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Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS)

Department of Biotechnology, Chemistry and Pharmacy–Department of Excellence 2018-2020, University of Siena, via Aldo Moro 2, 53100 Siena, Italy
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Molecules 2019, 24(8), 1638; https://doi.org/10.3390/molecules24081638
Received: 31 March 2019 / Revised: 18 April 2019 / Accepted: 25 April 2019 / Published: 25 April 2019
(This article belongs to the Section Chemical Biology)
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Abstract

In cells, thymidylate synthases provide the only de novo source of 2′-deoxythymidine-5′-monophosphate (dTMP), required for DNA synthesis. The activity of these enzymes is pivotal for cell survival and proliferation. Two main families of thymidylate synthases have been identified in bacteria, folate-dependent thymidylate synthase (TS) and flavin-dependent TS (FDTS). TS and FDTS are highly divergent enzymes, characterized by exclusive catalytic mechanisms, involving different sets of cofactors. TS and FDTS mechanisms of action have been recently revised, providing new perspectives for the development of antibacterial drugs targeting these enzymes. Nonetheless, some catalytic details still remain elusive. For bacterial TSs, half-site reactivity is still an open debate and the recent evidences are somehow controversial. Furthermore, different behaviors have been identified among bacterial TSs, compromising the definition of common mechanisms. Moreover, the redox reaction responsible for the regeneration of reduced flavin in FDTSs is not completely clarified. This review describes the recent advances in the structural and functional characterization of bacterial TSs and FDTSs and the current understanding of their mechanisms of action. Furthermore, the recent progresses in the development of inhibitors targeting TS and FDTS in human pathogenic bacteria are summarized. View Full-Text
Keywords: thymidylate synthase; flavin-dependent thymidylate synthase; mechanism of action; half-site reactivity; inhibitors; selectivity thymidylate synthase; flavin-dependent thymidylate synthase; mechanism of action; half-site reactivity; inhibitors; selectivity
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Pozzi, C.; Lopresti, L.; Tassone, G.; Mangani, S. Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS). Molecules 2019, 24, 1638.

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