NAD(P)H dehydrogenase [quinone] 1 (NQO1)

NAD(P)H dehydrogenase [quinone] 1 (NQO1) is a cytoplasmic FAD-binding flavoprotein that functions as a homodimeric two-electron reductase. The enzyme catalyzes the reduction of quinones and quinonoid compounds to hydroquinones using either NADH or NADPH as electron donors, with preference for short-chain acceptor quinones such as ubiquinone, benzoquinone, juglone, and duroquinone. The enzyme plays a critical role in cellular antioxidant defense by preventing the one-electron reduction of quinones that would otherwise generate harmful semiquinone radicals and reactive oxygen species. Beyond its detoxification function, NQO1 serves as a gatekeeper of the 20S proteasome and regulates the stability of tumor suppressor proteins p53 and TP73 through NADH-dependent interactions that prevent their ubiquitin-independent degradation. The enzyme exhibits functional cooperativity between its active sites, with NADH binding significantly decreasing protein dynamics and stabilizing the enzyme structure, particularly at the dimer core and interface. NQO1 is encoded by the NQO1 gene and is widely distributed in epithelial and endothelial tissues. Its expression can be induced by dioxin and inhibited by dicoumarol. The enzyme is overexpressed in various tumors, making it an attractive target for cancer therapy, and can activate quinone-based chemotherapeutic prodrugs. Genetic polymorphisms, particularly the P187S variant, have been associated with altered enzyme function and increased susceptibility to toxicity and disease.

Other names

DT-diaphoraseDTDQuinone reductase 1QR1NAD(P)H:quinone oxidoreductase 1Menadione reductaseAzoreductasePhylloquinone reductaseNMOR1DIA4

The enzyme catalyzes two-electron reduction using a ping-pong kinetic mechanism where electrons are sequentially transferred from NAD(P)H to FAD cofactor and then from reduced FAD to quinone, bypassing semiquinone formation. It can both detoxify quinones by producing stable hydroquinones for excretion, or activate quinone-based prodrugs by generating redox-reactive hydroquinones with DNA cross-linking antitumor potential. The enzyme also stabilizes tumor suppressors by preventing their proteasomal degradation in a NADH-dependent manner.