Alternative titles; symbolsNAD(P)H:MENADIONE OXIDOREDUCTASE 1, DIOXIN-INDUCIBLE 2; NMOR2HGNC Approved Gene Symbol: NQO2Cytogenetic location: 6p25.2 Genomic c...
Alternative titles; symbols
HGNC Approved Gene Symbol: NQO2
Cytogenetic location: 6p25.2 Genomic coordinates (GRCh38): 6:2,999,893-3,019,754 (from NCBI)
NQO2 (EC 184.108.40.206) is a flavoprotein that catalyzes the 2-electron reduction of various quinones, redox dyes, and the vitamin K menadione. NQO2 predominantly uses dihydronicotinamide riboside (NRH) as the electron donor (summary by Wu et al., 1997).
▼ Cloning and Expression
Jaiswal et al. (1988) described a cDNA that encodes a dioxin-inducible cytosolic form of human NAD(P)H:quinone oxidoreductase (NQO1; 125860). Jaiswal et al. (1990) cloned a cDNA clone that encodes a second form of this oxidoreductase, NQO2. It was isolated by screening a human liver cDNA library by hybridization with an NQO1 cDNA probe. The deduced 231-amino acid NQO2 protein has a calculated molecular mass of 25.95 kD and shares 49% similarity with the liver cytosolic NQO1 protein.
Using Northern blot analysis, Jaiswal (1994) detected variable expression of a single 1.2-kb NQO2 transcript in several human tissues, with highest expression in skeletal muscle, and little to no expression in pancreas and placenta.
Gaikwad et al. (2009) stated that NQO2 is ubiquitously expressed.
▼ Gene Function
By in vitro assay of human NQO2 expressed in transfected COS-1 cells, Jaiswal (1994) showed that NQO2 catalyzed nitroreduction of an antitumor analog of nitrophenylaziridine. However, unlike NQO1, NQO2 could not efficiently reduce DCIP (2,6-dichlorophenolindophenol) and menadione.
Wu et al. (1997) found that NQO2, like NQO1, functioned as a dimer with 1 FAD prosthetic group per 26-kD subunit. NRH was an efficient electron donor for NQO2-mediated 2-electron reduction of menadione and DCIP; however, NADH was a poor electron donor. NQO2 did not reduce 1-electron acceptors, such as potassium ferricyanide. NQO2 also catalyzed a 4-electron reduction of methyl red and a cytotoxic compound, CB 1954 (5-(aziridine-1-yl)-2,4-dinitrobenzamide). NQO2 was resistant to typical inhibitors of NQO1 and was sensitive to a different group of flavone inhibitors, including quercetin, a competitive inhibitor of NRH.
Estrogens are metabolized to reactive catechol estrogen quinones, and these quinones can depurinate DNA, leading to cancer-causing mutations. Using mass spectrometry, Gaikwad et al. (2009) showed that NQO2 could bind estrone-3,4-quinone (E1-3,4-Q) and estradiol-3,4-quinone (E2-3,4-Q). Preliminary kinetic studies revealed that NQO2 was faster in reducing and deactivating the estrogen quinones than NQO1. The reduction of E1-3,4-Q and E2-3,4-Q by NQO2 was confirmed by ultraviolet and liquid chromatography-tandem mass spectrometry assays. Both estrogens and melatonin bound NQO2, but melatonin did not affect estrogen quinone reduction by NQO2.
▼ Gene Structure
By Southern blot analysis, Jaiswal et al. (1990) demonstrated the presence of a single human NQO2 gene spanning approximately 14 to 17 kb.
Jaiswal (1994) determined that the NQO2 gene contains 7 exons and spans 20 kb. The first exon is noncoding. The promoter region contains a modified TATA box, 2 CCAAT boxes, 4 SP1 (189906)-binding sites, a single antioxidant response element (ARE), and 3 xenobiotic response elements (XREs).
By study of rodent/human somatic cell hybrids, Jaiswal et al. (1990) mapped the NQO2 gene to chromosome 6pter-q12. By fluorescence in situ hybridization, Jaiswal et al. (1999) narrowed the mapping of NQO2 to chromosome 6p25.
▼ Molecular Genetics
In a hospital-based study of 893 Chinese breast cancer patients and 711 Chinese cancer-free controls, Yu et al. (2009) genotyped 11 polymorphisms of the NQO2 gene, which encodes NRH:quinone oxidoreductase-2 and has enzymatic activity on estrogen-derived quinones and is able to stabilize p53 (TP53; 191170). The authors identified significant association between the incidence of breast cancer and a 29-bp insertion/deletion polymorphism (29-bp I/D; p = 0.0027; OR, 0.76) and the rs2071002 SNP (+237A-C; p = 0.0031; OR, 0.80), both of which are within the NQO2 promoter region. The findings were replicated in a second Chinese population of 403 familial/early-onset breast cancer patients and 1,039 controls. Decreased risk was associated with the D allele of 29 bp-I/D and the +237C allele of rs2071002. The susceptibility variants within NQO2 were notably associated with breast carcinomas with wildtype p53. The 29-bp insertion allele introduced a transcriptional repressor Sp3 binding sites, and the authors demonstrated that the 237A allele of rs2071002 abolished a transcriptional activator Sp1 binding site. Real-time PCR assay showed that normal breast tissues harboring protective genotypes expressed significantly higher levels of NQO2 mRNA than those in normal breast tissues harboring risk genotypes. Yu et al. (2009) suggested that NQO2 is a susceptibility gene for breast carcinogenesis.