NAD(P)H dehydrogenase
uinone1 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''NQO1''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
This protein-coding gene is a member of the
NAD(P)H dehydrogenase (quinone)
In enzymology, a NAD(P)H dehydrogenase (quinone) () is an enzyme that catalysis, catalyzes the chemical reaction
:NAD(P)H + H+ + a quinone \rightleftharpoons NAD(P)+ + a hydroquinone
The 4 substrate (biochemistry), substrates of this enzyme are n ...
family and encodes a 2-electron
reductase
A reductase is an enzyme that catalyzes a reduction reaction.
Examples
* 5α-Reductase
* 5β-Reductase
* Dihydrofolate reductase
* HMG-CoA reductase
* Methemoglobin reductase
* Ribonucleotide reductase
* Thioredoxin reductase
* ''E. coli'' ...
(enzyme). This
FAD
A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period.
Fads are objects or behaviors that achieve short- ...
-binding protein forms
homodimer
In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
s and performs two-electron reduction of
quinone
The quinones are a class of organic compounds that are formally "derived from aromatic compounds uch as benzene or naphthalene
Uch ( pa, ;
ur, ), frequently referred to as Uch Sharīf ( pa, ;
ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...
by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...
s to
hydroquinone
Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C6H4(OH)2. It has two hydroxyl groups bonded to a benzene ring in a ''para'' ...
s and of other
redox
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
dyes. It has a preference for short-chain acceptor quinones, such as
ubiquinone
Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10.
It is a 1,4-benzoq ...
,
benzoquinone Benzoquinone (C6H4O2) is a quinone with a single benzene ring. There are 2 (out of 3 hypothetical) benzoquinones:
* 1,4-Benzoquinone, most commonly, right image (also ''para''-benzoquinone, ''p''-benzoquinone, ''para''-quinone, or just quinone)
* 1 ...
,
juglone
Juglone, also called 5-hydroxy-1,4-naphthalenedione (IUPAC) is an organic compound with the molecular formula C10H6O3. In the food industry, juglone is also known as C.I. Natural Brown 7 and C.I. 75500. It is insoluble in benzene but soluble i ...
and
duroquinone
Duroquinone is an organic oxidant (C6(CH3)4O2). It is related to 1,4-benzoquinone by replacement of four H centres with methyl (Me) groups. The C10O2 core of this molecule is planar with two pairs of C=O and C=C bonds.J.-M. Lü, S. V. Rosokha, I. ...
.
This gene has an important
paralog
Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a spec ...
NQO2. This protein is located in the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
.
NQO1 enzyme expression can be induced by
dioxin
Dioxin may refer to:
* 1,2-Dioxin or 1,4-Dioxin, two unsaturated heterocyclic 6-membered rings where two carbon atoms have been replaced by oxygen atoms, giving the molecular formula C4H4O2
*Dibenzo-1,4-dioxin, the parent compound also known as ...
and inhibited by
dicoumarol
Dicoumarol (INN) or dicumarol (USAN) is a naturally occurring anticoagulant drug that depletes stores of vitamin K (similar to warfarin, a drug that dicoumarol inspired). It is also used in biochemical experiments as an inhibitor of reductases.
...
.
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
quinone
The quinones are a class of organic compounds that are formally "derived from aromatic compounds uch as benzene or naphthalene
Uch ( pa, ;
ur, ), frequently referred to as Uch Sharīf ( pa, ;
ur, ; ''"Noble Uch"''), is a historic city in the southern part of Pakistan's Punjab province. Uch may have been founded as Alexandria on the Indus, a town founded by Alexand ...
by conversion of an even number of –CH= groups into –C(=O)– groups with any necessary rearrangement of double ...
s 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.
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.
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. 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
Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins wit ...
) 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
mitosene
The mitosenes are a class of organic chemicals based on a quinone-containing three-ring structure related to the two-ring core of the indolequinones. They are derived from the mitomycins by reduction and are the active alkylating agents responsib ...
s,
indolequinone
Indolequinones are molecules which are based upon an indole but have two additional ketone groups ( quinone) attached to the ring structure.
This simple indolequinone indole-5,6-quinone is produced during the ripening of some fruit.
Other exam ...
s, aziridinylbenzoquinones and β-lapachone have been designed be bioactivated by NQO1 from various
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
s. 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 possess antioxidant properties that are superior to their non-reduced forms.
Polymorphisms
P187S
One widespread
single-nucleotide polymorphism
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
of the ''NQO1'' gene (NQO1*2), found
homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
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
Mitomycin C is a mitomycin that is used as a chemotherapeutic agent by virtue of its antitumour activity.
Medical uses
It is given intravenously to treat upper gastro-intestinal cancers (e.g. esophageal carcinoma), anal cancers, and breast c ...
. This single nucleotide polymorphism leads to a proline serine exchange on position 187. NAD(P)H dehydrogenase
uinone1 P187S has been shown to have a lowered activity and stability. Crystallographic and
nuclear magnetic resonance
Nuclear magnetic resonance (NMR) is a physical phenomenon in which nuclei in a strong constant magnetic field are perturbed by a weak oscillating magnetic field (in the near field) and respond by producing an electromagnetic signal with a ...
data show that the reason for this different behaviour is found in a flexible
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
of the protein leading to a destabilization of the whole protein.
Recent pharmacological research suggests feasibility of genotype-directed redox chemotherapeutic intervention targeting NQO1*2 breast cancer.
A comprehensive meta-analysis showed an association between overall cancer risk and P187S.
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.
Furthermore, an alternative
RNA splicing
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
site is created leading to a loss of the quinone binding site.
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. It has been recently shown that the NQO1*3 polymorphism may also lead to reduced NQO1 protein expression.
Interactions
NAD(P)H dehydrogenase (quinone 1) has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
HSPA4
Heat shock 70 kDa protein 4 is a protein that in humans is encoded by the ''HSPA4'' gene.
The protein encoded by this gene was originally suggested to be a member of the heat shock protein 70 family. However it is now known that human HSPA4 is a ...
,
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, p33 and
p73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized ...
.
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
Kelch-like ECH-associated protein 1 is a protein that in humans is encoded by the ''Keap1'' gene.
Structure
Keap1 has four discrete protein domains. The N-terminal Broad complex, Tramtrack and Bric-à-Brac (BTB) domain contains the Cys151 res ...
/
Nrf2
Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regul ...
/
ARE
Are commonly refers to:
* Are (unit), a unit of area equal to 100 m2
Are, ARE or Åre may also refer to:
Places
* Åre, a locality in Sweden
* Åre Municipality, a municipality in Sweden
**Åre ski resort in Sweden
* Are Parish, a municipa ...
. 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
A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
proteins and their degradation is tightly regulated by
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
. 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
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
and protects them from 20S
proteasomal degradation
Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by w ...
. This protein-protein interaction between p53 and NQO1 was
non-catalytic.
Ornithine decarboxylase
Ornithine decarboxylase
The enzyme ornithine decarboxylase (, ODC) catalyzes the decarboxylation of ornithine (a product of the urea cycle) to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids and fo ...
(ODC), is a
labile
Lability refers to something that is constantly undergoing change or is likely to undergo change.
Biochemistry
In reference to biochemistry, this is an important concept as far as kinetics is concerned in metalloproteins. This can allow for th ...
protein that is the first rate-limiting enzyme in
polyamine
A polyamine is an organic compound having more than two amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. ...
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
Tardive dyskinesia (TD) is a disorder that results in involuntary repetitive body movements, which may include grimacing, sticking out the tongue or smacking the lips. Additionally, there may be rapid jerking movements or slow writhing movemen ...
(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
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(AD).
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 has been linked to onset of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
(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
Load or LOAD may refer to:
Aeronautics and transportation
*Load factor (aeronautics), the ratio of the lift of an aircraft to its weight
*Passenger load factor, the ratio of revenue passenger miles to available seat miles of a particular transpo ...
patients and 128 control patients ''disproved'' this hypothesis.
Cancer
Meta-analyses have been performed to examine the association between NQO1 polymorphism and increased cancer risk.
The results from some of these analyses have been summarized in the table below:
References
Further reading
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{{DEFAULTSORT:Nad(P)H Dehydrogenase (Quinone 1)
EC 1.6.5
NADPH-dependent enzymes
NADH-dependent enzymes
Flavin enzymes
Enzymes of known structure