NQO2 is a cytosolic flavoprotein that functions as a homodimer . It contains two catalytic flavin adenine dinucleotide (FAD) cofactors and two zinc ions, although the role of zinc in its catalytic activity is not fully understood . The enzyme operates through a ping-pong mechanism involving its FAD cofactor . In the reductive phase, NQO2 binds to reduced dihydronicotinamide riboside (NRH) as an electron donor and mediates a hydride transfer from NRH to FAD. In the oxidative phase, NQO2 binds to its quinone substrate and reduces it to a dihydroquinone .
NQO2 is a phase II detoxification enzyme that can carry out two or four electron reductions of quinones . This detoxification process is essential as it protects cells against quinone-induced oxidative stress, cytotoxicity, and mutagenicity . Quinones are potentially dangerous because they can undergo one-electron reduction to form semiquinones, which elicit oxidative stress in cells . By reducing quinones to hydroquinones through a two-electron step, NQO2 prevents the formation of reactive oxygen species .
NQO2 has been found to be overexpressed in certain types of tumors and is upregulated as part of the oxidative stress response . It also has a melatonin-binding site, which may explain the antioxidant role of melatonin . Interestingly, NQO2 can be inhibited by resveratrol, a compound found in red wine .
The NQO gene family is ancient, believed to be between 2 and more than 3 billion years old . This family includes NQO1 and NQO2 in humans, and these genes encode enzymes that catalyze the beneficial two-electron reduction of quinones to hydroquinones . This evolutionary development likely provided a significant advantage by protecting early organisms from oxidative damage caused by quinones .
Recombinant NQO2 is used in various research applications to study its role in detoxification, oxidative stress response, and its potential involvement in cancer and other diseases . Understanding the function and regulation of NQO2 can provide insights into developing therapeutic strategies for conditions associated with oxidative stress and quinone toxicity.