NQO1

Identity

Other names	DIA4
	DT-Diaphorase
	NMO1
Hugo	NQO1
Location	16q22.1
	NQO1 (16q22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are welcome : contact rocchi@biologia.uniba.it

DNA/RNA

Description	Spans approximately 20 kb consisting of 6 exons and 5 introns. Highly inducible protein and the 5' flanking region contains an AP2, ARE or EpRE(antioxidant or electrophile responsive element) and an XRE (xenobiotic responsive element).
Transcription	Three mRNA sizes (1.2, 1.7 and 2.7 kb) have been observed due to multiple polyadenylation sites. An alternatively spliced form of NQO1 mRNA lacking exon 4 is also possible although the corresponding truncated protein has not been detected.

Protein

Description	NQO1 is a flavoprotein which functions as a homodimer. The physiological dimer has one catalytic site per monomer. Each monomer consists of 273 amino acids. For structures of human recombinant NQO1 with quinones complexed in the active site see Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release (Structure Explorer - 1D4A) and. Structure-based development of antitumor quinones. Complexes of NQO1 with three potential chemotherapeutic quinones (Structure Explorer - 1H66).
Expression	NQO1 is expressed in human epithelial and endothelial tissues and at high levels throughout many human solid tumors.
Localisation	NQO1 is a mainly cytosolic enzyme (approx. 90%) although it has also been localized in smaller amounts to mitochondria, endoplasmic reticulum and nucleus.
Function	NQO1 catalyzes obligate two electron reduction of a wide variety of substrates. The most efficient substrates are quinones but the enzyme will also reduce quinone-imines, nitro and azo compounds. The enzyme functions via a hydride transfer mechanism and requires a pyridine nucleotide cofactor. Reduction proceeds with equal facility with both NADH and NADPH. NQO1 can generate antioxidant forms of both vitamin E and ubiquinone after free radical attack. The capability to protect cells from oxidative challenge and the ability to reduce quinones via an obligate two electron mechanism, which precludes generation of reactive oxygen radicals, demonstrates that NQO1 is a chemoprotective enzyme. NQO1 knockout mice demonstrated increased susceptibility to benzo(a)pyrene and 7,12-dimethylbenz(a) anthracene induced skin carcinogenesis. NQO1 has been proposed to stabilize the tumor suppressor gene p53 and has been shown to interact with p53 in a protein-protein interaction. Certain compounds such as antitumor quinones, however, can be bioactivated by two electron reduction and in these cases NQO1 serves as an activating enzyme. Because of the high levels of NQO1 in certain tumors, this has led to an interest in designing compounds which can be efficiently bioactivated by NQO1 as antitumor agents.
Homology	Amino acid homology across species is high (mouse/human 86%, mouse/rat -94%, human/rat 86%). NQO2 is a separate gene product demonstrating 49% and 54% similarity at the amino acid and nucleotide levels respectively.

Mutations

Germinal

Two polymorphisms have been characterized. The NQO1 *2 allele represents a C609T change in the cDNA coding for a Pro187Ser change in the enzyme. The NQO1 *3 allele is a C465T change in the cDNA coding for an Arg139Trp change. The NQO1 * 2 allele is much more frequent than the *3 allele and has profound consequences for phenotype. The NQO1 *2 protein has diminished catalytic activity and the protein is rapidly degraded by the ubiquitin-proteasomal system. As a result, cells and tissues carrying the homozygous NQO1 *2 allele have no detectable NQO1 activity and at best, trace levels of NQO1 protein. The NQO1 *2/*2 genotype is effectively a null polymorphism. NQO1 is highly inducible and although NQO1 levels can vary considerably among individuals with the same genotype, the NQO1 *2 allele has been reported to show a gene dose effect since heterozygotes (NQO1 *1/*2) contained significantly less NQO1 protein than wild type (NQO1 *1/*1) samples.

Implicated in

Entity	Leukemia
Note	Increased risk of leukemia has been associated with the NQO1 *2 allele and diminished NQO1 activity. Childhood leukemia (particularly with MLL fusions) , adult leukemia (ALL, AML particularly with translocations or inversions) and secondary leukemias and myelodysplasias as a result of chemotherapy have been associated with the NQO1 *2 polymorphism. Increased benzene induced myelotoxicity in occupationally exposed individuals has also been linked to the NQO1 *2 polymorphism.
Entity	Solid tumors
Note	Increased risk of renal and urothelial cell carcinomas and cutaneous basal cell carcinomas have also been associated with the NQO1 *2 polymorphism but conflicting results have been obtained in colon cancer and lung cancer. A number of epidemiological studies have investigated the possible link between NQO1 and cancer and have been recently summarized [6].DISEASE

External links

	Nomenclature
Hugo	NQO1
GDB	NQO1
Entrez_Gene	NQO1  1728  NAD(P)H dehydrogenase, quinone 1
	Cards
Atlas	NQO1ID375
GeneCards	NQO1
Ensembl	NQO1 [Search_View]   ENSG00000181019 [Gene_View]
Genatlas	NQO1
GeneLynx	NQO1
eGenome	NQO1
euGene	1728
	Genomic and cartography
GoldenPath	NQO1  -  16q22.1   chr16:68300806-68318034 -  16q22.1   [Description]    (hg18-Mar_2006)
Ensembl	NQO1 - 16q22.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	NQO1
	Gene and transcription
Genbank	AK223050 [ ENTREZ ]
Genbank	AV729122 [ ENTREZ ]
Genbank	BC000906 [ ENTREZ ]
Genbank	BC007659 [ ENTREZ ]
Genbank	BC107739 [ ENTREZ ]
RefSeq	NM_000903 [ SRS ]    NM_000903 [ ENTREZ ]
RefSeq	NM_001025433 [ SRS ]    NM_001025433 [ ENTREZ ]
RefSeq	NM_001025434 [ SRS ]    NM_001025434 [ ENTREZ ]
RefSeq	AC_000059 [ SRS ]    AC_000059 [ ENTREZ ]
RefSeq	NC_000016 [ SRS ]    NC_000016 [ ENTREZ ]
RefSeq	NT_010498 [ SRS ]    NT_010498 [ ENTREZ ]
RefSeq	NW_926462 [ SRS ]    NW_926462 [ ENTREZ ]
AceView	NQO1 AceView - NCBI
Unigene	Hs.406515 [ SRS ]    Hs.406515 [ NCBI ]     HS406515 [ spliceNest ]
Fast-db	10722 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P15559 [ SRS]    P15559 [ EXPASY ]     P15559 [ INTERPRO ]
Interpro	IPR003680 Flavodoxin_fold [ SRS ]    IPR003680 Flavodoxin_fold [ EBI ]
CluSTr	P15559
Pfam	PF02525 Flavodoxin_2 [ SRS ]    PF02525 Flavodoxin_2 [ Sanger ]    pfam02525 [ NCBI-CDD ]
Blocks	P15559
PDB	1D4A [ SRS ]    1D4A [ PdbSum ],   1D4A [ IMB ]   1D4A [ RSDB ]
PDB	1DXO [ SRS ]    1DXO [ PdbSum ],   1DXO [ IMB ]   1DXO [ RSDB ]
PDB	1GG5 [ SRS ]    1GG5 [ PdbSum ],   1GG5 [ IMB ]   1GG5 [ RSDB ]
PDB	1H66 [ SRS ]    1H66 [ PdbSum ],   1H66 [ IMB ]   1H66 [ RSDB ]
PDB	1H69 [ SRS ]    1H69 [ PdbSum ],   1H69 [ IMB ]   1H69 [ RSDB ]
PDB	1KBO [ SRS ]    1KBO [ PdbSum ],   1KBO [ IMB ]   1KBO [ RSDB ]
PDB	1KBQ [ SRS ]    1KBQ [ PdbSum ],   1KBQ [ IMB ]   1KBQ [ RSDB ]
PDB	1QBG [ SRS ]    1QBG [ PdbSum ],   1QBG [ IMB ]   1QBG [ RSDB ]
PDB	2F1O [ SRS ]    2F1O [ PdbSum ],   2F1O [ IMB ]   2F1O [ RSDB ]
HPRD	00518
	Protein Interaction databases
DIP	P15559
IntAct	P15559
	Polymorphism : SNP, mutations, diseases
OMIM	125860    [ map ]
GENECLINICS	125860
SNP	NQO1 [dbSNP-NCBI]
SNP	NM_000903 [SNP-NCI]
SNP	NM_001025433 [SNP-NCI]
SNP	NM_001025434 [SNP-NCI]
SNP	NQO1 [GeneSNPs - Utah]  NQO1] [HGBASE - SRS]
HAPMAP	NQO1 [HAPMAP]
HGMD	NQO1
	General knowledge
Family Browser	NQO1 [UCSC Family Browser]
SOURCE	NM_000903
SOURCE	NM_001025433
SOURCE	NM_001025434
SMD	Hs.406515
SAGE	Hs.406515
Enzyme	1.6.5.2 [ Enzyme-SRS ]   1.6.5.2 [ Brenda-SRS ]   1.6.5.2 [ KEGG ]   1.6.5.2 [ WIT ]
GO	NAD(P)H dehydrogenase (quinone) activity [Amigo]  NAD(P)H dehydrogenase (quinone) activity
GO	cytochrome-b5 reductase activity [Amigo]  cytochrome-b5 reductase activity
GO	cytoplasm [Amigo]  cytoplasm
GO	electron transport [Amigo]  electron transport
GO	xenobiotic metabolic process [Amigo]  xenobiotic metabolic process
GO	nitric oxide biosynthetic process [Amigo]  nitric oxide biosynthetic process
GO	synaptic transmission, cholinergic [Amigo]  synaptic transmission, cholinergic
GO	response to toxin [Amigo]  response to toxin
GO	oxidoreductase activity [Amigo]  oxidoreductase activity
GO	coenzyme binding [Amigo]  coenzyme binding
BIOCARTA	Hypoxia and p53 in the Cardiovascular system    [Genes]
KEGG	Biosynthesis of steroids
PubGene	NQO1
TreeFam	NQO1
CTD	1728 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	Cancer Cytogenetics (Bari)
Probe	NQO1 Related clones (RZPD - Berlin)
	PubMed
PubMed	80 Pubmed reference(s) in LocusLink

Bibliography

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Meth Enzymol. 1967 ; 10 : 309-317.

Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin.

Jaiswal AK

Biochemistry. 1991 ; 30 (44) : 10647-10653.

PMID 1657151

Human dioxin-inducible cytosolic NAD(P)H:menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16.

Jaiswal AK, McBride OW, Adesnik M, Nebert DW

The Journal of biological chemistry. 1988 ; 263 (27) : 13572-13578.

PMID 2843525

DT-diaphorase: purification, properties, and function.

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Methods in enzymology. 1990 ; 186 : 287-301.

PMID 2233301

NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity.

Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, Gibson NW

Cancer research. 1992 ; 52 (4) : 797-802.

PMID 1737339

DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C.

Ross D, Siegel D, Beall H, Prakash AS, Mulcahy RT, Gibson NW

Cancer metastasis reviews. 1993 ; 12 (2) : 83-101.

PMID 8375023

Bioactivation of quinones by DT-diaphorase, molecular, biochemical, and chemical studies.

Ross D, Beall H, Traver RD, Siegel D, Phillips RM, Gibson NW

Oncology research. 1994 ; 6 (10-11) : 493-500.

PMID 7620217

Nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase (DT-diaphorase) as a target for bioreductive antitumor quinones: quinone cytotoxicity and selectivity in human lung and breast cancer cell lines.

Beall HD, Murphy AM, Siegel D, Hargreaves RH, Butler J, Ross D

Molecular pharmacology. 1995 ; 48 (3) : 499-504.

PMID 7565631

An alternatively spliced form of NQO1 (DT-diaphorase) messenger RNA lacking the putative quinone substrate binding site is present in human normal and tumor tissues.

Gasdaska PY, Fisher H, Powis G

Cancer research. 1995 ; 55 (12) : 2542-2547.

PMID 7780966

The three-dimensional structure of NAD(P)H:quinone reductase, a flavoprotein involved in cancer chemoprotection and chemotherapy: mechanism of the two-electron reduction.

Li R, Bianchet MA, Talalay P, Amzel LM

Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (19) : 8846-8850.

PMID 7568029

NAD(P)H:quinone oxidoreductase expression and mitomycin C resistance developed by human colon cancer HCT 116 cells.

Pan SS, Forrest GL, Akman SA, Hu LT

Cancer research. 1995 ; 55 (2) : 330-335.

PMID 7812966

The NAD(P)H:quinone oxidoreductase locus in human colon carcinoma HCT 116 cells resistant to mitomycin C.

Hu LT, Stamberg J, Pan S

Cancer research. 1996 ; 56 (22) : 5253-5259.

PMID 8912865

The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems.

Beyer RE, Segura-Aguilar J, Di Bernardo S, Cavazzoni M, Fato R, Fiorentini D, Galli MC, Setti M, Landi L, Lenaz G

Proceedings of the National Academy of Sciences of the United States of America. 1996 ; 93 (6) : 2528-2532.

PMID 8637908

Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy.

Kelsey KT, Ross D, Traver RD, Christiani DC, Zuo ZF, Spitz MR, Wang M, Xu X, Lee BK, Schwartz BS, Wiencke JK

British journal of cancer. 1997 ; 76 (7) : 852-854.

PMID 9328142

The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant.

Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D

Molecular pharmacology. 1997 ; 52 (2) : 300-305.

PMID 9271353

Regulation and function of NAD(P)H:quinone oxidoreductase (NQO1).

Kepa JK, Traver RD, Siegel D, Winski SL, and Ross D

Reviews in Toxicology. 1997.

Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase).

Traver RD, Siegel D, Beall HD, Phillips RM, Gibson NW, Franklin WA, Ross D

British journal of cancer. 1997 ; 75 (1) : 69-75.

PMID 9000600

NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations.

Gaedigk A, Tyndale RF, Jurima-Romet M, Sellers EM, Grant DM, Leeder JS

Pharmacogenetics. 1998 ; 8 (4) : 305-313.

PMID 9731717

Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity.

Radjendirane V, Joseph P, Lee YH, Kimura S, Klein-Szanto AJ, Gonzalez FJ, Jaiswal AK

The Journal of biological chemistry. 1998 ; 273 (13) : 7382-7389.

PMID 9516435

A new screening system for NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor quinones: identification of a new aziridinylbenzoquinone, RH1, as a NQO1-directed antitumor agent.

Winski SL, Hargreaves RH, Butler J, Ross D

Clinical cancer research : an official journal of the American Association for Cancer Research. 1998 ; 4 (12) : 3083-3088.

PMID 9865924

Prevalence of the inactivating 609C-->T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia.

Larson RA, Wang Y, Banerjee M, Wiemels J, Hartford C, Le Beau MM, Smith MT

Blood. 1999 ; 94 (2) : 803-807.

PMID 10397748

A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity.

Moran JL, Siegel D, Ross D

Proceedings of the National Academy of Sciences of the United States of America. 1999 ; 96 (14) : 8150-8155.

PMID 10393963

Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1.

Siegel D, McGuinness SM, Winski SL, Ross D

Pharmacogenetics. 1999 ; 9 (1) : 113-121.

PMID 10208650

A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions. United Kingdom Childhood Cancer Study Investigators.

Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF

Cancer research. 1999 ; 59 (16) : 4095-4099.

PMID 10463613

Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release.

Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, Amzel LM

Proceedings of the National Academy of Sciences of the United States of America. 2000 ; 97 (7) : 3177-3182.

PMID 10706635

NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis.

Long DJ 2nd, Waikel RL, Wang XJ, Perlaky L, Roop DR, Jaiswal AK

Cancer research. 2000 ; 60 (21) : 5913-5915.

PMID 11085502

Analysis of genetic polymorphism in NQO1, GST-M1, GST-T1, and CYP3A4 in 469 Japanese patients with therapy-related leukemia/ myelodysplastic syndrome and de novo acute myeloid leukemia.

Naoe T, Takeyama K, Yokozawa T, Kiyoi H, Seto M, Uike N, Ino T, Utsunomiya A, Maruta A, Jin-nai I, Kamada N, Kubota Y, Nakamura H, Shimazaki C, Horiike S, Kodera Y, Saito H, Ueda R, Wiemels J, Ohno R

Clinical cancer research : an official journal of the American Association for Cancer Research. 2000 ; 6 (10) : 4091-4095.

PMID 11051261

NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms.

Ross D, Kepa JK, Winski SL, Beall HD, Anwar A, Siegel D

Chemico-biological interactions. 2000 ; 129 (1-2) : 77-97.

PMID 11154736

Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues.

Siegel D, Ross D

Free radical biology & medicine. 2000 ; 29 (3-4) : 246-253.

PMID 11035253

Regulation of p53 stability and p53-dependent apoptosis by NADH quinone oxidoreductase 1.

Asher G, Lotem J, Cohen B, Sachs L, Shaul Y

Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (3) : 1188-1193.

PMID 11158615

NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin.

Long DJ 2nd, Waikel RL, Wang XJ, Roop DR, Jaiswal AK

Journal of the National Cancer Institute. 2001 ; 93 (15) : 1166-1170.

PMID 11481389

NAD(P)H:quinone oxidoreductases.

Ross D

Encyclopedia of Molecular Medicine. 2001.

Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.

Faig M, Bianchet MA, Winski S, Hargreaves R, Moody CJ, Hudnott AR, Ross D, Amzel LM

Structure (London, England : 1993). 2001 ; 9 (8) : 659-667.

PMID 11587640

Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1.

Siegel D, Anwar A, Winski SL, Kepa JK, Zolman KL, Ross D

Molecular pharmacology. 2001 ; 59 (2) : 263-268.

PMID 11160862

Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults.

Smith MT, Wang Y, Kane E, Rollinson S, Wiemels JL, Roman E, Roddam P, Cartwright R, Morgan G

Blood. 2001 ; 97 (5) : 1422-1426.

PMID 11222389

NQO1 stabilizes p53 through a distinct pathway.

Asher G, Lotem J, Kama R, Sachs L, Shaul Y

Proceedings of the National Academy of Sciences of the United States of America. 2002 ; 99 (5) : 3099-3104.

PMID 11867746

Interaction of human NAD(P)H:quinone oxidoreductase 1 (NQO1) with the tumor suppressor protein p53 in cells and cell-free systems.

Anwar A, Dehn D, Siegel D, Kepa JK, Tang LJ, Pietenpol JA, Ross D

The Journal of biological chemistry. 2003 ; 278 (12) : 10368-10373.

PMID 12529318

NAD(P)H:quinone oxidoreductase 1 (NQO1, DT-diaphorase), functions and pharmacogenetics.

Ross D, Siegel D

Methods in enzymology. 2004 ; 382 : 115-144.

PMID 15047100

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Contributor(s)

Written	12-2001	David Ross
		School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA

Citation

This paper should be referenced as such :

Ross D . NQO1. Atlas Genet Cytogenet Oncol Haematol. December 2001 . URL : http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html

Ross D . NQO1. Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:25:36 2008