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Updated: Jul 6, 2026

Extremely Rapid and Specific Metabolic Labelling of RNA In Vivo with 4-Thiouracil (Ers4tU)
Published on: August 22, 2019
Constrained dansyl derivatives reveal bacterial specificity of highly conserved thymidylate synthases
Sanuele Calò1, Donatella Tondi, Stefania Ferrari
1Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia via Campi 183, 41100 Modena, Italy.
Abstract:
The elucidation of the structural/functional specificities of highly conserved enzymes remains a challenging area of investigation, and enzymes involved in cellular replication are important targets for functional studies and drug discovery. Thymidylate synthase (TS, ThyA) governs the synthesis of thymidylate for use in DNA synthesis. The present study focused on Lactobacillus casei TS (LcTS) and Escherichia coli TS (EcTS), which exhibit 50 % sequence identity and strong folding similarity. We have successfully designed and validated a chemical model in which linear, but not constrained, dansyl derivatives specifically complement the LcTS active site. Conversely, chemically constrained dansyl derivatives showed up to 1000-fold improved affinity for EcTS relative to the inhibitory activity of linear derivatives. This study demonstrates that the accurate design of small ligands can uncover functional features of highly conserved enzymes.
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