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NQO1 NAD (P)H dehydrogenase, quinone 1

Identity

Other namesDIA4
DT-Diaphorase
NMO1
HGNC (Hugo) NQO1
LocusID (NCBI) 1728
Location 16q22.1
Location_base_pair Starts at 69743304 and ends at 69760533 bp from pter ( according to hg19-Feb_2009)  [Mapping]
 
  NQO1 (16q22) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

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
HGNC (Hugo)NQO1   2874
Entrez_Gene (NCBI)NQO1  1728  NAD(P)H dehydrogenase, quinone 1
Cards
AtlasNQO1ID375
GeneCards (Weizmann)NQO1
Ensembl (Hinxton)ENSG00000181019 [Gene_View]  chr16:69743304-69760533 [Contig_View]  NQO1 [Vega]
AceView (NCBI)NQO1
Genatlas (Paris)NQO1
SOURCE (Stanford)NM_000903 NM_001025433 NM_001025434
Genomic and cartography
GoldenPath (UCSC)NQO1  -  16q22.1   chr16:69743304-69760533 -  16q12-q22   [Description]    (hg19-Feb_2009)
EnsemblNQO1 - 16q12-q22 [CytoView]
Mapping of homologs : NCBINQO1 [Mapview]
OMIM125860   
Gene and transcription
Genbank (Entrez)AK223050 AK297125 AK297979 AK298896 AK307533
RefSeq transcript (SRS)NM_000903 NM_001025433 NM_001025434
RefSeq transcript (Entrez)NM_000903 NM_001025433 NM_001025434
RefSeq genomic (SRS)AC_000148 NC_000016 NC_018927 NG_011504 NT_010498 NW_001838290 NW_004078087
RefSeq genomic (Entrez)AC_000148 NC_000016 NC_018927 NG_011504 NT_010498 NW_001838290 NW_004078087
Consensus coding sequences : CCDS (NCBI)NQO1
Cluster EST : UnigeneHs.406515 [ SRS ] Hs.406515 [ NCBI ]
CGAP (NCI)Hs.406515
Alternative Splicing : Fast-db (Paris)GSHG0011942
Alternative Splicing GalleryENSG00000181019
Gene ExpressionNQO1 [ NCBI-GEO ]   NQO1 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP15559 (SRS) P15559 (Uniprot)
NextProtP15559
With graphics : InterProP15559
Splice isoforms : SwissVarP15559(Swissvar)
Domains : Interpro (SRS)Flavodoxin_fold   
Domains : Interpro (EBI)Flavodoxin_fold   
Related proteins : CluSTrP15559
Domain families : Pfam (SRS)Flavodoxin_2 (PF02525)   
Domain families : Pfam (Sanger)Flavodoxin_2 (PF02525)   
Domain families : Pfam (NCBI)pfam02525   
DMDM1728
Blocks (Seattle)P15559
PDB (SRS)1D4A    1DXO    1GG5    1H66    1H69    1KBO    1KBQ    1QBG    2F1O    3JSX   
PDB (PDBSum)1D4A    1DXO    1GG5    1H66    1H69    1KBO    1KBQ    1QBG    2F1O    3JSX   
PDB (IMB)1D4A    1DXO    1GG5    1H66    1H69    1KBO    1KBQ    1QBG    2F1O    3JSX   
PDB (RSDB)1D4A    1DXO    1GG5    1H66    1H69    1KBO    1KBQ    1QBG    2F1O    3JSX   
Human Protein AtlasENSG00000181019
HPRD00518
IPIIPI00012069   IPI00910902   IPI00619898   IPI00619966   
Protein Interaction databases
DIP (DOE-UCLA)P15559
IntAct (EBI)P15559
FunCoupENSG00000181019
REACTOMENQO1
Protein Interaction Database1728
BioGRIDNQO1
InParanoidP15559
Interologous Interaction database P15559
IntegromeDBNQO1
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)NQO1
SNP (GeneSNP Utah)NQO1
SNP : HGBaseNQO1
Genetic variants : HAPMAPNQO1
Somatic Mutations in Cancer : COSMICNQO1 
CONAN: Copy Number AnalysisNQO1 
Mutations and Diseases : HGMDNQO1
OMIM125860   
GENETests125860   
Disease Genetic AssociationNQO1
Huge Navigator NQO1 [HugePedia]  NQO1 [HugeCancerGEM]
Genomic VariantsNQO1  NQO1 [DGVbeta]
snp3D : Map Gene to Disease1728
General knowledge
Homologs : HomoloGeneNQO1
Homology/Alignments : Family Browser (UCSC)NQO1
Phylogenetic Trees/Animal Genes : TreeFamNQO1
Catalytic activity : Enzyme1.6.5.2 [ Enzyme-Expasy ]   1.6.5.2 [ Enzyme-SRS ]   1.6.5.2 [ IntEnz-EBI ]   1.6.5.2 [ BRENDA ]   1.6.5.2 [ KEGG ]   
Chemical/Protein Interactions : CTD1728
Chemical/Pharm GKB GenePA31744
Clinical trialNQO1
Cancer Resource (Charite)ENSG00000181019
Ontology : AmiGONAD(P)H dehydrogenase (quinone) activity  cytochrome-b5 reductase activity, acting on NAD(P)H  protein binding  cytoplasm  cytosol  regulation of cellular amino acid metabolic process  xenobiotic metabolic process  nitric oxide biosynthetic process  response to oxidative stress  synaptic transmission, cholinergic  response to toxin  cellular nitrogen compound metabolic process  negative regulation of catalytic activity  positive regulation of neuron apoptotic process  small molecule metabolic process  
Ontology : EGO-EBINAD(P)H dehydrogenase (quinone) activity  cytochrome-b5 reductase activity, acting on NAD(P)H  protein binding  cytoplasm  cytosol  regulation of cellular amino acid metabolic process  xenobiotic metabolic process  nitric oxide biosynthetic process  response to oxidative stress  synaptic transmission, cholinergic  response to toxin  cellular nitrogen compound metabolic process  negative regulation of catalytic activity  positive regulation of neuron apoptotic process  small molecule metabolic process  
Pathways : BIOCARTAHypoxia and p53 in the Cardiovascular system [Genes]   
Pathways : KEGGBiosynthesis of steroids
Other databases
Probes
ProbeCancer Cytogenetics (Bari)
Litterature
PubMed385 Pubmed reference(s) in Entrez
PubGeneNQO1
iHOPNQO1

Bibliography

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Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin.
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NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity.
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DT-diaphorase in activation and detoxification of quinones. Bioreductive activation of mitomycin C.
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Cancer metastasis reviews. 1993 ; 12 (2) : 83-101.
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Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy.
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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.
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Regulation and function of NAD(P)H:quinone oxidoreductase (NQO1).
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Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase).
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British journal of cancer. 1997 ; 75 (1) : 69-75.
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NAD(P)H:quinone oxidoreductase: polymorphisms and allele frequencies in Caucasian, Chinese and Canadian Native Indian and Inuit populations.
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PMID 9731717
 
Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity.
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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.
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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.
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A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity.
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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.
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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.
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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
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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
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NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms.
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Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues.
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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
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PMID 11158615
 
NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin.
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PMID 11481389
 
NAD(P)H:quinone oxidoreductases.
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Structure-based development of anticancer drugs: complexes of NAD(P)H:quinone oxidoreductase 1 with chemotherapeutic quinones.
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PMID 11587640
 
Rapid polyubiquitination and proteasomal degradation of a mutant form of NAD(P)H:quinone oxidoreductase 1.
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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.
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PMID 11222389
 
NQO1 stabilizes p53 through a distinct pathway.
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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
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PMID 15047100
 
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Contributor(s)

Written12-2001David Ross
School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA
Updated06-2004David Ross

Citation

This paper should be referenced as such :
Ross D . NQO1 NAD (P)H dehydrogenase, quinone 1. Atlas Genet Cytogenet Oncol Haematol. December 2001 .
URL : http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html
Ross D . NQO1 NAD (P)H dehydrogenase, quinone 1. Atlas Genet Cytogenet Oncol Haematol. June 2004 .
URL : http://AtlasGeneticsOncology.org/Genes/NQO1ID375.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/37830/1/12-2001-NQO1ID375.pdf   [ Bibliographic record ]
http://documents.irevues.inist.fr/bitstream/2042/38103/1/06-2004-NQO1ID375.pdf   [ Bibliographic record ]

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