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Thymidylate synthesis is the terminal step in the sole de novo synthetic pathway to deoxythymidine monophosphate (dTMP),
a nucleotide essential for the synthesis of DNA. Thymidylate synthase (TS) catalyzes this crucial reaction. TS inhibition
stops DNA production, arresting the cell cycle and eventually leading to "thymineless" cell death. Flavin-dependent Thymidylate
synthase (FDTS) are encoded by the thy1/thyX gene and are not homologous to classical TS encoded by thyA and thyB genes.
FDTSs are essential for cell survival of many pathogenic organisms (Treponema pallidum (syphilis), Bacillus anthracis (anthrax),
Mycobacterium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy), Borrelia burgdorferi (Lyme disease), Helicobacter pilori
(gastric ulcer), Clostridium botulinum (botulism), Rickettsia prowazekii (epidemic typhus), and Chlamydia pneumoniae (pneumonia)
are FDTS family members). FDTSs provide a unique alternative for the development of antimicrobials capable of simultaneously
targeting a wide range of organisms with potential use as biological weapons. Thymidylate synthases use N5
folate) to reductively methylate 2?-deoxyuridine-5?-monophosphate (dUMP) producing dTMP. In contrast
to classical TSase where the cofactor CH2
folate provides both the H- and methylene, in the FDTS reaction the H- is provided
by the FADH2
folate is used only as a source for the methylene moiety. The absence of homology between FDTS and
classical thymidylate synthase offers the possibility of developing specific inhibitors for many pathogenic microbes including various
biowarfare agents. We have identified the folate binding site of the FDTS enzyme that will enable the design of inhibitors for use as
antimicrobial compounds against deadly microbes.
Irimpan Mathews works at SLAC, Stanford University as a Staff Scientist. He has around 20 years of experience in structural biology including
pharmaceutical industry. Main focus of his research is the mechanistic study of enzymatic reactions with an emphasis on structure-based drug design. He
has published more than 45 papers in reputed journals.
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