2-hydroxy-dATP diphosphatase

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2-hydroxy-dATP diphosphatase
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EC no. 3.6.1.56
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2-hydroxy-dATP diphosphatase (EC 3.6.1.56, 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 that in humans is encoded by the NUDT1 gene. [1] [2] [3] 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.

Contents

Function

This enzyme catalyses the following chemical reaction

2-hydroxy-dATP + H2O 2-hydroxy-dAMP + diphosphate

The enzyme hydrolyses oxidized purine nucleoside triphosphates. The enzyme is used in DNA repair, where it hydrolysis the oxidized purines and prevents their addition onto the DNA chain. [4]

Misincorporation of oxidized nucleoside triphosphates into DNA and/or RNA during replication and transcription can cause mutations that may result in carcinogenesis or neurodegeneration. First isolated from Escherichia coli because of its ability to prevent occurrence of 8-oxoguanine in DNA, [5] the protein encoded by this gene is an enzyme that hydrolyzes oxidized purine 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.

Example hydrolysis of oxidized nucleotide catalyzed by MTH1 MTH1 Hydrolysis of Oxidized Nucleotide.tif
Example hydrolysis of oxidized nucleotide catalyzed by MTH1

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. [6]

Examples of the protonation state exchange between MTH1 residues Asp-119 and Asp-120 that allows the enzyme to recognize oxidized nucleotides. MTH1 Recognition of Oxidized Nucleotides.tif
Examples of the protonation state exchange between MTH1 residues Asp-119 and Asp-120 that allows the enzyme to recognize oxidized nucleotides.

The encoded protein is localized mainly in the cytoplasm, with some in the mitochondria, 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-induced oxidative stress, resulting in fewer dead cells and less accumulation of hydrogen peroxide. [7]

Several alternatively spliced transcript variants, some of which encode distinct isoforms, have been identified. Additional variants have been observed, but their full-length natures have not been determined. A single-nucleotide polymorphism that results in the production of an additional, longer isoform has been described. [3]

Research

Aging

A mouse model has been studied that over-expresses hMTH1-Tg (NUDT1). [8] 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. 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. [9] 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 hMTH1-Tg animals have a significantly longer lifespan than their wild-type littermates. These findings provide a link between ageing and oxidative DNA damage [8] (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, 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. [10] 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 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. [11] 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. [12] 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. [13] [14]

Disagreement exists concerning MTH1's functionality relative to prevention of DNA damage and cancer. Subsequent studies have had difficulty reproducing previously reported cytotoxic 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. [15] [16] 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. [17] 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. [18] 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. [19]

Karonudib, an MTH1 inhibitor, is currently being evaluated a phase I clinical trial for safety and tolerability. [18] [20] [21]

A potent and selective MTH1 inhibitor AZ13792138 has been developed by AstraZeneca has been made available as a chemical probe to academic researchers. [22] However AstraZeneca has found that neither AZ13792138 nor genetic knockdown of MTH1 displays any significant cytotoxicity to cancer cells. [23] [24]

See also

Related Research Articles

<span class="mw-page-title-main">Nucleotide</span> Biological molecules that form the building blocks of nucleic acids

Nucleotides are organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

<span class="mw-page-title-main">Purine</span> Heterocyclic aromatic organic compound

Purine is a heterocyclic aromatic organic compound that consists of two rings fused together. It is water-soluble. Purine also gives its name to the wider class of molecules, purines, which include substituted purines and their tautomers. They are the most widely occurring nitrogen-containing heterocycles in nature.

A salvage pathway is a pathway in which a biological product is produced from intermediates in the degradative pathway of its own or a similar substance. The term often refers to nucleotide salvage in particular, in which nucleotides are synthesized from intermediates in their degradative pathway.

A nucleoside triphosphate is a nucleoside containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

<span class="mw-page-title-main">Transversion</span> DNA point mutation that exchanges a purine (A or G) for a pyrimidine (C or T) or vice versa

Transversion, in molecular biology, refers to a point mutation in DNA in which a single purine is changed for a pyrimidine, or vice versa. A transversion can be spontaneous, or it can be caused by ionizing radiation or alkylating agents. It can only be reversed by a spontaneous reversion.

DNA glycosylases are a family of enzymes involved in base excision repair, classified under EC number EC 3.2.2. Base excision repair is the mechanism by which damaged bases in DNA are removed and replaced. DNA glycosylases catalyze the first step of this process. They remove the damaged nitrogenous base while leaving the sugar-phosphate backbone intact, creating an apurinic/apyrimidinic site, commonly referred to as an AP site. This is accomplished by flipping the damaged base out of the double helix followed by cleavage of the N-glycosidic bond.

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

<span class="mw-page-title-main">Nucleoside-diphosphate kinase</span>

Nucleoside-diphosphate kinases are enzymes that catalyze the exchange of terminal phosphate between different nucleoside diphosphates (NDP) and triphosphates (NTP) in a reversible manner to produce nucleotide triphosphates. Many NDP serve as acceptor while NTP are donors of phosphate group. The general reaction via ping-pong mechanism is as follows: XDP + YTP ←→ XTP + YDP. NDPK activities maintain an equilibrium between the concentrations of different nucleoside triphosphates such as, for example, when guanosine triphosphate (GTP) produced in the citric acid (Krebs) cycle is converted to adenosine triphosphate (ATP). Other activities include cell proliferation, differentiation and development, signal transduction, G protein-coupled receptor, endocytosis, and gene expression.

<span class="mw-page-title-main">MUTYH</span> Protein-coding gene in the species Homo sapiens

MUTYH is a human gene that encodes a DNA glycosylase, MUTYH glycosylase. It is involved in oxidative DNA damage repair and is part of the base excision repair pathway. The enzyme excises adenine bases from the DNA backbone at sites where adenine is inappropriately paired with guanine, cytosine, or 8-oxo-7,8-dihydroguanine, a common form of oxidative DNA damage.

<span class="mw-page-title-main">Succinyl coenzyme A synthetase</span>

Succinyl coenzyme A synthetase is an enzyme that catalyzes the reversible reaction of succinyl-CoA to succinate. The enzyme facilitates the coupling of this reaction to the formation of a nucleoside triphosphate molecule from an inorganic phosphate molecule and a nucleoside diphosphate molecule. It plays a key role as one of the catalysts involved in the citric acid cycle, a central pathway in cellular metabolism, and it is located within the mitochondrial matrix of a cell.

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-electron reduction potential than the other nucleosides in DNA. The one electron reduction potentials of the nucleosides are guanine 1.29, adenine 1.42, cytosine 1.6 and thymine 1.7. About 1 in 40,000 guanines in the genome are present as 8-oxo-dG under normal conditions. This means that >30,000 8-oxo-dGs may exist at any given time in the genome of a human cell. Another product of DNA oxidation is 8-oxo-dA. 8-oxo-dA occurs at about 1/10 the frequency of 8-oxo-dG. The reduction potential of guanine may be reduced by as much as 50%, depending on the particular neighboring nucleosides stacked next to it within DNA.

<span class="mw-page-title-main">Purine nucleoside phosphorylase</span> Enzyme

Purine nucleoside phosphorylase, PNP, PNPase or inosine phosphorylase is an enzyme that in humans is encoded by the NP gene. It catalyzes the chemical reaction

<span class="mw-page-title-main">Nucleic acid metabolism</span> Process

Nucleic acid metabolism is a collective term that refers to the variety of chemical reactions by which nucleic acids are either synthesized or degraded. Nucleic acids are polymers made up of a variety of monomers called nucleotides. Nucleotide synthesis is an anabolic mechanism generally involving the chemical reaction of phosphate, pentose sugar, and a nitrogenous base. Degradation of nucleic acids is a catabolic reaction and the resulting parts of the nucleotides or nucleobases can be salvaged to recreate new nucleotides. Both synthesis and degradation reactions require multiple enzymes to facilitate the event. Defects or deficiencies in these enzymes can lead to a variety of diseases.

<span class="mw-page-title-main">CTP synthetase</span> Enzyme

CTP synthase is an enzyme involved in pyrimidine biosynthesis that interconverts UTP and CTP.

<span class="mw-page-title-main">Oxoguanine glycosylase</span> DNA glycosylase enzyme

8-Oxoguanine glycosylase, also known as OGG1, is a DNA glycosylase enzyme that, in humans, is encoded by the OGG1 gene. It is involved in base excision repair. It is found in bacterial, archaeal and eukaryotic species.

<span class="mw-page-title-main">Deoxycytidine kinase</span> Protein-coding gene in the species Homo sapiens

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

<span class="mw-page-title-main">8-Oxo-2'-deoxyguanosine</span> Chemical compound

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is an oxidized derivative of deoxyguanosine. 8-Oxo-dG is one of the major products of DNA oxidation. Concentrations of 8-oxo-dG within a cell are a measurement of oxidative stress.

<span class="mw-page-title-main">H2TH domain</span>

In molecular biology, the H2TH domain is a DNA-binding domain found in DNA glycosylase/AP lyase enzymes, which are involved in base excision repair of DNA damaged by oxidation or by mutagenic agents. Most damage to bases in DNA is repaired by the base excision repair pathway. These enzymes are primarily from bacteria, and have both DNA glycosylase activity EC 3.2.2.- and AP lyase activity EC 4.2.99.18. Examples include formamidopyrimidine-DNA glycosylases and endonuclease VIII (Nei).

8-oxo-dGTP diphosphatase (EC 3.6.1.55, MutT, 7,8-dihydro-8-oxoguanine triphosphatase, 8-oxo-dGTPase, 7,8-dihydro-8-oxo-dGTP pyrophosphohydrolase) is an enzyme with systematic name 8-oxo-dGTP diphosphohydrolase. This enzyme catalyses the following chemical reaction:

8-oxo-dGDP phosphatase (EC 3.6.1.58, NUDT5) is an enzyme with systematic name 8-oxo-dGDP phosphohydrolase. This enzyme catalyses the following chemical reaction

References

  1. ↑ Ponnambalam S, Jackson AP, LeBeau MM, Pravtcheva D, Ruddle FH, Alibert C, Parham P (December 1994). "Chromosomal location and some structural features of human clathrin light-chain genes (CLTA and CLTB)". Genomics. 24 (3): 440–4. doi: 10.1006/geno.1994.1650 . PMID   7713494.
  2. ↑ Sakumi K, Furuichi M, Tsuzuki T, Kakuma T, Kawabata S, Maki H, Sekiguchi M (November 1993). "Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis". The Journal of Biological Chemistry. 268 (31): 23524–30. doi: 10.1016/S0021-9258(19)49494-5 . PMID   8226881.
  3. 1 2 "Entrez Gene: NUDT1 nudix (nucleoside diphosphate linked moiety X)-type motif 1".
  4. ↑ Rudling, Axel; Gustafsson, Robert; Almlöf, Ingrid; Homan, Evert; Scobie, Martin; Warpman Berglund, Ulrika; Helleday, Thomas; Stenmark, Pål; Carlsson, Jens (2017-10-12). "Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space". Journal of Medicinal Chemistry. 60 (19): 8160–8169. doi:10.1021/acs.jmedchem.7b01006. ISSN   1520-4804. PMID   28929756.
  5. ↑ Tchou J, Kasai H, Shibutani S, Chung MH, Laval J, Grollman AP, Nishimura S (June 1991). "8-oxoguanine (8-hydroxyguanine) DNA glycosylase and its substrate specificity". Proceedings of the National Academy of Sciences of the United States of America. 88 (11): 4690–4. Bibcode:1991PNAS...88.4690T. doi: 10.1073/pnas.88.11.4690 . PMC   51731 . PMID   2052552.
  6. 1 2 Waz S, Nakamura T, Hirata K, Koga-Ogawa Y, Chirifu M, Arimori T, Tamada T, Ikemizu S, Nakabeppu Y, Yamagata Y (February 2017). "Structural and Kinetic Studies of the Human Nudix Hydrolase MTH1 Reveal the Mechanism for Its Broad Substrate Specificity". The Journal of Biological Chemistry. 292 (7): 2785–2794. doi: 10.1074/jbc.m116.749713 . PMC   5314174 . PMID   28035004.
  7. ↑ Yoshimura K, Ogawa T, Tsujimura M, Ishikawa K, Shigeoka S (September 2014). "Ectopic expression of the human MutT-type Nudix hydrolase, hMTH1, confers enhanced tolerance to oxidative stress in arabidopsis". Plant & Cell Physiology. 55 (9): 1534–43. doi: 10.1093/pcp/pcu083 . PMID   24928220.
  8. 1 2 De Luca G, Ventura I, Sanghez V, Russo MT, Ajmone-Cat MA, Cacci E, Martire A, Popoli P, Falcone G, Michelini F, Crescenzi M, Degan P, Minghetti L, Bignami M, Calamandrei G (August 2013). "Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1". Aging Cell. 12 (4): 695–705. doi: 10.1111/acel.12094 . PMID   23648059.
  9. ↑ Kajitani K, Yamaguchi H, Dan Y, Furuichi M, Kang D, Nakabeppu Y (February 2006). "MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kainate-induced excitotoxicity". The Journal of Neuroscience. 26 (6): 1688–98. doi:10.1523/jneurosci.4948-05.2006. PMC   6793619 . PMID   16467516.
  10. ↑ Tsuzuki T, Egashira A, Igarashi H, Iwakuma T, Nakatsuru Y, Tominaga Y, Kawate H, Nakao K, Nakamura K, Ide F, Kura S, Nakabeppu Y, Katsuki M, Ishikawa T, Sekiguchi M (September 2001). "Spontaneous tumorigenesis in mice defective in the MTH1 gene encoding 8-oxo-dGTPase". Proceedings of the National Academy of Sciences of the United States of America. 98 (20): 11456–61. Bibcode:2001PNAS...9811456T. doi: 10.1073/pnas.191086798 . PMC   58751 . PMID   11572992.
  11. ↑ Gad H, Koolmeister T, Jemth AS, Eshtad S, Jacques SA, Ström CE, et al. (April 2014). "MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool". Nature. 508 (7495): 215–21. Bibcode:2014Natur.508..215G. doi:10.1038/nature13181. PMID   24695224. S2CID   4468358.
  12. ↑ Coskun E, Jaruga P, Jemth AS, Loseva O, Scanlan LD, Tona A, Lowenthal MS, Helleday T, Dizdaroglu M (September 2015). "Addiction to MTH1 protein results in intense expression in human breast cancer tissue as measured by liquid chromatography-isotope-dilution tandem mass spectrometry". DNA Repair. 33: 101–10. doi:10.1016/j.dnarep.2015.05.008. PMID   26202347.
  13. ↑ Ji D, Beharry AA, Ford JM, Kool ET (July 2016). "A Chimeric ATP-Linked Nucleotide Enables Luminescence Signaling of Damage Surveillance by MTH1, a Cancer Target". Journal of the American Chemical Society. 138 (29): 9005–8. doi:10.1021/jacs.6b02895. PMC   5500214 . PMID   27413803.
  14. ↑ Samaranayake GJ, Troccoli CI, Huynh MQ, Win A, Ji D, Kool ET, Rai P (July 2017). "Towards a better understanding of MTH1 as a therapeutic target in RAS-driven cancer [abstract]". Cancer Res. 77 (13): 5473. doi:10.1158/1538-7445.AM2017-5473.
  15. ↑ Petrocchi A, Leo E, Reyna NJ, Hamilton MM, Shi X, Parker CA, Mseeh F, Bardenhagen JP, Leonard P, Cross JB, Huang S, Jiang Y, Cardozo M, Draetta G, Marszalek JR, Toniatti C, Jones P, Lewis RT (March 2016). "Identification of potent and selective MTH1 inhibitors". Bioorganic & Medicinal Chemistry Letters. 26 (6): 1503–7. doi:10.1016/j.bmcl.2016.02.026. PMID   26898335.
  16. ↑ Ellermann M, Eheim A, Rahm F, Viklund J, Guenther J, Andersson M, et al. (July 2017). "Novel Class of Potent and Cellularly Active Inhibitors Devalidates MTH1 as Broad-Spectrum Cancer Target". ACS Chemical Biology. 12 (8): 1986–1992. doi: 10.1021/acschembio.7b00370 . PMID   28679043.
  17. ↑ Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, Fillery S, Foote KM, Goodwin L, Jones DR, Käck H, Lau A, Nissink JW, Read J, Scott JS, Taylor B, Walker G, Wissler L, Wylot M (March 2016). "Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival". Journal of Medicinal Chemistry. 59 (6): 2346–61. doi: 10.1021/acs.jmedchem.5b01760 . PMID   26878898.
  18. 1 2 Warpman Berglund U, Sanjiv K, Gad H, Kalderén C, Koolmeister T, Pham T, et al. (December 2016). "Validation and development of MTH1 inhibitors for treatment of cancer". Annals of Oncology. 27 (12): 2275–2283. doi: 10.1093/annonc/mdw429 . PMID   27827301.
  19. ↑ Samaranayake GJ, Huynh M, Rai P (2017). "MTH1 as a Chemotherapeutic Target: The Elephant in the Room". Cancers. 9 (5): 47. doi: 10.3390/cancers9050047 . PMC   5447957 . PMID   28481306.
  20. ↑ Thomas A (21 September 2016). "The Helleday Team presents potent MTH1 inhibitor 'Karonudib' and experimentally addresses the non-active MTH1 inhibitors". Helleday Laboratory. Retrieved 19 July 2017.
  21. ↑ "MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class (MASTIFF)". ClinicalTrials.gov. U.S. National Institutes of Health. 14 February 2017. Retrieved 19 July 2017.
  22. ↑ "AZ13792138". Open Innovation. AstraZeneca. 2016. Retrieved 19 July 2017.
  23. ↑ Kettle JG, Alwan H, Bista M, Breed J, Davies NL, Eckersley K, et al. (2016). "Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival". Journal of Medicinal Chemistry. 59 (6): 2346–61. doi: 10.1021/acs.jmedchem.5b01760 . PMID   26878898.
  24. ↑ Papeo G (2016). "MutT Homolog 1 (MTH1): The Silencing of a Target". Journal of Medicinal Chemistry. 59 (6): 2343–5. doi: 10.1021/acs.jmedchem.6b00283 . PMID   26924380.

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