quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinones and thereby prevent generation of toxic radicals. Quinone methides (QMs) covalently react with cellular macromolecules to form DNA adducts and/or protein conjugates resulting in toxicity and carcinogenesis. Based on similar structural features of quinones and QMs, it is logical to assume that NQO1 and/or NQO2 could also catalyze the two-electron reduction of QMs. However, hitherto the reduction of QMs, as both endogenous and/or exogenous biological substrates, by either NQO1/NQO2 has never been demonstrated. Here we show for the first time that both NQO1 and NQO2 can catalyze the reduction of electrophilic ortho-/para-QMs. The involvement of the enzyme in the reduction of p-cresol quinone methide (PCQM) and o-cresol quinone methide (OCQM) was demonstrated by reappearance of NQO1/NQO2-FAD peak at 450 nm after addition of the QMs to the assay mixture. Further reduction of methides by NQO1/NQO2 was confirmed by analyzing the assay mixture by tandem mass spectrometry. Preliminary kinetic studies show that NQO2 is faster in reducing QMs than its homolog NQO1, and moreover, ortho-QMs are reduced faster than para-QMs. Enzyme-substrate docking studies showed results consistent with enzyme catalysis. Thus, NQO1/NQO2 can play a significant role in deactivation of QMs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.3109/10715762.2013.847527 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Evolutionary analysis of Quinone Reductases 1 and 2 suggests that NQO2 evolved to function as a pseudoenzyme.
Protein Sci
December 2024
Department of Biochemistry, University of Western Ontario, London, Ontario, Canada.
Quinone reductases 1 and 2 (NQO1 and NQO2) are paralogous FAD-linked enzymes found in all amniotes. NQO1 and NQO2 have similar structures, and both catalyze the reduction of quinones and other electrophiles; however, the two enzymes differ in their cosubstrate preference. While NQO1 can use both redox couples NADH and NADPH, NQO2 is almost inactive with these cosubstrates and instead must use dihydronicotinamide riboside (NRH) and small synthetic cosubstrates such as N-benzyl-dihydronicotinamide (BNAH) for efficient catalysis.
View Article and Find Full Text PDFPolymorphisms and Pharmacogenomics of : The Past and the Future.
Genes (Basel)
January 2024
Institute for Biomedical Research and Innovation (IRIB), National Research Council of Italy (CNR), 88100 Catanzaro, Italy.
The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids.
View Article and Find Full Text PDFThe Unusual Cosubstrate Specificity of NQO2: Conservation Throughout the Amniotes and Implications for Cellular Function.
Front Pharmacol
April 2022
Department of Biochemistry, University of Western Ontario, London, ON, Canada.
Article Synopsis
- NQO2 is a pharmacological target that interacts with kinase-targeted drugs, but its cellular functions remain unclear.
- Disruption of the NQO2 gene in HCT116 cells showed that NQO2 cannot activate the DNA cross-linking reagent CB1954 without an external cofactor.
- Evolutionary analysis indicated that NQO2 has a conserved unusual preference for specific cosubstrates across amniotes but is poorly conserved in amphibians, diverging from NQO1 around 450 million years ago.
Roles of NAD(P)H:quinone Oxidoreductase 1 in Diverse Diseases.
Life (Basel)
November 2021
Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 06974, Korea.
NAD(P)H:quinone oxidoreductase (NQO) is an antioxidant flavoprotein that catalyzes the reduction of highly reactive quinone metabolites by employing NAD(P)H as an electron donor. There are two NQO enzymes-NQO1 and NQO2-in mammalian systems. In particular, NQO1 exerts many biological activities, including antioxidant activities, anti-inflammatory effects, and interactions with tumor suppressors.
View Article and Find Full Text PDFInteractions of the antioxidant enzymes NAD(P)H: Quinone oxidoreductase 1 (NQO1) and NRH: Quinone oxidoreductase 2 (NQO2) with pharmacological agents, endogenous biochemicals and environmental contaminants.
Chem Biol Interact
August 2021
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada. Electronic address:
Quinone Oxidoreductase 1 (NQO1) is an antioxidant enzyme that catalyzes the two-electron reduction of several different classes of quinone-like compounds (quinones, quinone imines, nitroaromatics, and azo dyes). One-electron reduction of quinone or quinone-like metabolites is considered to generate semiquinones to initiate redox cycling that is responsible for the generation of reactive oxygen species and oxidative stress and may contribute to the initiation of adverse drug reactions and adverse health effects. On the other hand, the two-electron reduction of quinoid compounds appears important for drug activation (bioreductive activation) via chemical rearrangement or autoxidation.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!