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

NAD(P)H quinone dehydrogenase 1 (NQO1) is a cytosolic homodimeric flavoenzyme that primarily functions as a detoxifying enzyme by catalyzing the two-electron reduction of quinones to stable hydroquinones [UniProt: P15559]. This reaction prevents the formation of highly reactive semiquinone radicals and the subsequent generation of reactive oxygen species (ROS). However, NQO1 is significantly overexpressed in various solid tumors, including lung, pancreatic, and breast cancers, which has led to its exploitation as a target for bioactivatable prodrugs [PMID: 28933538]. Drugs such as beta-lapachone (ARQ 761) utilize NQO1 to undergo a futile catalytic cycle, where the resulting hydroquinone spontaneously autoxidizes back to the quinone form. This process generates a massive burst of ROS that induces extensive DNA damage and PARP-1-mediated cell death [PMID: 17475935]. Beyond its catalytic activity, NQO1 also functions as a molecular chaperone that stabilizes key tumor suppressors like p53 against proteasomal degradation, further linking it to cancer progression and therapy [PMID: 24513305]. Consequently, NQO1 serves as both a potent therapeutic target and a critical biomarker for identifying patients likely to respond to NQO1-directed therapies.

Other names

DT-diaphoraseQuinone reductase 1QR1Menadione reductasePhylloquinone reductaseAzoreductaseDiaphorase-4

NQO1 catalyzes a mandatory two-electron reduction of quinones to hydroquinones using NADH or NADPH as electron donors [UniProt: P15559]. In the context of bioactivation, specific prodrugs like beta-lapachone are reduced to unstable hydroquinones that undergo rapid, spontaneous autoxidation back to the quinone form. This creates a futile cycle that consumes cellular reducing equivalents and generates lethal levels of reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, leading to oxidative stress-induced DNA damage and cell death [PMID: 28933538, PMID: 17475935].