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SLAC National Accelerator Laboratory

Closing in on a Means to Inhibit FDTS Enzymes
SSRL Science Summary - September 2012

Figure 1.
The Active site view of the FDTS enzyme in complex with FAD, dUMP and folate derivatives.

Flavin-dependant thymidylate synthases (FDTSs) are a recently identified family of thymidylate synthases that employ a novel mechanism for the thymidylate synthase reaction. These enzymes convert 2'-deoxyuridine-5'-monophosphate (dUMP) to 2'-deoxythymine-5'-monophosphate (dTMP), a reaction crucial for the survival of the organism. Since FDTS enzymes are mainly found in very pathogenic microbes, including the pathogens causing leprosy, botulism, diarrhea, anthrax, pneumonia, syphilis, and more, the FDTS enzyme is an attractive target for antibiotic drugs, but until recently researchers had not been able to successfully characterize any crystal structures with folates, due to difficulties in crystallizing a complex containing methylenetetrahydrofolate. This limited understanding of the molecular mechanism and the scope of drug design for these enzymes.

A team of researchers from SSRL and the University of Iowa used SSRL's Beam Lines 9-2 and 12-2 to uncover the folate binding site in FDTS. They solved high-resolution structures of the FDTS enzyme with methylenetetrahydrofolate and the anticancer drugs tomudex and leucovorin. Their study was published in the September 10 online edition of the Proceedings of the National Academy of Sciences.

These findings will likely facilitate further elucidation of FDTS's mechanism and the design of structure-based inhibitors as potential leads to new antimicrobial drugs.

Primary Citation

Folate binding site of flavin-dependent thymidylate synthase. Koehn, E.M., Perissinotti, L.L., Moghram. S., Prabhakar, A., Lesley, S.A., Mathews, I.I., and Kohen, A. Proc. Natl. Acad. Sci. USA,109, 15722 (2012) doi/10.1073/pnas.1206077109

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Irimpan Mathews (SSRL) and Amnon Kohen (University of Iowa)

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