NAD(P)H quinone oxidoreductase (NQO1): an enzyme which needs just enough mobility, in just the right places

Abstract

NAD(P)H quinone oxidoreductase 1 (NQO1) catalyses the two electron reduction of quinones and a wide range of other organic compounds. Its physiological role is believed to be partly the reduction of free radical load in cells and the detoxification of xenobiotics. It also has non-enzymatic functions stabilising a number of cellular regulators including p53. Functionally, NQO1 is a homodimer with two active sites formed from residues from both polypeptide chains. Catalysis proceeds via a substituted enzyme mechanism involving a tightly bound FAD cofactor. Dicoumarol and some structurally related compounds act as competitive inhibitors of NQO1. There is some evidence for negative cooperativity in quinine oxidoreductases which is most likely to be mediated at least in part by alterations to the mobility of the protein. Human NQO1 is implicated in cancer. It is often over-expressed in cancer cells and as such is considered as a possible drug target. Interestingly, a common polymorphic form of human NQO1, p.P187S, is associated with an increased risk of several forms of cancer. This variant has much lower activity than the wild-type, primarily due to its substantially reduced affinity for FAD which results from lower stability. This lower stability results from inappropriate mobility of key parts of the protein. Thus, NQO1 relies on correct mobility for normal function, but inappropriate mobility results in dysfunction and may cause disease.

Dicoumarol, an NQO1 inhibitor, blocks cccDNA transcription by promoting degradation of HBx

“…It is also well known to act as a competitive inhibitors of NAD(P)H:quinone oxidoreductase (NQO1) that competes with NAD(P)H for NQO1 binding. The best-described physiological role of NQO1 is a cytosolic reductase which catalyzes the two-electron reduction of quinones to hydroquinones [26] and plays an important role in the cellular defense mechanism against oxidative stress [27][28][29][30]. Interestingly, accumulating studies have shown that NQO1 functions as a "gate keeper" of the 20S proteasome and stabilizes many proteins [31], such as p53 and the viral protein Tat.…”

Targeting HIF-1α Function in Cancer through the Chaperone Action of NQO1

“…NQO1apo exists as a stable and expanded dimer characterized by significantly large conformational flexibility [76,78,79,80,119,130,131,132]. Although no high resolution structural model is available for this state, recent kinetic studies using hydrogen-deuterium exchange mass spectrometry (HDXMS) have identified a minimal stable core that holds the protein dimer while most of the protein exists forming a highly dynamic structural ensemble, including the FAD and substrate binding sites in non-competent states for binding [129].…”

“…In addition, and to the best of our knowledge, only one other naturally-occurring single amino acid variant, p.K240Q (found in gnomAD and COSMIC databases), has been characterized. Since the studies aimed at characterizing the effects of these single amino acid variants have been recently reviewed [76,132], we will just outline in this section some of the key features described for them focusing on their potential impact on the interaction with protein partners and with those ligands known to modulate NQO1:protein interactions.…”

Biological Application and Disease of Oxidoreductase Enzymes

“…There are different disease conditions resulting from deficiency (quantitative and qualitative) and excess of oxidoreductase, which may contribute to the metabolic abnormalities and decreased normal performance of life [13,14]. For example, relative decreases in the activities of NADH dehydrogenase and ubiquinolcytochrome c oxidoreductase are highly associated with the developments of peripheral arterial disease.…”