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Gene Review

Tyms  -  thymidylate synthetase

Rattus norvegicus

Synonyms: TS, TSase, Thymidylate synthase
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Disease relevance of Tyms

  • The structures represent the first views of any mammalian TS bound to ligands and suggest that the rat protein undergoes a ligand-induced conformational change similar to that of the Escherichia coli protein [1].
  • It has previously been shown that colorectal cancer patients who are homozygous for the triple tandem repeats (L/L) have significantly higher thymidylate synthase mRNA expression than those homozygous for the double repeat variant (S/S) [2].
  • A third domain, unique to the 13S protein, was required for the accelerated activation of the cellular thymidylate synthase gene in a manner similar to the 13S-dependent stimulation of adenovirus early region genes [3].
  • Treatment of the hepatoma cells with the reductase inhibitors for 72 h during growth caused approximately a 75% reduction in total cellular folates and 5,10-methylenetetrahydrofolate (primarily as polyglutamates) the substrate for thymidylate synthase [4].
  • The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity [5].

High impact information on Tyms


Chemical compound and disease context of Tyms

  • Surprisingly, Tomudex does not induce the "closed" conformation in rat TS that is seen on binding to E. coli TS, resulting in inhibitor atoms that differ in position by more than 1.5 A [1].
  • Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer [2].
  • TS and TK activities in 1,2-dimethylhydrazine (DMH)-induced colon carcinomas in rats increased significantly to 331 and 207% of the activities in normal colon, respectively, and were well correlated inversely (y = -0.93x + 5.24), with a correlation coefficient of -0.787 [10].
  • Focusing on the effects of TS, we may conclude that the ILP administration of 5FU offered the important advantage of a lack of severe TS inhibition in normal tissues, which corresponds with the low systemic toxicity observed [11].
  • Sequential methotrexate/5-FU: FdUMP formation and TS inhibition in a transplantable rodent colon adenocarcinoma [12].

Biological context of Tyms

  • Thymidylate synthetase (TS) and thymidine kinase (TK) are known to catalyse the methylation of dUMP for the de novo synthesis of dTMP and the phosphorylation of thymidine for the salvage synthesis of dTMP in the pyrimidine pathway, respectively [10].
  • However, the pattern of recovery of TS activity and cell cycle alterations were different in the liver than in the hindlimb, probably reflecting the higher cell proliferative rate in the liver at this stage [13].
  • Micromethods for assay of 5-fluoro-2'-deoxyuridylate (FdUMP) and thymidylate synthetase (TS) were used to study the in vivo intracellular pharmacokinetics of 5-FU [12].
  • The purpose of this study was to determine the intestinal absorption characteristics of AG337, a mechanism-based inhibitor of thymidylate synthase, using a perfused rat intestinal model [14].
  • Peak FdUMP levels were modest compared to those observed after equimolar administration of 5-FU, but FdUMP persisted in amounts well above available binding sites on TS for the 24 h observation time [15].

Anatomical context of Tyms

  • There was an excellent correlation between the effects of these drugs on inhibiting TS and cytotoxicity as measured by a clonogenic assay, when the exposure time was 4 hr and those when the rat sarcoma cell line was employed (p less than 0.001) [16].
  • These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2) [17].
  • TS activity and FdUMP binding to TS in bone marrow was strongly inhibited after administration of 5FU by all routes, but administration by ILP seemed slightly advantageous, since a smaller extent of TS inhibition was observed compared to the other routes of administration [11].
  • The effects of macrophage (M) and granulocyte (G) colony-stimulating factors (CSFs) on the activity of thymidylate synthase and thymidine kinase, which are involved in de novo and salvage pathways for pyrimidine nucleotide synthesis, were investigated in the hematopoietic cells of rats treated with cyclophasphamide [18].
  • In intestinal mucosa, both induction of TS activity (by ILP) and inhibition of TS activity (by HAI) were observed, while i.p. injection did not cause major changes [11].

Associations of Tyms with chemical compounds


Other interactions of Tyms


Analytical, diagnostic and therapeutic context of Tyms


  1. Crystal structures of rat thymidylate synthase inhibited by Tomudex, a potent anticancer drug. Sotelo-Mundo, R.R., Ciesla, J., Dzik, J.M., Rode, W., Maley, F., Maley, G.F., Hardy, L.W., Montfort, W.R. Biochemistry (1999) [Pubmed]
  2. Thymidylate synthase gene polymorphism predicts response to capecitabine in advanced colorectal cancer. Park, D.J., Stoehlmacher, J., Zhang, W., Tsao-Wei, D., Groshen, S., Lenz, H.J. International journal of colorectal disease. (2002) [Pubmed]
  3. Different functional domains of the adenovirus E1A gene are involved in regulation of host cell cycle products. Zerler, B., Roberts, R.J., Mathews, M.B., Moran, E. Mol. Cell. Biol. (1987) [Pubmed]
  4. The role of cellular folates in the enhancement of activity of the thymidylate synthase inhibitor 10-propargyl-5,8-dideazafolate against hepatoma cells in vitro by inhibitors of dihydrofolate reductase. Galivan, J., Rhee, M.S., Johnson, T.B., Dilwith, R., Nair, M.G., Bunni, M., Priest, D.G. J. Biol. Chem. (1989) [Pubmed]
  5. Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency. Jones, T.R., Thornton, T.J., Flinn, A., Jackman, A.L., Newell, D.R., Calvert, A.H. J. Med. Chem. (1989) [Pubmed]
  6. Stable transfection of malaria parasite blood stages. van Dijk, M.R., Waters, A.P., Janse, C.J. Science (1995) [Pubmed]
  7. Synergistic growth inhibition of rat hepatoma cells exposed in vitro to N10-propargyl-5,8-dideazafolate with methotrexate or the lipophilic antifolates trimetrexate or metoprine. Galivan, J., Nimec, Z., Rhee, M. Cancer Res. (1987) [Pubmed]
  8. Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model. Cao, S., Lu, K., Tóth, K., Slocum, H.K., Shirasaka, T., Rustum, Y.M. Clin. Cancer Res. (1999) [Pubmed]
  9. Biochemical studies on PT523, a potent nonpolyglutamatable antifolate, in cultured cells. Rhee, M.S., Galivan, J., Wright, J.E., Rosowsky, A. Mol. Pharmacol. (1994) [Pubmed]
  10. Relative activities of thymidylate synthetase and thymidine kinase in 1,2-dimethylhydrazine-induced colon carcinomas in rats. Sakamoto, S., Kuwa, K., Tsukada, K., Sagara, T., Kasahara, N., Okamoto, R. Carcinogenesis (1987) [Pubmed]
  11. The effect of different routes of administration of 5-fluorouracil on thymidylate synthase inhibition in the rat. van der Wilt, C.L., Marinelli, A., Pinedo, H.M., Cloos, J., Smid, K., van de Velde, C.J., Peters, G.J. Eur. J. Cancer (1995) [Pubmed]
  12. Sequential methotrexate/5-FU: FdUMP formation and TS inhibition in a transplantable rodent colon adenocarcinoma. Berne, M.H., Gustavsson, B.G., Almersjö, O., Spears, P.C., Frösing, R. Cancer Chemother. Pharmacol. (1986) [Pubmed]
  13. Biologically based dose-response modeling in developmental toxicology: biochemical and cellular sequelae of 5-fluorouracil exposure in the developing rat. Shuey, D.L., Lau, C., Logsdon, T.R., Zucker, R.M., Elstein, K.H., Narotsky, M.G., Setzer, R.W., Kavlock, R.J., Rogers, J.M. Toxicol. Appl. Pharmacol. (1994) [Pubmed]
  14. Determination of absorption characteristics of AG337, a novel thymidylate synthase inhibitor, using a perfused rat intestinal model. Hu, M., Roland, K., Ge, L., Chen, J., Li, Y., Tyle, P., Roy, S. Journal of pharmaceutical sciences. (1998) [Pubmed]
  15. Inhibition of thymidylate synthase after administration of doxifluridine in a transplantable colon carcinoma in the rat. Berne, M., Gustavsson, B., Almersjö, O., Spears, P., Sundström, E. Cancer Invest. (1988) [Pubmed]
  16. Prediction of antifolate efficacy in a rat sarcoma model. Li, W.W., Lin, J.T., Chang, Y.M., Schweitzer, B., Bertino, J.R. Int. J. Cancer (1991) [Pubmed]
  17. Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil. Matulic-Adamic, J., Takahashi, K., Chou, T.C., Gadler, H., Price, R.W., Reddy, A.R., Kalman, T.I., Watanabe, K.A. J. Med. Chem. (1988) [Pubmed]
  18. Effects of macrophage- and granulocyte-colony stimulating factors on thymidylate synthase and thymidine kinase activity in rat hematopoietic cells. Kudo, H., Suzuki, S., Kuwa, K., Nakayama, T., Maemura, M., Sakamoto, S. Haematologica (1997) [Pubmed]
  19. Pyrimidine metabolism during restorative brain growth after neonatal undernutrition in the rat. Weichsel, M.E., Clark, B.R. Pediatr. Res. (1977) [Pubmed]
  20. An isotopic assay of dUTPase activity based on coupling with thymidylate synthase. Gołos, B., Rode, W. Acta Biochim. Pol. (1999) [Pubmed]
  21. Inhibition of thymidylate synthase and thymidine kinase by okadaic acid in regenerating rat liver after partial hepatectomy. Tsukamoto, I., Yoshida, Y., Kitamura, Y., Nomura, S. Biochem. Pharmacol. (1996) [Pubmed]
  22. Latent Pneumocystis carinii infection in commercial rat colonies: comparison of inductive immunosuppressants plus histopathology, PCR, and serology as detection methods. Weisbroth, S.H., Geistfeld, J., Weisbroth, S.P., Williams, B., Feldman, S.H., Linke, M.J., Orr, S., Cushion, M.T. J. Clin. Microbiol. (1999) [Pubmed]
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