thymine nucleotides


Summary: Phosphate esters of THYMIDINE in N-glycosidic linkage with ribose or deoxyribose, as occurs in nucleic acids. (From Dorland, 28th ed, p1154)

Top Publications

  1. Radivoyevitch T. Equilibrium model selection: dTTP induced R1 dimerization. BMC Syst Biol. 2008;2:15 pubmed publisher
    ..Comprehensive model space based biochemical equilibrium model selection methods are realizable. Their significance to systems biology as mappings of data into mathematical models warrants their development. ..
  2. Boyer P, Sarafianos S, Arnold E, Hughes S. The M184V mutation reduces the selective excision of zidovudine 5'-monophosphate (AZTMP) by the reverse transcriptase of human immunodeficiency virus type 1. J Virol. 2002;76:3248-56 pubmed
    ..Based on these results, and on the results of other excision experiments, we present a model to explain how the M184V mutation affects AZTMP excision. ..
  3. Kim D, Narayan M, Patel S. T7 DNA helicase: a molecular motor that processively and unidirectionally translocates along single-stranded DNA. J Mol Biol. 2002;321:807-19 pubmed
    ..We propose that the ability of T7 helicase to translocate unidirectionally along ssDNA in an efficient manner plays a crucial role in DNA unwinding. ..
  4. Birringer M, Claus M, Folkers G, Kloer D, Schulz G, Scapozza L. Structure of a type II thymidine kinase with bound dTTP. FEBS Lett. 2005;579:1376-82 pubmed
    ..This results in a specificity difference exploited for antiviral therapy. The presented structure will foster the development of new drugs and prodrugs for numerous therapeutic applications. ..
  5. Welin M, Kosinska U, Mikkelsen N, Carnrot C, Zhu C, Wang L, et al. Structures of thymidine kinase 1 of human and mycoplasmic origin. Proc Natl Acad Sci U S A. 2004;101:17970-5 pubmed
    ..The TK1 structure differs fundamentally from the structures of the other deoxyribonucleoside kinases, indicating a different evolutionary origin. ..
  6. Liao J, Jeong Y, Kim D, Patel S, Oster G. Mechanochemistry of t7 DNA helicase. J Mol Biol. 2005;350:452-75 pubmed
    ..Our analysis methods provide a systematic procedure to study kinetic pathways of multi-subunit, multi-state cooperative enzymes...
  7. Pontarin G, Ferraro P, Valentino M, Hirano M, Reichard P, Bianchi V. Mitochondrial DNA depletion and thymidine phosphate pool dynamics in a cellular model of mitochondrial neurogastrointestinal encephalomyopathy. J Biol Chem. 2006;281:22720-8 pubmed
    ..Thus MNGIE patients may increase their consumption of ATP to counteract an unlimited expansion of the dTTP pool caused by circulating thymidine...
  8. Zhang Y, Yuan F, Wu X, Wang Z. Preferential incorporation of G opposite template T by the low-fidelity human DNA polymerase iota. Mol Cell Biol. 2000;20:7099-108 pubmed
    ..The unique features of preferential G incorporation opposite template T and T stop suggest that DNA Pol(iota) may additionally play a specialized function in human biology. ..
  9. Nair D, Johnson R, Prakash L, Prakash S, Aggarwal A. Hoogsteen base pair formation promotes synthesis opposite the 1,N6-ethenodeoxyadenosine lesion by human DNA polymerase iota. Nat Struct Mol Biol. 2006;13:619-25 pubmed

More Information


  1. Tu X, Das K, Han Q, Bauman J, Clark A, Hou X, et al. Structural basis of HIV-1 resistance to AZT by excision. Nat Struct Mol Biol. 2010;17:1202-9 pubmed publisher
    ..Thus, the resistance mutations create a high-affinity ATP-binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision. ..
  2. Larsson K, Jordan A, Eliasson R, Reichard P, Logan D, Nordlund P. Structural mechanism of allosteric substrate specificity regulation in a ribonucleotide reductase. Nat Struct Mol Biol. 2004;11:1142-9 pubmed publisher
    ..The mechanism of substrate specificity regulation is probably general for most class I and class II RNRs...
  3. Crampton D, Guo S, Johnson D, Richardson C. The arginine finger of bacteriophage T7 gene 4 helicase: role in energy coupling. Proc Natl Acad Sci U S A. 2004;101:4373-8 pubmed
    ..However, gp4-R522K cannot stimulate T7 polymerase activity on double-stranded DNA. These findings support the involvement of the Arg-522 residue in the energy coupling mechanism...
  4. Dharmasena S, Pongracz Z, Arnold E, Sarafianos S, Parniak M. 3'-Azido-3'-deoxythymidine-(5')-tetraphospho-(5')-adenosine, the product of ATP-mediated excision of chain-terminating AZTMP, is a potent chain-terminating substrate for HIV-1 reverse transcriptase. Biochemistry. 2007;46:828-36 pubmed
  5. Boyer P, Sarafianos S, Arnold E, Hughes S. Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. J Virol. 2002;76:9143-51 pubmed
    ..If the ternary complex is unstable, the end of the primer can gain access to the N site and excision can occur. This could explain the enhanced excision of the nucleoside analogs. ..
  6. Arad S, Zattra E, Hebert J, Epstein E, Goukassian D, Gilchrest B. Topical thymidine dinucleotide treatment reduces development of ultraviolet-induced basal cell carcinoma in Ptch-1+/- mice. Am J Pathol. 2008;172:1248-55 pubmed publisher
    ..01). We conclude that topical pTT treatment during a prolonged period of intermittent UV exposure decreases the number and size of UV-induced BCCs through several anti-cancer mechanisms. ..
  7. Vastmans K, Froeyen M, Kerremans L, Pochet S, Herdewijn P. Reverse transcriptase incorporation of 1,5-anhydrohexitol nucleotides. Nucleic Acids Res. 2001;29:3154-63 pubmed
    ..These results could be rationalised based on the X-ray structure of HIV-1 reverse transcriptase. ..
  8. Fidalgo da Silva E, Mandal S, Reha Krantz L. Using 2-aminopurine fluorescence to measure incorporation of incorrect nucleotides by wild type and mutant bacteriophage T4 DNA polymerases. J Biol Chem. 2002;277:40640-9 pubmed
    ..If nucleotide binding is hindered, initiation of the proofreading pathway acts as an error avoidance mechanism to prevent incorporation of incorrect nucleotides. ..
  9. Desler C, Munch Petersen B, Stevnsner T, Matsui S, Kulawiec M, Singh K, et al. Mitochondria as determinant of nucleotide pools and chromosomal stability. Mutat Res. 2007;625:112-24 pubmed
    ..Our results suggest that mitochondria are central players in maintaining genomic stability and in controlling essential nuclear processes such as upholding a balanced supply of nucleotides. ..
  10. Kosinska U, Carnrot C, Eriksson S, Wang L, Eklund H. Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme. FEBS J. 2005;272:6365-72 pubmed
    ..The tight interaction with the substrate allows minor substitutions at the 3 and 5 positions of the base, only fluorine substitutions at the 2'-Ara position, but larger substitutions at the 3' position of the deoxyribose. ..
  11. Ke P, Kuo Y, Hu C, Chang Z. Control of dTTP pool size by anaphase promoting complex/cyclosome is essential for the maintenance of genetic stability. Genes Dev. 2005;19:1920-33 pubmed
    ..We conclude that down-regulation of dTTP pool size by the APC/C pathway during mitosis and the G1 phase is an essential means to maintain a balanced dNTP pool and to avoid genetic instability. ..
  12. Lee S, Richardson C. Molecular basis for recognition of nucleoside triphosphate by gene 4 helicase of bacteriophage T7. J Biol Chem. 2010;285:31462-71 pubmed publisher
    ..Results from this study suggest that the NTP must be stabilized by specific interactions within the NTP-binding site of the protein to achieve efficient hydrolysis. These interactions dictate NTP specificity...
  13. Xia S, Konigsberg W, Wang J. Hydrogen-bonding capability of a templating difluorotoluene nucleotide residue in an RB69 DNA polymerase ternary complex. J Am Chem Soc. 2011;133:10003-5 pubmed publisher
    ..Therefore, this structure provides evidence that a templating dF can form novel hydrogen bonds with the incoming dTTP and with the enzyme that differ from those formed with a templating dT. ..
  14. Anderson P, Zheng J, King T, Bushman L, Predhomme J, Meditz A, et al. Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS. 2007;21:1849-54 pubmed
    ..Thus, TP concentrations differ according to cell type in vivo with corresponding efficacy and toxicity implications for cells with low or high triphosphates. ..
  15. Kohli E, Han H, Zeman A, Vinogradov S. Formulations of biodegradable Nanogel carriers with 5'-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. J Control Release. 2007;121:19-27 pubmed
  16. Vinogradov S, Kohli E, Zeman A. Cross-linked polymeric nanogel formulations of 5'-triphosphates of nucleoside analogues: role of the cellular membrane in drug release. Mol Pharm. 2005;2:449-61 pubmed
    ..The results illustrate therapeutic potential of the phosphorylated nucleoside analogues formulated in nanosized cross-linked polymeric carriers for cancer chemotherapy. ..
  17. Szu P, He X, Zhao L, Liu H. Biosynthesis of TDP-D-desosamine: identification of a strategy for C4 deoxygenation. Angew Chem Int Ed Engl. 2005;44:6742-6 pubmed publisher
  18. Pontarin G, Gallinaro L, Ferraro P, Reichard P, Bianchi V. Origins of mitochondrial thymidine triphosphate: dynamic relations to cytosolic pools. Proc Natl Acad Sci U S A. 2003;100:12159-64 pubmed
    ..Our results are relevant for an understanding of certain genetic mitochondrial diseases. ..
  19. Crampton D, Mukherjee S, Richardson C. DNA-induced switch from independent to sequential dTTP hydrolysis in the bacteriophage T7 DNA helicase. Mol Cell. 2006;21:165-74 pubmed
    ..We propose that sequential hydrolysis of dTTP is coupled to the transfer of single-stranded DNA from subunit to adjacent subunit. ..
  20. Gu J, Xie Y, Schaefer H. Electron attachment to DNA single strands: gas phase and aqueous solution. Nucleic Acids Res. 2007;35:5165-72 pubmed
    ..Thus the base-centered radical anions of the pyrimidine nucleotides might be the possible intermediates for DNA single-strand breakage. ..
  21. McKee E, Bentley A, Hatch M, Gingerich J, Susan Resiga D. Phosphorylation of thymidine and AZT in heart mitochondria: elucidation of a novel mechanism of AZT cardiotoxicity. Cardiovasc Toxicol. 2004;4:155-67 pubmed
    ..0 +/- 0.9 microM. Thus, the toxicity of AZT in some tissues may be mediated by disrupting the substrate supply of TTP for mt-DNA replication. ..
  22. Song S, Wheeler L, Mathews C. Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA. J Biol Chem. 2003;278:43893-6 pubmed
    ..Our finding of dTTP and dGTP elevations and dATP depletion in mitochondrial dNTP pools are consistent with a mutagenic mechanism involving T-G mispairing followed by a next-nucleotide effect involving T insertion opposite A...
  23. Donmez I, Patel S. Mechanisms of a ring shaped helicase. Nucleic Acids Res. 2006;34:4216-24 pubmed
    ..The slow unwinding rate is greatly stimulated when DNA synthesis by T7 DNA polymerase is coupled to DNA unwinding. Using the T7 helicase as an example, we highlight critical findings and discuss possible mechanisms of helicase action...
  24. Jeong Y, Kim D, Patel S. Kinetic pathway of dTTP hydrolysis by hexameric T7 helicase-primase in the absence of DNA. J Biol Chem. 2002;277:43778-84 pubmed
    ..Acad. Sci. U.S.A. 94, 5012-5017), and they support a model of dTTP hydrolysis by T7 helicase hexamer that is similar to the binding change mechanism of F(1)-ATPase with dTTP hydrolysis occurring sequentially at the catalytic sites. ..
  25. Lim S, Copeland W. Differential incorporation and removal of antiviral deoxynucleotides by human DNA polymerase gamma. J Biol Chem. 2001;276:23616-23 pubmed
    ..Thus, although their greatest inhibitory effects are through incorporation and chain termination, persistence of these analogs in DNA and inhibition of exonucleolytic proofreading may also contribute to mitochondrial toxicity. ..
  26. Boyer P, Sarafianos S, Arnold E, Hughes S. Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase. J Virol. 2001;75:4832-42 pubmed
    ..Steric constraints involving the azido group cause the end of an AZT 5'-monophosphate-terminated primer to preferentially reside at the nucleotide binding site, which favors excision. ..
  27. Højland T, Veedu R, Vester B, Wengel J. Enzymatic synthesis of DNA strands containing ?-L-LNA (?-L-configured locked nucleic acid) thymine nucleotides. Artif DNA PNA XNA. 2012;3:14-21 pubmed publisher
    ..Three dispersed ?-L-LNA thymine nucleotides can be incorporated into DNA strands by all four polymerases, but they were unable to perform consecutive ..
  28. Vinogradov S. Polymeric nanogel formulations of nucleoside analogs. Expert Opin Drug Deliv. 2007;4:5-17 pubmed
    ..The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery. ..
  29. Ferraro P, Nicolosi L, Bernardi P, Reichard P, Bianchi V. Mitochondrial deoxynucleotide pool sizes in mouse liver and evidence for a transport mechanism for thymidine monophosphate. Proc Natl Acad Sci U S A. 2006;103:18586-91 pubmed
    ..At nM external dTMP the nucleotide is concentrated 100-fold inside the mt matrix. Export of thymidine phosphates was much slower and possibly occurred at the level of dTDP. ..
  30. Xia Q, Radzio J, Anderson K, Sluis Cremer N. Probing nonnucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase by transient kinetic analyses. Protein Sci. 2007;16:1728-37 pubmed
  31. Kashlan O, Cooperman B. Comprehensive model for allosteric regulation of mammalian ribonucleotide reductase: refinements and consequences. Biochemistry. 2003;42:1696-706 pubmed
  32. Sarafianos S, Clark A, Das K, Tuske S, Birktoft J, Ilankumaran P, et al. Structures of HIV-1 reverse transcriptase with pre- and post-translocation AZTMP-terminated DNA. EMBO J. 2002;21:6614-24 pubmed
    ..Structural differences between complexes N and P suggest that the conserved YMDD loop is involved in translocation, acting as a springboard that helps to propel the primer terminus from the N to the P site after dNMP incorporation. ..
  33. Kohalmi S, Glattke M, McIntosh E, Kunz B. Mutational specificity of DNA precursor pool imbalances in yeast arising from deoxycytidylate deaminase deficiency or treatment with thymidylate. J Mol Biol. 1991;220:933-46 pubmed
    ..We consider several possibilities, including potential roles for the regulation and specificity of proofreading and for mismatch correction. ..
  34. Strahl C, Blackburn E. The effects of nucleoside analogs on telomerase and telomeres in Tetrahymena. Nucleic Acids Res. 1994;22:893-900 pubmed
    ..However, AZT decreased the efficiency of programmed de novo telomere addition during macronuclear development in mating cells. ..
  35. Ingemarson R, Thelander L. A kinetic study on the influence of nucleoside triphosphate effectors on subunit interaction in mouse ribonucleotide reductase. Biochemistry. 1996;35:8603-9 pubmed
  36. Eriksson M, Uhlin U, Ramaswamy S, Ekberg M, Regnstrom K, Sjoberg B, et al. Binding of allosteric effectors to ribonucleotide reductase protein R1: reduction of active-site cysteines promotes substrate binding. Structure. 1997;5:1077-92 pubmed
    ..The general allosteric effector site, located far from the active site, appears to regulate subunit interactions within the holoenzyme. ..
  37. Meier C, Balzarini J. Application of the cycloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules. Antiviral Res. 2006;71:282-92 pubmed
    ..The cycloSal-approach is not restricted to the delivery of bioactive nucleotides but also useful for the intracellular delivery of hexose-1-phosphates. ..
  38. Lampinen Salomonsson M, Bondesson U, Petersson C, Hedeland M. Differentiation of estriol glucuronide isomers by chemical derivatization and electrospray tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006;20:1429-40 pubmed
  39. Uckun F, Venkatachalam T, Erbeck D, Chen C, Petkevich A, Vassilev A. Zidampidine, an aryl phosphate derivative of AZT: in vivo pharmacokinetics, metabolism, toxicity, and anti-viral efficacy against hemorrhagic fever caused by Lassa virus. Bioorg Med Chem. 2005;13:3279-88 pubmed
    ..0001). This pilot study provides the basis for future preclinical evaluation of Zidampidine and its potential as a new agent for the treatment of viral hemorrhagic fevers caused by Lassa virus. ..
  40. Sluis Cremer N, Sheen C, Zelina S, Torres P, Parikh U, Mellors J. Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2007;51:48-53 pubmed
    ..Taken together, these findings indicate that the K70E mutation, like the K65R mutation, reduces susceptibility to NRTI by selectively decreasing NRTI-TP incorporation and is antagonistic to TAM-mediated nucleotide excision. ..
  41. Mansuri R, Ansari M, Singh J, Rana S, Sinha S, Sahoo G, et al. Computational Elucidation of Structural Basis for Ligand Binding with Mycobacterium tuberculosis Glucose-1-Phosphate Thymidylyltransferase (RmlA). Curr Pharm Biotechnol. 2016;17:1089-1099 pubmed
    ..84 Kcal/mol). All these results suggest that these two compounds have more stable interaction than that of substrate inside the solvent condition and can be used as competitive inhibitors. ..
  42. Lawrance A, Deng L, Rozen R. Methylenetetrahydrofolate reductase deficiency and low dietary folate reduce tumorigenesis in Apc min/+ mice. Gut. 2009;58:805-11 pubmed publisher
    ..36, p = 0.08). Low dietary folate and Mthfr deficiency reduce adenoma formation in mice predisposed to tumorigenesis, possibly through increased apoptosis consequent to hyperhomocysteinaemia and nucleotide imbalances. ..
  43. Li T, Shang G, Xia H, Wang Y. [Cloning of the sugar related biosynthesis gene cluster from Streptomyces tenebrarius H6]. Sheng Wu Gong Cheng Xue Bao. 2001;17:329-31 pubmed
    ..A DNA sequence highly homologous to strL coding dTDP-4-dehydrorhamnose reductase was found linked with aprE gene. ..
  44. Alnajjar K, Negahbani A, Nakhjiri M, Krylov I, Kashemirov B, McKenna C, et al. DNA Polymerase ? Cancer-Associated Variant I260M Exhibits Nonspecific Selectivity toward the ?-? Bridging Group of the Incoming dNTP. Biochemistry. 2017;56:5449-5456 pubmed publisher
    ..Additionally, we provide evidence that I260M fidelity is altered in the presence of some of the analogues, possibly resulting from a lack of coordination between the fingers and palm subdomains in the presence of the I260M mutation...
  45. Kubiak R, Phillips R, Zmudka M, Ahn M, Maka E, Pyeatt G, et al. Structural and functional studies on a 3'-epimerase involved in the biosynthesis of dTDP-6-deoxy-D-allose. Biochemistry. 2012;51:9375-83 pubmed publisher
    ..Our results indicate that the orientation of the tyrosine residue in ChmJ is a function of the ligand occupying the active site cleft. ..
  46. Taguchi T, Fukuda M, Ohashi M. Differences in DNA synthesis in vitro using isolated nuclei from regenerating livers of young and aged rats. Mech Ageing Dev. 2001;122:141-55 pubmed
  47. Anderson D, Stover P. SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PLoS ONE. 2009;4:e5839 pubmed publisher
  48. Durand Gasselin L, Pruvost A, Dehee A, Vaudre G, Tabone M, Grassi J, et al. High levels of zidovudine (AZT) and its intracellular phosphate metabolites in AZT- and AZT-lamivudine-treated newborns of human immunodeficiency virus-infected mothers. Antimicrob Agents Chemother. 2008;52:2555-63 pubmed publisher
    ..8-fold [P = 0.0415]) than those in males. Unexpectedly, newborns on AZT monotherapy whose mothers' treatment included 3TC displayed residual plasma 3TC and intracellular 3TC-TP levels up to 1 week after birth. ..
  49. Zuccotti S, Zanardi D, Rosano C, Sturla L, Tonetti M, Bolognesi M. Kinetic and crystallographic analyses support a sequential-ordered bi bi catalytic mechanism for Escherichia coli glucose-1-phosphate thymidylyltransferase. J Mol Biol. 2001;313:831-43 pubmed
    ..e. dTDP-glucose biosynthesis and pyrophosphorolysis, follow a sequential ordered bi bi catalytic mechanism. ..
  50. Rampazzo C, Ferraro P, Pontarin G, Fabris S, Reichard P, Bianchi V. Mitochondrial deoxyribonucleotides, pool sizes, synthesis, and regulation. J Biol Chem. 2004;279:17019-26 pubmed
    ..These results suggest that mdN modulates the synthesis of mt dTTP by counteracting in a substrate cycle the phosphorylation of thymidine by the mt thymidine kinase. ..
  51. Chow D, Chilkoti A. Surface-initiated enzymatic polymerization of DNA. Langmuir. 2007;23:11712-7 pubmed
    ..TdTase-mediated SIEP can also be used to grow spatially defined three-dimensional DNA structures by soft lithography and is a new tool for bioinspired fabrication at the micro- and nanoscale. ..
  52. Alnouti Y, White C, Bartlett M. Simultaneous quantitation of zidovudine and zidovudine monophosphate from plasma, amniotic fluid and tissues by micellar capillary electrophoresis. Biomed Chromatogr. 2004;18:523-31 pubmed
    ..We also report the enzymatic dephosphorylation of AZT-MP in the placental tissue of rats. This new enzymatic pathway provides increased understanding of the mechanism of anti-viral transport in the rat during pregnancy. ..
  53. Fioravanti E, Adam V, Munier Lehmann H, Bourgeois D. The crystal structure of Mycobacterium tuberculosis thymidylate kinase in complex with 3'-azidodeoxythymidine monophosphate suggests a mechanism for competitive inhibition. Biochemistry. 2005;44:130-7 pubmed
    ..Magnesium is prevented from binding, and the resulting electrostatic environment precludes phosphoryl transfer from occurring. Our data provide a model for drug development against tuberculosis. ..