NAD(P)H dehydrogenase (quinone 1)

NQO1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1D4A, 1DXO, 1GG5, 1H66, 1H69, 1KBO, 1KBQ, 1QBG, 2F1O, 3JSX, 4CET, 4CF6, 5EA2, 5EAI, 5A4K
Identifiers
Aliases	NQO1 , DHQU, DIA4, DTD, NMOR1, NMORI, QR1, NAD(P)H dehydrogenase, NAD(P)H quinone dehydrogenase 1
External IDs	MGI: 103187 HomoloGene: 695 GeneCards: NQO1
Gene location (Human) Chr. Chromosome 16 (human) [1] Band 16q22.1 Start 69,706,996 bp [1] End 69,726,668 bp [1]
Gene location (Mouse) Chr. Chromosome 8 (mouse) [2] Band 8 D3|8 54.08 cM Start 108,114,857 bp [2] End 108,129,838 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gallbladder stromal cell of endometrium glomerulus metanephric glomerulus bronchial epithelial cell islet of Langerhans pylorus duodenum pancreatic ductal cell rectum Top expressed in epithelium of stomach pyloric antrum olfactory epithelium mucous cell of stomach duodenum esophagus proximal tubule myocardium of ventricle ascending aorta right ventricle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function superoxide dismutase activity cytochrome-b5 reductase activity, acting on NAD(P)H protein binding identical protein binding oxidoreductase activity NAD(P)H dehydrogenase (quinone) activity RNA binding electron transfer activity Cellular component neuronal cell body extracellular exosome cytoplasm cytosol dendrite Biological process response to estradiol negative regulation of catalytic activity nitric oxide biosynthetic process regulation of cellular amino acid metabolic process response to organic cyclic compound response to nutrient removal of superoxide radicals human ageing synaptic transmission, cholinergic response to oxidative stress positive regulation of neuron apoptotic process xenobiotic metabolic process response to ethanol response to toxic substance superoxide metabolic process negative regulation of apoptotic process response to electrical stimulus cellular response to metal ion electron transport chain cellular response to hydrogen peroxide response to nitrogen compound response to hydrogen sulfide Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1728 18104 Ensembl ENSG00000181019 ENSMUSG00000003849 UniProt P15559 Q64669 RefSeq (mRNA) NM_001286137 NM_000903 NM_001025433 NM_001025434 NM_008706 RefSeq (protein) NP_000894 NP_001020604 NP_001020605 NP_001273066 NP_032732 Location (UCSC) Chr 16: 69.71 – 69.73 Mb Chr 8: 108.11 – 108.13 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

NAD(P)H dehydrogenase [quinone] 1 is an enzyme that in humans is encoded by the NQO1 gene. ^[5] This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein forms homodimers and performs two-electron reduction of quinones to hydroquinones and of other redox dyes. It has a preference for short-chain acceptor quinones, such as ubiquinone, benzoquinone, juglone and duroquinone. ^[6] This gene has an important paralog NQO2. This protein is located in the cytosol. ^[7]

NQO1 enzyme expression can be induced by dioxin ^[8] and inhibited by dicoumarol. ^[9]

Function

This gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 2-electron reductase. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. This enzyme facilitates the two electron reduction of quinone to hydroquinone. NQO1-mediated two electron reduction of quinone to hydroquinone thereby indirectly prevents the one electron reduction of quinone to the semiquinone free radical. ^[10]

The ubiquitin-independent p53 degradation pathway is regulated by NQO1. NQO1 stabilizes p53, protecting it from degradation. Individuals with decreased NQO1 expression/activity have reduced p53 stability, which may lead to resistance to drugs such as chemotherapeutics. ^[11]

Detoxification

Quinonoid compounds generate reactive oxygen species (ROS) via redox cycling mechanisms and arylating nucleophiles. NQO1 removes quinone from biological systems through detoxification reaction:  NAD(P)H + a quinone → NAD(P)⁺ + a hydroquinone.  This reaction oxidises the substrate without the formation of damaging semiquinone and oxygen free radical species. The localization of NQO1 in epithelial and endothelial tissues of mice, rats and humans indicates their importance in detoxifying agent, since their location facilitates exposure to compounds entering the body.

Vitamin K metabolism

The enzyme is also involved in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis. ^[12] NQO1 catalyzes the reduction of vitamin K1, K2 and K3 into their hydroquinone form, but it only has a high affinity for Vitamin K3. Vitamin K hydroquinone serves as a cofactor for vitamin K γ‐carboxylase that catalyzes γ‐carboxylation of specific glutamic acid residues in Gla‐factors/proteins (Gla domain) leading to their activation and participation in blood clotting and bone metabolism. Vitamin K is used as radiation sensitizer or in mixtures with other chemotherapeutic drugs to treat several types of cancer. ROS generated in redox cycling contributes to anticancer activity of vitamin K. NQO1 competes with enzymes that redox cycle vitamin K to formation of semiquinone and ROS. NQO1is therefore able to detoxify vitamin K3 and protect cells against oxidative stress. ^[13]

Bioactivation of antitumor agents

Several anti-tumor agents such as mitosenes, indolequinones, aziridinylbenzoquinones and β-lapachone have been designed be bioactivated by NQO1 from various prodrugs. The high levels of NQO1 expression in many human solid tumors compared to normal tissue ensures their selective activation within tumor cells. ^{[14] [15]}

Reduction of endogenous quinones

NQO1 plays a role in ubiquinone and vitamin E quinone metabolism. These quinones protect cellular membranes from peroxidative injury in their reduced state. Furthermore, reduced forms of ubiquinone and vitamin E quinone have been shown to possess antioxidant properties that are superior to their non-reduced forms. ^[16]

Polymorphisms

P187S

One widespread single-nucleotide polymorphism of the NQO1 gene (NQO1*2), found homozygous in 4% to 20% of different populations, has found to be connected with different forms of cancer and a lowered efficiency of some chemotherapeutics like mitomycin C. This single nucleotide polymorphism leads to a proline serine exchange on position 187. NAD(P)H dehydrogenase [quinone] 1 P187S has been shown to have a lowered activity and stability. Crystallographic and nuclear magnetic resonance data show that the reason for this different behaviour is found in a flexible C-terminus of the protein leading to a destabilization of the whole protein. ^[17] Recent pharmacological research suggests feasibility of genotype-directed redox chemotherapeutic intervention targeting NQO1*2 breast cancer. ^[18]

A comprehensive meta-analysis showed an association between overall cancer risk and P187S. ^[19]

R139W

One further single nucleotide polymorphism, found homozygous in 0% to 5% of different ethnic population, is leading to an amino acid exchange on position 139 from arginine to tryptophane. ^[20] Furthermore, an alternative RNA splicing site is created leading to a loss of the quinone binding site. ^[21] The variant protein of NQO1*3 has similar stability as its wild-type counterpart. The variation between the two is substrate specific and it has reduced activity for some substrates. ^[22] It has been recently shown that the NQO1*3 polymorphism may also lead to reduced NQO1 protein expression. ^[11]

Interactions

NAD(P)H dehydrogenase (quinone 1) has been shown to interact with HSPA4, ^[23] p53, p33 and p73. ^[17]

Regulation by Keap1/Nrf2/ARE pathway

External (via chemicals) and internal (stress response or caloric restriction) induction of NQO1 is mediated solely through the Keap1/Nrf2/ARE. Keap1 acts as the sensor which loses its ability to target Nrf2 for degradation upon exposure to the inducers. Nrf2 is consequently stabilized and accumulated in the nucleus upon which it binds to the AREs and initiates expression of cytoprotective genes including NQO1. ^[24]

p53 and p73

p53 and p73 are tumor suppressor proteins and their degradation is tightly regulated by ubiquitination. Recently it was shown that their degradation can also occur via an ubiquitin-independent process; ^[25] NQO1 blocks p53 and p73 degradation in the presence of NADH and protects them from 20S proteasomal degradation. This protein-protein interaction between p53 and NQO1 was non-catalytic. ^[26]

Ornithine decarboxylase

Ornithine decarboxylase (ODC), is a labile protein that is the first rate-limiting enzyme in polyamine biosynthesis. Its degradation is regulated by antizyme that is induced by polyamine production. NQO1 has been shown to stabilize the degradation of ODC by binding to it and protecting it from 20S proteasomal degradation.

Clinical significance

Mutations in this gene have been associated with tardive dyskinesia (TD), an increased risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer. Altered expression of this protein has been seen in many tumors and is also associated with Alzheimer's disease (AD). ^[10]

Benzene toxicity

Benzene poisoning can increase risk of hematological cancers and other disorders. The mechanism of benzene metabolism and how it affects toxicity has not been completely understood. A general observation is that there is high variation in the extent of damage due to benzene poisoning. A possible explanation is the accumulation of phenols and hydroquinone in the target organ—the bone marrow—and subsequent oxidation of these metabolites to reactive quinone metabolites via a number of possible pathways. ^[11] A case-control study conducted in China showed that patients with two copies of the NQO1 C609T (NQO1*2 polymorphism) mutation had a 7.6-fold increased risk of benzene poisoning compared to those who carried one or two wild-type NQO1 alleles. ^[27]

Alzheimer's disease

Oxidative stress has been linked to onset of Alzheimer's disease (AD) ^[28] Since the NQO1*2 polymorphism affects the NQO1 activity and hence increase in oxidative stress, it has been postulated that this might increase the susceptibility of affected subjects for developing AD. A study conducted with a Chinese population consisting of 104 LOAD patients and 128 control patients disproved this hypothesis. ^[29]

Cancer

Meta-analyses have been performed to examine the association between NQO1 polymorphism and increased cancer risk. ^[19] The results from some of these analyses have been summarized in the table below:

Cancer Type	Polymorphism	Risk Odds Ratio (95% Confidence Interval)	Reference
Prostate	C609T	All ethnicities: No significant change Asians: 1.419 (1.1053-1.913)	[30]
Acute Lymphoblastic Leukemia	C609T	All ethnicities: 1.46 (1.18-1.79) Non-Asians 1.74 (1.29-2.36)	[31]
Breast	C609T	All ethnicities: No significant change Caucasians: 1.177 (1.041-1.331)	[32]
Colorectal	C609T	All ethnicities: 1.34 (1.10-1.64)	[33]
Bladder	C609T	All ethnicities: 1.18 (1.06-1.31)	[34]
De novo childhood leukemia	C609T	All ethnicities: 1.58 (1.22-2.07) Europeans, Asians: 1.52 (1.05-2.19) English, Japanese: No significant change	[35]

References

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21. Gasdaska PY, Fisher H, Powis G (1995). "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". Cancer Res. 55 (12): 2542–7. PMID   7780966.
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23. Anwar A, Siegel D, Kepa JK, Ross D (2002). "Interaction of the molecular chaperone Hsp70 with human NAD(P)H:quinone oxidoreductase 1". J. Biol. Chem. 277 (16): 14060–7. doi: 10.1074/jbc.M111576200 . PMID   11821413.
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27. Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, Li GL, Dosemeci M, Linet M, Zhang L, Xi L, Wacholder S, Lu W, Meyer KB, Titenko-Holland N, Stewart JT, Yin S, Ross D (Jul 1997). "Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone". Cancer Research. 57 (14): 2839–42. PMID   9230185.
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Further reading

• Vasiliou V, Ross D, Nebert DW (2006). "Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family". Hum. Genomics. 2 (5): 329–35. doi: 10.1186/1479-7364-2-5-329 . PMC   3500182 . PMID   16595077.
• Li Y, Jaiswal AK (1992). "Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element". J. Biol. Chem. 267 (21): 15097–104. doi: 10.1016/S0021-9258(18)42151-5 . PMID   1340765.
• Jaiswal AK (1991). "Human NAD(P)H:quinone oxidoreductase (NQO1) gene structure and induction by dioxin". Biochemistry. 30 (44): 10647–53. doi:10.1021/bi00108a007. PMID   1657151.
• Traver RD, Horikoshi T, Danenberg KD, Stadlbauer TH, Danenberg PV, Ross D, Gibson NW (1992). "NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity". Cancer Res. 52 (4): 797–802. PMID   1737339.
• Chen LZ, Harris PC, Apostolou S, Baker E, Holman K, Lane SA, Nancarrow JK, Whitmore SA, Stallings RL, Hildebrand CE (1991). "A refined physical map of the long arm of human chromosome 16". Genomics. 10 (2): 308–12. doi:10.1016/0888-7543(91)90313-4. PMID   2071140.
• Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID   8125298.
• Rothman N, Smith MT, Hayes RB, Traver RD, Hoener B, Campleman S, Li GL, Dosemeci M, Linet M, Zhang L, Xi L, Wacholder S, Lu W, Meyer KB, Titenko-Holland N, Stewart JT, Yin S, Ross D (1997). "Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C-->T mutation and rapid fractional excretion of chlorzoxazone". Cancer Res. 57 (14): 2839–42. PMID   9230185.
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID   9373149.
• Smiley JF, Levey AI, Mesulam MM (1998). "Infracortical interstitial cells concurrently expressing m2-muscarinic receptors, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate-diaphorase in the human and monkey cerebral cortex". Neuroscience. 84 (3): 755–69. doi:10.1016/S0306-4522(97)00524-1. PMID   9579781. S2CID   25807845.
• Moran JL, Siegel D, Ross D (1999). "A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity". Proc. Natl. Acad. Sci. U.S.A. 96 (14): 8150–5. Bibcode:1999PNAS...96.8150M. doi: 10.1073/pnas.96.14.8150 . PMC   22203 . PMID   10393963.
• Kristiansen OP, Larsen ZM, Johannesen J, Nerup J, Mandrup-Poulsen T, Pociot F (1999). "No linkage of P187S polymorphism in NAD(P)H: quinone oxidoreductase (NQO1/DIA4) and type 1 diabetes in the Danish population. DIEGG and DSGD. Danish IDDM Epidemiology and Genetics Group and The Danish Study Group of Diabetes in Childhood". Hum. Mutat. 14 (1): 67–70. doi: 10.1002/(SICI)1098-1004(1999)14:1<67::AID-HUMU8>3.0.CO;2-5 . PMID   10447260. S2CID   20598830.
• Eliasson M, Boström M, DePierre JW (1999). "Levels and subcellular distributions of detoxifying enzymes in the ovarian corpus luteum of the pregnant and non-pregnant pig". Biochem. Pharmacol. 58 (8): 1287–92. doi:10.1016/S0006-2952(99)00185-9. PMID   10487530.
• Skelly JV, Sanderson MR, Suter DA, Baumann U, Read MA, Gregory DS, Bennett M, Hobbs SM, Neidle S (1999). "Crystal structure of human DT-diaphorase: a model for interaction with the cytotoxic prodrug 5-(aziridin-1-yl)-2,4-dinitrobenzamide (CB1954)". J. Med. Chem. 42 (21): 4325–30. doi:10.1021/jm991060m. PMID   10543876.
• Faig M, Bianchet MA, Talalay P, Chen S, Winski S, Ross D, Amzel LM (2000). "Structures of recombinant human and mouse NAD(P)H:quinone oxidoreductases: species comparison and structural changes with substrate binding and release". Proc. Natl. Acad. Sci. U.S.A. 97 (7): 3177–82. doi: 10.1073/pnas.050585797 . PMC   16212 . PMID   10706635.
• Harada S, Fujii C, Hayashi A, Ohkoshi N (2001). "An association between idiopathic Parkinson's disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2". Biochem. Biophys. Res. Commun. 288 (4): 887–92. doi:10.1006/bbrc.2001.5868. PMID   11688992.
• Siegel D, Ryder J, Ross D (2001). "NAD(P)H: quinone oxidoreductase 1 expression in human bone marrow endothelial cells". Toxicol. Lett. 125 (1–3): 93–8. doi:10.1016/S0378-4274(01)00426-X. PMID   11701227.
• Anwar A, Siegel D, Kepa JK, Ross D (2002). "Interaction of the molecular chaperone Hsp70 with human NAD(P)H:quinone oxidoreductase 1". J. Biol. Chem. 277 (16): 14060–7. doi: 10.1074/jbc.M111576200 . PMID   11821413.
• Winski SL, Koutalos Y, Bentley DL, Ross D (2002). "Subcellular localization of NAD(P)H:quinone oxidoreductase 1 in human cancer cells". Cancer Res. 62 (5): 1420–4. PMID   11888914.
• Begleiter A, Lange L (2002). "Lack of NQO1 induction in human tumor cells is not due to changes in the promoter region of the gene". Int. J. Oncol. 20 (4): 835–8. doi:10.3892/ijo.20.4.835. PMID   11894133.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.