A malleable catalyst dominates the metabolism of drugs

In this issue of PNAS, Ekroos and Sjögren (1) present new structures of a cytochrome P450 (P450, or “CYP”), in one case bound with two ligands. The results are of considerable importance not only in regard to the practical issues in drug development but also because they have general significance in consideration of the flexibility of enzymes in recognizing substrates. The concept of how some enzymes accommodate a broad variety of ligands and catalyze multiple, regioselective reactions on a single substrate is a challenge to a classical lock-and-key model of catalysis. The current work has broad implications for a number of important enzyme systems and how we understand them. The P450 enzymes dominate the metabolism of drugs, accounting for ≈75% (2, 3). P450 3A4 is the most abundant P450 in the liver and small intestine and plays a role in the metabolism of one-half of the drugs on the market and in development (2–4). P450 3A4 was discovered two decades ago in early studies on the purification of P450s from human liver (5, 6) and was soon shown to have a wide repertoire of substrates, ranging in size from acetaminophen (M r 151) to cyclosporin A (M r 1201). The en-zyme is highly inducible by barbiturates and numerous other compounds (7) and is also prone to both competitive and mechanism-based inhibition by drugs, leading to important drug–drug interactions. To date, attempts to understand the variability of P450 3A4 activity among humans at the level of allelic variants have been disappointing, and a pharmacogenetic approach to predicting interindividual patient variation in P450 3A4 and therapeutic effects has not been very successful (4). Because of the significance of P450 3A4, a goal in pharmaceutical discovery and development is the prediction of modes …