes and drug transporters.