Like many enzymes involved in xenobiotic metabolism, human carboxylesterase 1 (hCE1) is promiscuous, hydrolysing numerous structurally distinct substrates, including fatty acid and cholesterol derivatives, drugs such as cocaine and heroin, and organophosphate toxins such as sarin. Two recent papers describing crystal structures of hCE1 with different substrates shed light on the structural basis of this promiscuity, and might provide new avenues for treating narcotic abuse and cholesterol-related diseases.

hCE1 hydrolyses cocaine to generate its primary urinary metabolite benzoylecognine, and converts heroin to morphine. In the first of the two studies — both of which are from the Redinbo laboratory — the authors investigated the basis of these activities by determining the structures of hCE1 complexed with the cocaine analogue homatropine, and also the heroin analogue naloxone. Their data show that the substrate-binding gorge of hCE1 has both a small, rigid binding pocket and a large, conformationally flexible binding pocket, which allows hCE1 to act on chemically divergent substrates such as cocaine and heroin. The details of the interactions will facilitate the engineering of highly selective forms of the enzyme with improved catalytic activity towards cocaine for treating acute overdoses, and might also aid in engineering hCE1 to protect against organophosphate toxins.

In the second study, the authors determined the structure of hCE1 in complex with tacrine, a potent inhibitor of the related enzyme acetylcholinesterase (AcChE) that is approved for the treatment of Alzheimer's disease. This structure provides a further illustration of how hCEl achieves its ligand-binding promiscuity by using a large, flexible binding site, which allows tacrine to bind in several orientations at once. By contrast, the previously determined structure of an AcChE–tacrine complex shows that tacrine largely fills the smaller AcChE active site, explaining why tacrine is a nanomolar-affinity inhibitor of AcChE, but does not inhibit hCE1 up to concentrations of 100 μM. However, on the basis of the crystal structure of hCE1, the authors identified analogues of tacrine that were selective, low-micromolar inhibitors of hCE1, which might be leads for cardiovascular drug development, as hCE1 seems to be important in cholesterol transport. Furthermore, as hCE1 is also responsible for producing the toxic metabolite cocaethylene that is formed when cocaine and alcohol are abused together, hCE1 inhibitors could be useful in limiting toxicity in this abuse situation.