Thymidylate Synthase and Fluorouracil
A knowledge of the catalytic mechanism of thymidylate synthase (TS), and its inhibition by 5-fluorodeoxyuridylate (FdUMP) was instrumental in developing the FUra-CF combination for cancer chemotherapy. The generation of the ideas which led to the current combination cleary demonstrates the importance of a fundamental knowledge of the interactions of inhibitors with their targets, and of how basic studies can be translated to clinical practice. The history of the development of the FUra-CF combination is a paradigm for the rational development of chemotherapeutic regimens. This report summarizes current knowledge of (a) the enzymology of the interaction of TS with FdUMP, (b) the 3-dimensional structure of TS, and (c) the effect of FUra on tRNA-uracil methyltranferase. Also, we suggest a possible molecular mechanism for the RNA effects of FUra.
KeywordsCarbon Unit Covalent Complex Covalent Adduct Covalent Bond Formation Pyrimidine Nucleotide Biosynthesis
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