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Gene Review

TYMS  -  thymidylate synthetase

Homo sapiens

Synonyms: HST422, HsT422, OK/SW-cl.29, TMS, TS, ...
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Disease relevance of TYMS

  • These data suggest that genetic amplification of TYMS is a major mechanism of 5-FU resistance in vivo and have important implications for the management of colorectal cancer patients with recurrent disease [1].
  • Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1,021 days, P <0.01) [1].
  • The TYMS 6 base pair (bp)(-)6bp- (homozygous for 6bp deletion), IVS6 -68C>T, and 1053C>T genotypes (all in complete linkage disequilibrium) were all inversely associated with NHL (TYMS; odds ratio [OR] = 0.57; 0.34-0.94), particularly with diffuse large cell lymphoma (DLCL; OR = 0.29; 0.10-0.82) [2].
  • In conclusion, the TYMS polymorphisms, especially the TS3'UTR polymorphism, are associated with GC risk, especially the non-cardiac gastric cancer, and the TSER 2R and TS3'UTR 6 bp alleles may jointly play a role in the etiology of GC in the southern Chinese population [3].
  • Increased risks for NHL [odds ratio (OR), 1.48; 95% confidence intervals (CI), 1.12-1.97], and marginal zone lymphoma (OR, 3.38; 95% CI, 1.30-8.82) were associated with the TYMS 2R/3R variant [4].

Psychiatry related information on TYMS

  • In contrast, the patients in the TS H-group survived longer than those in the L-group when limited to stage I and MTHFR T-group (p = 0.052) [5].
  • Procedural learning during the serial reaction time task (SRTT) is used as a model of neural plasticity to illustrate the applications of TMS [6].
  • The effects of TMS on target absent trials are interpreted in terms of fronto-parietal connections and the role of frontal cortex in decision-making [7].
  • A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations [8].
  • 5 Hz repetitive TMS increases anticipatory motor activity in the human cortex [9].

High impact information on TYMS


Chemical compound and disease context of TYMS


Biological context of TYMS


Anatomical context of TYMS


Associations of TYMS with chemical compounds

  • In two of four patients, we identified amplification of an approximately 100-kb region on 18p11.32 that was of particular interest because it contained the gene encoding thymidylate synthase (TYMS), a molecular target of 5-FU [1].
  • The thymidylate synthase gene ( TYMS or TS) encodes a tightly regulated enzyme that catalyzes the conversion of deoxyuridylate to thymidylate, and contains a tandem repeat polymorphism that affects expression of the enzyme [23].
  • Our findings indicate that the TYMS 3R3R genotype is not a determinant of homocysteine in this sample of healthy young Caucasian adults from Northern Ireland [18].
  • In ALL, polymorphisms in the genes of folate metabolism are associated with poor prognosis, and the 3R3R TYMS polymorphism in particular is associated with methotrexate resistance [24].
  • Growth inhibition by MTX and FdUrd was increased and DHFR and TS activities and expression were correspondingly decreased in Rb transfectants of SaOS-2 cells [25].

Physical interactions of TYMS

  • Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex [26].
  • The DHFR-TS nucleic acid sequence contains no introns and the single 1563-bp open reading frame encodes a 179 residue N-terminal DHFR domain connected by a 55 amino acid junction peptide to a 287 residue C-terminal TS domain [27].
  • However, deletion of the two potential E2F binding sites in the human TS promoter did not prevent the virus-induced increase in TS promoter activity [28].
  • In this regard, thymidylate synthase interacts with the mRNAs of the c-myc onocogene and the p53 tumor suppressor gene [29].

Regulatory relationships of TYMS

  • The effect of MTX on TS activity and DNA synthesis were measured in stimulated normal PBMC and in PBMC obtained from 6 RA patients treated with oral MTX before and 2 hours after intake of their weekly MTX dose [30].
  • Relative mRNA amounts of DPD or TS were expressed as the ratios of targeted gene to glyceraldehyde-3-phosphate dehydrogenase reverse transcription-PCR products [17].
  • Finally, the CDK inhibitor roscovitine potentiated the cytotoxic activity of ZD9331 in both wt and p21Cip1-/- cells, strongly suggesting a role for p21Cip1-dependent CDK inhibition in cytotoxicity induced by thymidylate synthase inhibition [31].
  • p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex) [32].
  • Both inducible TS expression and the addition of exogenous thymidine (10 microM) blocked p53 and p21 induction by the antifolates but not by 5-FU in the M7TS90 cell line [33].

Other interactions of TYMS


Analytical, diagnostic and therapeutic context of TYMS

  • Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses [38].
  • Formalin-fixed, paraffin wax-embedded pre-operative biopsies (n = 14) and surgical resection specimens (n = 40) from patients with rectal carcinoma (clinical UICC stage II/III) receiving neo-adjuvant 5-FU-based chemoradiotherapy were studied for TS-, TP-, and DPD-gene expression by quantitative TaqMan real-time PCR after laser microdissection [34].
  • TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody [39].
  • TS and TP as measured by various assays were correlated with overall and disease-free survival in this patient group [16].
  • Moreover, intra-tumoural TS- and TP-gene expression in surgical rectal specimens after neo-adjuvant chemoradiotherapy correlates significantly with histopathological tumour regression when microdissection is applied [34].


  1. Digital karyotyping identifies thymidylate synthase amplification as a mechanism of resistance to 5-fluorouracil in metastatic colorectal cancer patients. Wang, T.L., Diaz, L.A., Romans, K., Bardelli, A., Saha, S., Galizia, G., Choti, M., Donehower, R., Parmigiani, G., Shih, I.e.M., Iacobuzio-Donahue, C., Kinzler, K.W., Vogelstein, B., Lengauer, C., Velculescu, V.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Skibola, C.F., Forrest, M.S., Coppedé, F., Agana, L., Hubbard, A., Smith, M.T., Bracci, P.M., Holly, E.A. Blood (2004) [Pubmed]
  3. Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case-control analysis. Zhang, Z., Xu, Y., Zhou, J., Wang, X., Wang, L., Hu, X., Guo, J., Wei, Q., Shen, H. Carcinogenesis (2005) [Pubmed]
  4. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Lightfoot, T.J., Skibola, C.F., Willett, E.V., Skibola, D.R., Allan, J.M., Coppede, F., Adamson, P.J., Morgan, G.J., Roman, E., Smith, M.T. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  5. Prognostic significance of the polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase gene in lung cancer. Takehara, A., Kawakami, K., Ohta, N., Oyama, K., Ota, Y., Oda, M., Watanabe, G. Anticancer Res. (2005) [Pubmed]
  6. Transcranial magnetic stimulation and neuroplasticity. Pascual-Leone, A., Tarazona, F., Keenan, J., Tormos, J.M., Hamilton, R., Catala, M.D. Neuropsychologia. (1999) [Pubmed]
  7. Temporal aspects of visual search studied by transcranial magnetic stimulation. Ashbridge, E., Walsh, V., Cowey, A. Neuropsychologia. (1997) [Pubmed]
  8. A double blind study showing that two weeks of daily repetitive TMS over the left or right temporoparietal cortex reduces symptoms in patients with schizophrenia who are having treatment-refractory auditory hallucinations. Lee, S.H., Kim, W., Chung, Y.C., Jung, K.H., Bahk, W.M., Jun, T.Y., Kim, K.S., George, M.S., Chae, J.H. Neurosci. Lett. (2005) [Pubmed]
  9. 5 Hz repetitive TMS increases anticipatory motor activity in the human cortex. Holler, I., Siebner, H.R., Cunnington, R., Gerschlager, W. Neurosci. Lett. (2006) [Pubmed]
  10. The catalytic mechanism and structure of thymidylate synthase. Carreras, C.W., Santi, D.V. Annu. Rev. Biochem. (1995) [Pubmed]
  11. Unstable DNA amplifications in methotrexate-resistant Leishmania consist of extrachromosomal circles which relocalize during stabilization. Beverley, S.M., Coderre, J.A., Santi, D.V., Schimke, R.T. Cell (1984) [Pubmed]
  12. Thymidylate synthase expression and response to neoadjuvant chemotherapy in patients with advanced head and neck cancer. Johnston, P.G., Mick, R., Recant, W., Behan, K.A., Dolan, M.E., Ratain, M.J., Beckmann, E., Weichselbaum, R.R., Allegra, C.J., Vokes, E.E. J. Natl. Cancer Inst. (1997) [Pubmed]
  13. Fluorouracil: active in ZD1694 (tomudex)-resistant cell lines with markedly elevated thymidylate synthase levels. Johnston, P.G., Behan, K.A., Allegra, C.J., Drake, J.C. J. Natl. Cancer Inst. (1995) [Pubmed]
  14. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Skibola, C.F., Smith, M.T., Hubbard, A., Shane, B., Roberts, A.C., Law, G.R., Rollinson, S., Roman, E., Cartwright, R.A., Morgan, G.J. Blood (2002) [Pubmed]
  15. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. Rustum, Y.M., Harstrick, A., Cao, S., Vanhoefer, U., Yin, M.B., Wilke, H., Seeber, S. J. Clin. Oncol. (1997) [Pubmed]
  16. Prognostic role of thymidylate synthase, thymidine phosphorylase/platelet-derived endothelial cell growth factor, and proliferation markers in colorectal cancer. van Triest, B., Pinedo, H.M., Blaauwgeers, J.L., van Diest, P.J., Schoenmakers, P.S., Voorn, D.A., Smid, K., Hoekman, K., Hoitsma, H.F., Peters, G.J. Clin. Cancer Res. (2000) [Pubmed]
  17. Combination of dihydropyrimidine dehydrogenase and thymidylate synthase gene expressions in primary tumors as predictive parameters for the efficacy of fluoropyrimidine-based chemotherapy for metastatic colorectal cancer. Ichikawa, W., Uetake, H., Shirota, Y., Yamada, H., Nishi, N., Nihei, Z., Sugihara, K., Hirayama, R. Clin. Cancer Res. (2003) [Pubmed]
  18. The thymidylate synthase tandem repeat polymorphism is not associated with homocysteine concentrations in healthy young subjects. Brown, K.S., Kluijtmans, L.A., Young, I.S., McNulty, H., Mitchell, L.E., Yarnell, J.W., Woodside, J.V., Boreham, C.A., McMaster, D., Murray, L., Strain, J.J., Whitehead, A.S. Hum. Genet. (2004) [Pubmed]
  19. A common insertion/deletion polymorphism of the thymidylate synthase (TYMS) gene is a determinant of red blood cell folate and homocysteine concentrations. Kealey, C., Brown, K.S., Woodside, J.V., Young, I., Murray, L., Boreham, C.A., McNulty, H., Strain, J.J., McPartlin, J., Scott, J.M., Whitehead, A.S. Hum. Genet. (2005) [Pubmed]
  20. Unfavourable expression of pharmacologic markers in mucinous colorectal cancer. Glasgow, S.C., Yu, J., Carvalho, L.P., Shannon, W.D., Fleshman, J.W., McLeod, H.L. Br. J. Cancer (2005) [Pubmed]
  21. Thymidine kinase, thymidylate synthase, and dihydropyrimidine dehydrogenase profiles of cell lines of the National Cancer Institute's Anticancer Drug Screen. Grem, J.L., Danenberg, K.D., Behan, K., Parr, A., Young, L., Danenberg, P.V., Nguyen, D., Drake, J., Monks, A., Allegra, C.J. Clin. Cancer Res. (2001) [Pubmed]
  22. Enzyme expression profiles suggest the novel tumor-activated fluoropyrimidine carbamate capecitabine (Xeloda) might be effective against papillary thyroid cancers of children and young adults. Patel, A., Pluim, T., Helms, A., Bauer, A., Tuttle, R.M., Francis, G.L. Cancer Chemother. Pharmacol. (2004) [Pubmed]
  23. Thymidylate synthase: a novel genetic determinant of plasma homocysteine and folate levels. Trinh, B.N., Ong, C.N., Coetzee, G.A., Yu, M.C., Laird, P.W. Hum. Genet. (2002) [Pubmed]
  24. Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Bolufer, P., Barragan, E., Collado, M., Cervera, J., L??pez, J.A., Sanz, M.A. Leuk. Res. (2006) [Pubmed]
  25. Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines. Li, W., Fan, J., Hochhauser, D., Banerjee, D., Zielinski, Z., Almasan, A., Yin, Y., Kelly, R., Wahl, G.M., Bertino, J.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  26. 5-fluorouracil: a pharmacological paradigm in the use of cytotoxics. Thomas, D.M., Zalcberg, J.R. Clin. Exp. Pharmacol. Physiol. (1998) [Pubmed]
  27. Potential antifolate resistance determinants and genotypic variation in the bifunctional dihydrofolate reductase-thymidylate synthase gene from human and bovine isolates of Cryptosporidium parvum. Vásquez, J.R., Goozé, L., Kim, K., Gut, J., Petersen, C., Nelson, R.G. Mol. Biochem. Parasitol. (1996) [Pubmed]
  28. Human cytomegalovirus infection induces cellular thymidylate synthase gene expression in quiescent fibroblasts. Gribaudo, G., Riera, L., Rudge, T.L., Caposio, P., Johnson, L.F., Landolfo, S. J. Gen. Virol. (2002) [Pubmed]
  29. The role of thymidylate synthase in cellular regulation. Chu, E., Allegra, C.J. Adv. Enzyme Regul. (1996) [Pubmed]
  30. The effects of low-dose methotrexate on thymidylate synthetase activity in human peripheral blood mononuclear cells. Hornung, N., Stengaard-Pedersen, K., Ehrnrooth, E., Ellingsen, T., Poulsen, J.H. Clinical and experimental rheumatology. (2000) [Pubmed]
  31. P21Cip1 is a critical mediator of the cytotoxic action of thymidylate synthase inhibitors in colorectal carcinoma cells. Geller, J.I., Szekely-Szucs, K., Petak, I., Doyle, B., Houghton, J.A. Cancer Res. (2004) [Pubmed]
  32. p53 and WAF1 are induced and Rb protein is hypophosphorylated during cell growth inhibition by the thymidylate synthase inhibitor ZD1694 (Tomudex). Yin, M.B., Voigt, W., Panadero, A., Vanhoefer, U., Frank, C., Pajovic, S., Azizkhan, J., Rustum, Y.M. Mol. Pharmacol. (1997) [Pubmed]
  33. The role of thymidylate synthase induction in modulating p53-regulated gene expression in response to 5-fluorouracil and antifolates. Longley, D.B., Boyer, J., Allen, W.L., Latif, T., Ferguson, P.R., Maxwell, P.J., McDermott, U., Lynch, M., Harkin, D.P., Johnston, P.G. Cancer Res. (2002) [Pubmed]
  34. Thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase expression, and histological tumour regression after 5-FU-based neo-adjuvant chemoradiotherapy in rectal cancer. Jakob, C., Aust, D.E., Meyer, W., Baretton, G.B., Schwabe, W., Häusler, P., Becker, H., Liersch, T. J. Pathol. (2004) [Pubmed]
  35. Biological markers as a predictor for response and prognosis of unresectable gastric cancer patients treated with 5-fluorouracil and cis-platinum. Boku, N., Chin, K., Hosokawa, K., Ohtsu, A., Tajiri, H., Yoshida, S., Yamao, T., Kondo, H., Shirao, K., Shimada, Y., Saito, D., Hasebe, T., Mukai, K., Seki, S., Saito, H., Johnston, P.G. Clin. Cancer Res. (1998) [Pubmed]
  36. The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer. Harpole, D.H., Moore, M.B., Herndon, J.E., Aloia, T., D'Amico, T.A., Sporn, T., Parr, A., Linoila, I., Allegra, C. Clin. Cancer Res. (2001) [Pubmed]
  37. Polymorphisms in the thymidylate synthase and methylenetetrahydrofolate reductase genes and sensitivity to the low-dose methotrexate therapy in patients with rheumatoid arthritis. Kumagai, K., Hiyama, K., Oyama, T., Maeda, H., Kohno, N. Int. J. Mol. Med. (2003) [Pubmed]
  38. Prognostic value of tumoral thymidylate synthase and p53 in metastatic colorectal cancer patients receiving fluorouracil-based chemotherapy: phenotypic and genotypic analyses. Etienne, M.C., Chazal, M., Laurent-Puig, P., Magné, N., Rosty, C., Formento, J.L., Francoual, M., Formento, P., Renée, N., Chamorey, E., Bourgeon, A., Seitz, J.F., Delpero, J.R., Letoublon, C., Pezet, D., Milano, G. J. Clin. Oncol. (2002) [Pubmed]
  39. Thymidylate synthase expression in advanced colorectal cancer predicts for response to raltitrexed. Farrugia, D.C., Ford, H.E., Cunningham, D., Danenberg, K.D., Danenberg, P.V., Brabender, J., McVicar, A.D., Aherne, G.W., Hardcastle, A., McCarthy, K., Jackman, A.L. Clin. Cancer Res. (2003) [Pubmed]
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