Closing in on a Means to Inhibit FDTS Enzymes
SSRL Science
Summary - September 2012
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.1206077109Related Links
- Full Science Highlight
- PDF Version
- SLAC Today: Team Uses SSRL to Decipher Structural Details of Deadly Enzyme
