C O N T E N T S
Thymidylate synthase (TS), a central enzyme in folate metabolism exists as several polymorphisms. Functional polymorphisms in this gene? may affect carcinogenesis via effects on nucleotide synthesis, particularly if such genetic variation is combined with low folate or coenzymes of folate metabolism (vitamin B12 and B6).
A repeat polymorphism in the TS promoter enhancer region (2rpt versus 3rpt of 28 bp) is associated with decreased expression, and a 6-bp deletion in the 3'untranslated region may affect RNA stability. This repeat polymorphism has been reported among Japanese individuals (allele frequency 19%), but has not been investigated in previous epidemiologic research.
TS catalyzes the final step in the de novo synthesis of deoxy-thymidine monophosphate (dTMP) using the substrate, dUMP, and a cofactor, [5,10-methylenetetrahydrofolate reductase (MTHFR)? 5,10-methylene tetrahydrofolate]. Because of its essential role in DNA? replication, human TS is an anticancer drug target and TS from infectious pathogens are infectious disease drug targets.
TS is the limiting irreversible step in de novo DNA, catalyzing the conversion of dUMP to dTMP. It is the target for the widely used anticancer agent 5-fluorouracil (5-FU), which is active against solid tumors like breast, head and neck and colon cancers. Increased TS levels in tumors are associated with resistance to chemotherapy with 5-FU. In addition, TS expression has been shown to be an independent prognostic factor in several cancers.
Thymidylate Synthase Promoter Polymorphism, Interaction with Folate Intake, and Risk of Colorectal Adenomas
Cancer Research 62, 3361-3364, June 15, 2002
Cornelia M. Ulrich, Jeannette Bigler, Roberd Bostick, Lisa Fosdick and John D. Potter
Polymorphisms of thymidylate synthase in the 5'- and 3'-untranslated regions associated with risk of gastric cancer in South China: a case–control analysis
Carcinogenesis 2005 26(10):1764-1769;
Zhengdong Zhang, Yaochu Xu, Jianwei Zhou, Xinru Wang, Liwei Wang, Xu Hu, Jiangtao Guo, Qingyi Wei and Hongbing Shen
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