User:Abhinavachreja/sandbox

Summary
This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a cytoplasmic 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. This gene has an important paralog NQO2. This protein is located in the cytosol.

NQO1 enzyme expression can be induced by Dioxin and inhibited by Dicoumarol.

Catalytic functions
This protein's enzymatic activity prevents the one electron reduction of quinones that results in the production of radical species. 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. 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). Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Detoxification
Quinonoid compounds generate reactive oxygen species (ROS) via redox cycling mechanisms and arylating nucleophiles. NQO1 is employed in the removal of a quinone from biological systems as a detoxification reaction: NAD(P)H + a quinone → NAD(P)+ + a hydroquinone. This reaction ensures complete oxidation of the substrate without the formation of semiquinones and species with reactive oxygen radicals that are deleterious to cells. 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. 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.

Bioactivation of antitumor agents
Several anti-tumor agents such as mitosenes, indolequinones, aziridinylbenzoquinones and β-lapachonehave been designed be bioactivated NQO1. The high levels of NQO1 expression in many human solid tumors compared to normal tissue ensures their selective activation within tumor cells.

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 posses antioxidant properties that are superior to their non-reduced forms.

NQO1*3
The variant protein of NQO1*3 has similar stability as its wild-type counterpart. The variation between the two is substrate specific; it has reduced activity for some substrates. It has been recently shown that the NQO1*3 polymorphism may also lead to reduced NQO1 protein expression.

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.

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 ; 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.

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 stabilze the degradation of ODC by binding to it and protecting it from 20S proteasomal degradation.

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. 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.

Alzheimer's disease
Oxidative stress been linked to onset of Alzheimer's disease (AD). 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.