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2-hydroxy-dATP diphosphatase (, also known as oxidized purine nucleoside triphosphatase, or (2'-deoxy) ribonucleoside 5'-triphosphate pyrophosphohydrolase, or Nudix hydrolase 1 (NUDT1), or MutT homolog 1 (MTH1), or 7,8-dihydro-8-oxoguanine triphosphatase) 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 ''NUDT1''
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 ...
. During DNA repair, the enzyme hydrolyses oxidized purines and prevents their addition onto the DNA chain. As such it has important role in aging and cancer development.


Function

This enzyme catalyses the following
chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
: 2-hydroxy-dATP + H2O \rightleftharpoons 2-hydroxy-dAMP + diphosphate The enzyme hydrolyses oxidized purine
nucleoside triphosphate A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar (either ribose or deoxyribose), with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are cha ...
s. The enzyme is used in DNA repair, where it hydrolysis the oxidized purines and prevents their addition onto the DNA chain. Misincorporation of
oxidized Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
nucleoside triphosphate A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar (either ribose or deoxyribose), with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are cha ...
s into DNA and/or
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
during replication and transcription can cause mutations that may result in
carcinogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...
or
neurodegeneration A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
. First
isolated Isolation is the near or complete lack of social contact by an individual. Isolation or isolated may also refer to: Sociology and psychology *Isolation (health care), various measures taken to prevent contagious diseases from being spread **Is ...
from ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' because of its ability to prevent occurrence of 8-oxoguanine in DNA, the protein encoded by this gene is an enzyme that
hydrolyzes Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
oxidized
purine Purine is a heterocyclic compound, heterocyclic aromatic organic compound that consists of two rings (pyrimidine and imidazole) fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which includ ...
nucleoside triphosphates, such as 8-oxo-dGTP, 8-oxo-dATP, 2-oxo-dATP, 2-hydroxy-dATP, and 2-hydroxy rATP, to monophosphates, thereby preventing misincorporation. MutT enzymes in non-human organisms often have substrate specificity for certain types of oxidized nucleotides, such as that of ''E. coli'', which is specific to 8-oxoguanine nucleotides. Human MTH1, however, has substrate specificity for a much broader range of oxidatively damaged nucleotides. The mechanism of hMTH1's broad specificity for these oxidized nucleotides is derived from their recognition in the enzyme's substrate binding pocket due to an exchange of protonation state between two nearby aspartate residues. The encoded protein is localized mainly in the
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
, with some in the
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
, suggesting that it is involved in the sanitization of nucleotide pools both for nuclear and mitochondrial genomes. In plants, MTH1 has also been shown to enhance resistance to heat- and
paraquat Paraquat (trivial name; ), or ''N'',''N''′-dimethyl-4,4′-bipyridinium dichloride (systematic name), also known as methyl viologen, is an organic compound with the chemical formula C6H7N)2l2. It is classified as a viologen, a family of redox ...
-induced oxidative stress, resulting in fewer dead cells and less accumulation of
hydrogen peroxide Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3%†...
. Several
alternatively spliced Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...
transcript variants, some of which encode distinct
isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A
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 ...
that results in the production of an additional, longer isoform has been described.


Research


Aging

A mouse model has been studied that over-expresses hMTH1-Tg (NUDT1). The hMTH1-Tg mice express high levels of the hMTH1 hydrolase that degrades 8-oxodGTP and 8-oxoGTP and therefore excludes 8-oxoguanine from DNA and
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
. The steady state levels of 8-oxoguanine in DNA of several organs including the brain are significantly reduced in hMTH1-Tg over-expressing mice. Conversely, MTH1-null mice exhibit a significantly higher level of 8-oxo-dGTP accumulation than that of the wild type. Over-expression of hMTH1 prevents the age-dependent accumulation of DNA 8-oxoguanine that occurs in wild-type mice. The lower levels of oxidized guanines are associated with greater
longevity The word " longevity" is sometimes used as a synonym for "life expectancy" in demography. However, the term ''longevity'' is sometimes meant to refer only to especially long-lived members of a population, whereas ''life expectancy'' is always d ...
. The hMTH1-Tg animals have a significantly longer lifespan than their wild-type littermates. These findings provide a link between
ageing Ageing ( BE) or aging ( AE) is the process of becoming older. The term refers mainly to humans, many other animals, and fungi, whereas for example, bacteria, perennial plants and some simple animals are potentially biologically immortal. In ...
and
oxidative DNA damage DNA oxidation is the process of oxidative damage of deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guanine has a lower one-e ...
(see DNA damage theory of aging).


Cancer

Studies have suggested that this enzyme plays a role in both preventing the formation of cancer cells and the proliferation of cancer cells. This makes it a topic of interest in
cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate and ...
, both as a potential method for healthy cells to prevent cancer and a weakness to target within existing cancer cells. Eliminating the MTH1 gene in mice results in over three times more mice developing tumors compared to a
control group In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one tr ...
. The enzyme's much-studied ability to sanitize a cell's nucleotide pool prevents it from developing mutations, including cancerous ones. Specifically, another study found that MTH1
inhibition Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...
in cancer cells leads to incorporation of 8-oxo-dGTP and other oxidatively damaged nucleotides into the cell's DNA, damaging it and causing cell death. However, cancer cells have also been shown to benefit from use of MTH1. Cells from malignant breast tumors exhibit extreme MTH1 expression compared to other human cells. Because a cancer cell divides much more rapidly than a normal human cell, it is far more in need of an enzyme like MTH1 that prevents fatal mutations during replication. This property of cancer cells could allow for monitoring of cancer treatment efficacy by measuring MTH1 expression. Development of suitable probes for this purpose is currently underway. Disagreement exists concerning MTH1's functionality relative to prevention of DNA damage and cancer. Subsequent studies have had difficulty reproducing previously reported
cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...
or antiproliferation effects of MTH1 inhibition on cancer cells, even calling into question whether MTH1 truly does serve to remove oxidatively damaged nucleotides from a cell's nucleotide pool. One study of newly discovered MTH1 inhibitors suggests that these anticancer properties exhibited by the older MTH1 inhibitors may be due to off-target cytotoxic effects. After revisiting the experiment, the original authors of this claim found that while the original MTH1 inhibitors in question lead to damaged nucleotides being incorporated into DNA, they demonstrate the others that do not induce toxicity fail to introduce the DNA lesion. Research into this topic is ongoing.


As a drug target

MTH1 is a potential drug target to treat cancer, however there are conflicting results regarding the cytotoxicity of MTH1 inhibitors toward cancer cells. Karonudib, an MTH1 inhibitor, is currently being evaluated a
phase I Phase 1, Phase I or Phase One may refer to: Media * Marvel Cinematic Universe: Phase One, six American superhero films from 2008–2012 * ''Phase One'' (Art Ensemble of Chicago album), 1971 * ''Phase One'' (Saga album), 1998 * ''Phase One'', r ...
clinical trial for safety and tolerability. A potent and selective MTH1 inhibitor AZ13792138 has been developed by AstraZeneca has been made available as a chemical probe to academic researchers. However AstraZeneca has found that neither AZ13792138 nor genetic knockdown of MTH1 displays any significant cytotoxicity to cancer cells.


See also

* NUDT15 * 8-oxo-dGTP diphosphatase


References


Further reading

* * * * * * * * * * * * * * * * *


External links

* {{Portal bar, Biology, border=no Nudix hydrolases EC 3.6.1 DNA repair