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Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and

Cecilia Pozzi1, Ludovica Lopresti2, Giusy Tassone3

  • 1Department of Biotechnology, Chemistry and Pharmacy⁻Department of Excellence 2018-2020, University of Siena, via Aldo Moro 2, 53100 Siena, Italy. pozzi4@unisi.it.

Molecules (Basel, Switzerland)
|April 28, 2019
PubMed

Insights

Thymidylate synthases are crucial for DNA synthesis in bacteria. This review explores recent advances in understanding folate-dependent thymidylate synthase (TS) and flavin-dependent TS (FDTS) mechanisms and drug development.

Area of Science:

  • Biochemistry
  • Enzymology
  • Molecular Biology

Background:

  • Thymidylate synthases (TS and FDTS) are essential bacterial enzymes for DNA synthesis.
  • These enzymes, crucial for cell survival and proliferation, utilize distinct cofactors and catalytic mechanisms.
  • Understanding their action is key for developing novel antibacterial strategies.

Purpose of the Study:

  • To review recent structural and functional characterizations of bacterial TS and FDTS.
  • To summarize current knowledge on the mechanisms of action for both enzyme families.
  • To highlight progress in developing inhibitors targeting these enzymes in human pathogens.

Main Methods:

  • Literature review of recent structural and functional studies.
  • Analysis of mechanistic insights into bacterial TS and FDTS.
  • Summary of inhibitor development for antibacterial drug discovery.

Main Results:

  • Recent revisions of TS and FDTS mechanisms offer new antibacterial drug development perspectives.
  • Elucidated catalytic details and addressed controversies surrounding bacterial TS half-site reactivity.
  • Clarified aspects of flavin regeneration in FDTS.

Conclusions:

  • Advances in understanding bacterial TS and FDTS mechanisms are crucial for targeting essential enzymes.
  • Ongoing research into enzyme mechanisms and inhibitor development holds promise for combating bacterial infections.
  • Further investigation is needed to fully resolve remaining mechanistic questions.
Keywords:
flavin-dependent thymidylate synthasehalf-site reactivityinhibitorsmechanism of actionselectivitythymidylate synthase

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