Alternative titles; symbols
HGNC Approved Gene Symbol: NDOR1
Cytogenetic location: 9q34.3 Genomic coordinates (GRCh38): 9:137,205,700-137,219,361 (from NCBI)
By screening an EST database for sequences homologous to cytochrome P-450 reductase (POR; 124015), Paine et al. (2000) identified a cDNA encoding a protein they termed NR1 (novel reductase-1). The predicted 597-amino acid, 62-kD NR1 protein shares 41 to 44% sequence similarity with nitric oxide synthase-2 (see 163730), methionine synthase transferase (602568), and POR. Northern blot analysis detected 3.0-kb and 6.0-kb NR1 transcripts in a broad range of normal tissues and cancer cell lines. NR1 expression was generally low in normal human tissues, with highest levels in the placenta. In cancer cell lines, highest levels of NR1 were in HeLa and colonic adenoma cells, followed by myeloid leukemia cells and melanoma cells. Immunoblot analysis determined that NR1 is cytoplasmic and is highly expressed in a panel of human cancer cell lines derived from ovary, breast, bladder, lung, colon, liver, and cervical carcinoma tissues. Using HPLC analysis of heat-denatured recombinant NR1, Paine et al. (2000) determined that NR1 binds FMN, FAD, and NADPH cofactors. They reported that NR1 exhibits an ultraviolet-visible spectrum with absorbance maxima at 380, 460, and 626 nm. Purified NR1 enzyme reduced cytochrome c and metabolized the 1-electron acceptors doxorubicin, menadione, and potassium ferricyanide. Paine et al. (2000) concluded that NR1 is a member of the FNR family of flavoenzymes that may play a role in the metabolic activation of bioreductive anticancer drugs and other chemicals activated by 1-electron reduction.
Kwasnicka et al. (2003) showed that the C. elegans ortholog of DCPS (610534), dcs1, is transcribed as a bicistronic pre-mRNA with fre1, the ortholog of human NDOR1. RT-PCR analysis showed DCPS and NDOR1 expression in human brain, liver, kidney, and testis. Immunocytochemistry of COS cells showed endogenous DCPS staining in a distinct perinuclear structure, coincident with NDOR1 staining. Although DCPS and NDOR1 are not neighboring genes in humans, Kwasnicka et al. (2003) noted that their expression profile is highly correlated.
Using HEK cells transfected with NDOR1 and DCPS, Kwasnicka-Crawford and Vincent (2005) showed that NDOR1 overexpression enhanced cytotoxicity of the bioreductive anticancer agent, menadione, and that coexpression of DCPS reduced this toxicity. Western blot analysis showed increased DCPS protein levels in response to menadione, and immunoprecipitation assays showed that DCPS and NDOR1 interacted.
Using FISH, Paine et al. (2000) mapped the NDOR1 gene to chromosome 9q34.3.
Kwasnicka, D. A., Krakowiak, A., Thacker, C., Brenner, C., Vincent, S. R. Coordinate expression of NADPH-dependent flavin reductase, Fre-1, and Hint-related 7meGMP-directed hydrolase, DCS-1. J. Biol. Chem. 278: 39051-39058, 2003. [PubMed: 12871939] [Full Text: https://doi.org/10.1074/jbc.M306355200]
Kwasnicka-Crawford, D. A., Vincent, S. R. Role of a novel dual flavin reductase (NR1) and an associated histidine triad protein (DCS-1) in menadione-induced cytotoxicity. Biochem. Biophys. Res. Commun. 336: 565-571, 2005. [PubMed: 16140270] [Full Text: https://doi.org/10.1016/j.bbrc.2005.08.129]
Paine, M. J. I., Garner, A. P., Powell, D., Sibbald, J., Sales, M., Pratt, N., Smith, T., Tew, D. G., Wolf, C. R. Cloning and characterization of a novel human dual flavin reductase. J. Biol. Chem. 275: 1471-1478, 2000. [PubMed: 10625700] [Full Text: https://doi.org/10.1074/jbc.275.2.1471]