Molecular pharmacology of NRH:quinone oxidoreductase 2: A detoxifying enzyme acting as an undercover toxifying enzyme.

NRH:quinone oxidoreductase 2 (NQO2/QR2, EC 1.10.99.2) is a cytosolic enzyme, abundant in the liver and variably expressed in mammalian tissues. Cloned 30 years ago, it was characterized as a flavoenzyme catalyzing the reduction of quinones and pseudoquinones. To do so, it uses exclusively N-alkyl nicotinamide derivatives, without being able to recognize NADH, the reference hydrure donor compound, in contrast to its next of a kind, NADH: quinone oxidoreductase 1 (NQO1). For a long time both enzymes have been considered as key detoxifying enzymes in quinone metabolism, but more recent findings point to a more toxifying function of NQO2, particularly with respect to ortho-quinones. In fact, during the reduction of substrates, NQO2 generates fairly unstable intermediates that re-oxidize immediately back to the original quinone, creating a futile cycle, the by-products of which are deleterious reactive oxygen species (ROS). Beside this peculiarity, it is a target for numerous drugs and natural compounds such as melatonin, chloroquine, imiquimod, resveratrol, piceatannol, quercetin and other flavonoids. Most of these enzyme-ligand interactions have been documented by numerous crystallographic studies and now, NQO2 is one of the best represented proteins in the structural biology database. Despite evidence for a causative role in several important diseases, the functional role of NQO2 remains poorly explored. In the present review, we aimed at detailing the main characteristics of NQO2 from a molecular pharmacology perspective. By drawing a clear border between facts and speculations. we hope to stimulate the future research toward a better understanding of this intriguing drug target. Significance Statement Evidence is reviewed on the prevalent toxifying function of NQO2 while catalyzing the reduction of o-quinones such as dopamine quinone. The product of this reaction is unstable and generates a futile but harmful cycle (substrate/product/substrate) associated with ROS generation.