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| Deoxyguanosine triphosphate (dGTP) is a nucleoside triphosphate, and a nucleotide precursor used in cells for DNA synthesis. The substance is used in the polymerase chain reaction technique, in sequencing, and in cloning. It is also the competitor of inhibition onset by acyclovir in the treatment of HSV virus.
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Read full article at Wikipedia
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InChI=1S/C10H16N5O13P3/c11- 10-13-8-7(9(17)14-10)12-3-15(8)6-1-4(16)5(26-6)2-25-30(21,22)28-31(23,24)27-29(18,19)20/h3-6,16H,1-2H2,(H,21,22)(H,23,24)(H2,18,19,20)(H3,11,13,14,17)/t4-,5+,6+/m0/s1 |
| HAAZLUGHYHWQIW-KVQBGUIXSA-N |
| NC1=NC2=C(N=CN2[C@H]2C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O2)C(=O)N1 |
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Mus musculus
(NCBI:txid10090)
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Source: BioModels - MODEL1507180067
See:
PubMed
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Mus musculus
(NCBI:txid10090)
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From MetaboLights
See:
MetaboLights Study
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Arabidopsis thaliana
(NCBI:txid3702)
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From MetaboLights
See:
MetaboLights Study
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Solanum lycopersicum
(NCBI:txid4081)
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Found in
leaf
(BTO:0000713).
From MetaboLights
See:
MetaboLights Study
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Saccharomyces cerevisiae
(NCBI:txid4932)
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See:
PubMed
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Escherichia coli
(NCBI:txid562)
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See:
PubMed
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Homo sapiens
(NCBI:txid9606)
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See:
DOI
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Escherichia coli metabolite
Any bacterial metabolite produced during a metabolic reaction in Escherichia coli.
human metabolite
Any mammalian metabolite produced during a metabolic reaction in humans (Homo sapiens).
Saccharomyces cerevisiae metabolite
Any fungal metabolite produced during a metabolic reaction in Baker's yeast (Saccharomyces cerevisiae ).
mouse metabolite
Any mammalian metabolite produced during a metabolic reaction in a mouse (Mus musculus).
(via nucleoside 5'-triphoshate )
Arabidopsis thaliana metabolite
Any plant metabolite that is produced by Arabidopsis thaliana.
plant metabolite
Any eukaryotic metabolite produced during a metabolic reaction in plants, the kingdom that include flowering plants, conifers and other gymnosperms.
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View more via ChEBI Ontology
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2'-deoxyguanosine 5'-(tetrahydrogen triphosphate)
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2'-deoxy-GTP
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ChEBI
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2'-deoxyguanosine 5'-triphosphate
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KEGG COMPOUND
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2'-deoxyguanosine triphosphate
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ChEBI
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deoxy-GTP
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HMDB
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deoxyguanosine 5'-triphosphate
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KEGG COMPOUND
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deoxyguanosine triphosphate
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KEGG COMPOUND
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dGTP
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KEGG COMPOUND
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2564-35-4
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CAS Registry Number
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ChemIDplus
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73481
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Reaxys Registry Number
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Reaxys
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Rabuffetti M, Rinaldi F, Lo Bianco A, Speranza G, Ubiali D, de Moraes MC, Rodrigues Pereira da Silva LC, Massolini G, Calleri E, Lavecchia A (2021)
Discovery of a Novel Inhibitor of Human Purine Nucleoside Phosphorylase by a Simple Hydrophilic Interaction Liquid Chromatography Enzymatic Assay.
ChemMedChem 16, 1325-1334 [PubMed:33405358]
[show Abstract]
Human purine nucleoside phosphorylase (HsPNP) belongs to the purine salvage pathway of nucleic acids. Genetic deficiency of this enzyme triggers apoptosis of activated T-cells due to the accumulation of deoxyguanosine triphosphate (dGTP). Therefore, potential chemotherapeutic applications of human PNP inhibitors include the treatment of T-cell leukemia, autoimmune diseases and transplant tissue rejection. In this report, we present the discovery of novel HsPNP inhibitors by coupling experimental and computational tools. A simple, inexpensive, direct and non-radioactive enzymatic assay coupled to hydrophilic interaction liquid chromatography and UV detection (LC-UV using HILIC as elution mode) was developed for screening HsPNP inhibitors. Enzymatic activity was assessed by monitoring the phosphorolysis of inosine (Ino) to hypoxanthine (Hpx) by LC-UV. A small library of 6- and 8-substituted nucleosides was synthesized and screened. The inhibition potency of the most promising compound, 8-aminoinosine (4), was quantified through Ki and IC50 determinations. The effect of HsPNP inhibition was also evaluated in vitro through the study of cytotoxicity on human T-cell leukemia cells (CCRF-CEM). Docking studies were also carried out for the most potent compound, allowing further insights into the inhibitor interaction at the HsPNP active site. This study provides both new tools and a new lead for developing novel HsPNP inhibitors. | Davenne T, Klintman J, Sharma S, Rigby RE, Blest HTW, Cursi C, Bridgeman A, Dadonaite B, De Keersmaecker K, Hillmen P, Chabes A, Schuh A, Rehwinkel J (2020)
SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.
Cell reports 31, 107640 [PubMed:32402273]
[show Abstract]
The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression. | Barnes CO, Wu Y, Song J, Lin G, Baxter EL, Brewster AS, Nagarajan V, Holmes A, Soltis SM, Sauter NK, Ahn J, Cohen AE, Calero G (2019)
The crystal structure of dGTPase reveals the molecular basis of dGTP selectivity.
Proceedings of the National Academy of Sciences of the United States of America 116, 9333-9339 [PubMed:31019074]
[show Abstract]
Deoxynucleotide triphosphohydrolases (dNTPases) play a critical role in cellular survival and DNA replication through the proper maintenance of cellular dNTP pools. While the vast majority of these enzymes display broad activity toward canonical dNTPs, such as the dNTPase SAMHD1 that blocks reverse transcription of retroviruses in macrophages by maintaining dNTP pools at low levels, Escherichia coli (Ec)-dGTPase is the only known enzyme that specifically hydrolyzes dGTP. However, the mechanism behind dGTP selectivity is unclear. Here we present the free-, ligand (dGTP)- and inhibitor (GTP)-bound structures of hexameric Ec-dGTPase, including an X-ray free-electron laser structure of the free Ec-dGTPase enzyme to 3.2 Å. To obtain this structure, we developed a method that applied UV-fluorescence microscopy, video analysis, and highly automated goniometer-based instrumentation to map and rapidly position individual crystals randomly located on fixed target holders, resulting in the highest indexing rates observed for a serial femtosecond crystallography experiment. Our structures show a highly dynamic active site where conformational changes are coupled to substrate (dGTP), but not inhibitor binding, since GTP locks dGTPase in its apo- form. Moreover, despite no sequence homology, Ec-dGTPase and SAMHD1 share similar active-site and HD motif architectures; however, Ec-dGTPase residues at the end of the substrate-binding pocket mimic Watson-Crick interactions providing guanine base specificity, while a 7-Å cleft separates SAMHD1 residues from dNTP bases, abolishing nucleotide-type discrimination. Furthermore, the structures shed light on the mechanism by which long distance binding (25 Å) of single-stranded DNA in an allosteric site primes the active site by conformationally "opening" a tyrosine gate allowing enhanced substrate binding. | Itsko M, Schaaper RM (2017)
Suppressors of dGTP Starvation in Escherichia coli.
Journal of bacteriology 199, e00142-17 [PubMed:28373271]
[show Abstract]
dGTP starvation, a newly discovered phenomenon in which Escherichia coli cells are starved specifically for the DNA precursor dGTP, leads to impaired growth and, ultimately, cell death. Phenomenologically, it represents an example of nutritionally induced unbalanced growth: cell mass amplifies normally as dictated by the nutritional status of the medium, but DNA content growth is specifically impaired. The other known example of such a condition, thymineless death (TLD), involves starvation for the DNA precursor dTTP, which has been found to have important chemotherapeutic applications. Experimentally, dGTP starvation is induced by depriving an E. coligpt optA1 strain of its required purine source, hypoxanthine. In our studies of this phenomenon, we noted the emergence of a relatively high frequency of suppressor mutants that proved resistant to the treatment. To study such suppressors, we used next-generation sequencing on a collection of independently obtained mutants. A significant fraction was found to carry a defect in the PurR transcriptional repressor, controlling de novo purine biosynthesis, or in its downstream purEK operon. Thus, upregulation of de novo purine biosynthesis appears to be a major mode of overcoming the lethal effects of dGTP starvation. In addition, another large fraction of the suppressors contained a large tandem duplication of a 250- to 300-kb genomic region that included the purEK operon as well as the acrAB-encoded multidrug efflux system. Thus, the suppressive effects of the duplications could potentially involve beneficial effects of a number of genes/operons within the amplified regions.IMPORTANCE Concentrations of the four precursors for DNA synthesis (2'-deoxynucleoside-5'-triphosphates [dNTPs]) are critical for both the speed of DNA replication and its accuracy. Previously, we investigated consequences of dGTP starvation, where the DNA precursor dGTP was specifically reduced to a low level. Under this condition, E. coli cells continued cell growth but eventually developed a DNA replication defect, leading to cell death due to formation of unresolvable DNA structures. Nevertheless, dGTP-starved cultures eventually resumed growth due to the appearance of resistant mutants. Here, we used whole-genome DNA sequencing to identify the responsible suppressor mutations. We show that the majority of suppressors can circumvent death by upregulating purine de novo biosynthesis, leading to restoration of dGTP to acceptable levels. | Ji X, Wu Y, Yan J, Mehrens J, Yang H, DeLucia M, Hao C, Gronenborn AM, Skowronski J, Ahn J, Xiong Y (2013)
Mechanism of allosteric activation of SAMHD1 by dGTP.
Nature structural & molecular biology 20, 1304-1309 [PubMed:24141705]
[show Abstract]
SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutières syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS. | Torti A, Lossani A, Savi L, Focher F, Wright GE, Brown NC, Xu WC (2011)
Clostridium difficile DNA polymerase IIIC: basis for activity of antibacterial compounds.
Current enzyme inhibition 7, 147-153 [PubMed:22844265]
[show Abstract]
Based on the finding that aerobic Gram-positive antibacterials that inhibit DNA polymerase IIIC (pol IIIC) were potent inhibitors of the growth of anaerobic Clostridium difficile (CD) strains, we chose to clone and express the gene for pol IIIC from this organism. The properties of the recombinant enzyme are similar to those of related pol IIICs from Gram-positive aerobes, e.g. B. subtilis. Inhibitors of the CD enzyme also inhibited B. subtilis pol IIIC, and were competitive with respect to the cognate substrate 2'-deoxyguanosine 5'-triphosphate (dGTP). Significantly, several of these inhibitors of the CD pol IIIC had potent activity against the growth of CD clinical isolates in culture. | Ray AS, Feng JY, Murakami E, Chu CK, Schinazi RF, Anderson KS (2007)
Interaction of 2'-deoxyguanosine triphosphate analogue inhibitors of HIV reverse transcriptase with human mitochondrial DNA polymerase gamma.
Antiviral chemistry & chemotherapy 18, 25-33 [PubMed:17354649]
[show Abstract]
Mitochondrial toxicity is a limiting factor in the use of some nucleoside reverse transcriptase inhibitors of HIV. To further understand the impact of structural features on the incorporation and exonuclease removal of nucleoside monophosphate (MP) analogues by human mitochondrial DNA polymerase (pol gamma), transient kinetic studies were done with analogues of 2'-deoxyguanosine triphosphate. The kinetic parameters for the incorporation and removal of carbovir (CBV)-MP, dioxolane guanosine (DXG)-MP and 2',3'-dideoxy-2',3'-didehydroguanosine (d4G)-MP were studied with pol gamma holoenzyme. The importance of the ribose oxygen in incorporation by pol gamma was illustrated by an approximate 3,000-fold decrease in the incorporation efficiency of an analogue lacking the ribose oxygen (CBV-TP) relative to those containing a ribose oxygen (DXG-TP and d4G-TP). As a result, a comparison with previous data for the incorporation by HIV reverse transcriptase showed CBV-TP to be approximately 800-8,000-fold more selective for its antiviral target over pol gamma relative to the other guanosine analogues. However, DXG-TP and d4G-TP were found to be much more selective than previously reported values for mitochondrial toxic nucleoside analogues. Structural modelling based on sequence homology with other polymerase A family members suggests that an interaction between the ribose oxygen and arginine 853 in pol gamma may play a critical role in causing this differential incorporation. Exonuclease removal of a chain-terminating CBV-MP was also found to be more efficient by pol gamma. These results help to further elucidate the structure activity relationships for pol gamma and should aid in the design of more selective antiviral agents. | Kaczmarek P, Jezowska-Bojczuk M, Bal W, Kasprzak KS (2005)
Determination of the stability constants and oxidation susceptibility of nickel(II) complexes with 2'-deoxyguanosine 5'-triphosphate and L-histidine.
Journal of inorganic biochemistry 99, 737-746 [PubMed:15708794]
[show Abstract]
The formation of binary Ni(II) complexes with 2'-deoxyguanosine 5'-triphosphate (dGTP, L) as well as ternary complexes thereof with L-histidine (His, A) was studied with the use of potentiometry and electronic absorption spectroscopy. In the binary and ternary systems, the complexes with stoichiometries NiH2L-, NiHL2-, NiL3- and NiH2LA2-, NiHLA3-, NiLA4- respectively, were detected. The ternary complexes are very stable at pH 7.4 and thus may constitute biologically relevant Ni(II) carriers in the cell. In the presence of hydrogen peroxide, the binary and ternary systems both generate hydroxyl radical-like species and undergo dGTP degradation with the formation of the 8-oxo-dGTP intermediate. The latter, along with dGTP complexation and degradation, may lead to mutagenesis and carcinogenesis due to base-mispairing properties of 8-oxoguanine and the disturbance in the physiological balance among the four canonical triphosphodeoxynucleotide substrates for DNA synthesis. | Hardy CD, Schultz CS, Collins K (2001)
Requirements for the dGTP-dependent repeat addition processivity of recombinant Tetrahymena telomerase.
The Journal of biological chemistry 276, 4863-4871 [PubMed:11096070]
[show Abstract]
Telomerase is a reverse transcriptase responsible for adding simple sequence repeats to chromosome 3'-ends. The template for telomeric repeat synthesis is carried within the RNA component of the telomerase ribonucleoprotein complex. Telomerases can copy their internal templates with repeat addition processivity, reusing the same template multiple times in the extension of a single primer. For some telomerases, optimal repeat addition processivity requires high micromolar dGTP concentrations, a much higher dGTP concentration than required for processive nucleotide addition within a repeat. We have investigated the requirements for dGTP-dependent repeat addition processivity using recombinant Tetrahymena telomerase. By altering the template sequence, we show that repeat addition processivity retains the same dGTP-dependence even if dGTP is not the first nucleotide incorporated in the second repeat. Furthermore, no dNTP other than dGTP can stimulate repeat addition processivity, even if it is the first nucleotide incorporated in the second repeat. Using structural variants of dGTP, we demonstrate that the stimulation of repeat addition processivity is specific for dGTP base and sugar constituents but requires only a single phosphate group. However, all nucleotides that stimulate repeat addition processivity also inhibit or compete with dGTP incorporation into product DNA. By assaying telomerase complexes reconstituted with a variety of altered templates, we find that repeat addition processivity has an unanticipated template or product sequence specificity. Finally, we show that a novel, nascent product DNA binding site establishes dGTP-dependent repeat addition processivity. | Muller EG (1994)
Deoxyribonucleotides are maintained at normal levels in a yeast thioredoxin mutant defective in DNA synthesis.
The Journal of biological chemistry 269, 24466-24471 [PubMed:7929110]
[show Abstract]
Deletion of both thioredoxin genes TRX1 and TRX2 of Saccharomyces cerevisiae reduces the rate of DNA replication. This observation, originally determined by flow cytometry, was confirmed by radiochemical labeling of synchronized cultures. Since thioredoxin is a hydrogen donor to ribonucleotide reductase, a priori the inhibition of DNA synthesis was predicted to be caused by a reduction in the deoxyribonucleotide pools. However, the levels of TTP, dCTP, dATP, and dGTP were either unchanged or slightly greater in the thioredoxin mutant (3.2, 0.91, 1.4, and 1.21 pmol/10(6) cells, respectively) versus the wild-type culture (2.5, 0.91, 1.0, and 0.68 pmol/10(6) cells, respectively). An impact on ribonucleotide reduction was seen by an increased accumulation of RNR1 and RNR2 transcripts in the thioredoxin mutant (4.3- and 6.8-fold, respectively). Increased RNR expression did not reflect a general response of the DNA replication machinery. POL1 (DNA polymerase I) and CDC8 (thymidylate kinase) transcription were unaltered, while histone H2B transcripts actually decreased by half. Two alternative models incorporating these results are discussed. One suggests that thioredoxin reduces a multiprotein complex channeling nucleotides to the replication apparatus. The second proposes that thioredoxin regulates the tempo of DNA replication directly by activating a component of the replication machinery. | Sato A, Cory JG (1981)
Evaluation of combinations of drugs that inhibit Ehrlich tumor cell ribonucleotide reductase.
Cancer research 41, 1637-1641 [PubMed:6783298]
[show Abstract]
The nature of the inhibition of Ehrlich tumor cell ribonucleotide reductase by combinations of agents directed at the non-heme iron-containing component and the effector-binding component was studied with the use of isobolograms. From these studies, it was determined that the combinations of pyrazoloimidazole (IMPY) and dialdehyde of inosine, IMPY and deoxyguanosine triphosphate (dGTP), IMPY and deoxyadenosine triphosphate (dATP), and IMPY and deoxythymidine triphosphate (dTTP) gave synergistic inhibition of cytidine diphosphate reductase. The combination of dATP and dGTP also gave synergistic inhibition. The combinations of hydroxyurea and IMPY, 4-methyl-5-aminoisoquinoline thiosemicarbazone (MAIQ) and IMPY, and dialdehyde of inosine and dialdehyde derivative of 5'-deoxyinosine gave antagonistic inhibition. Other combinations utilizing MAIQ and dATP, MAIQ and dGTP, MAIQ and dTTP, hydroxyurea and dGTP, and hydroxyurea and dTTP gave inhibition which was additive. |
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