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Constrained Dansyl Derivatives Reveal Bacterial Specificity of Highly Conserved Thymidylate Synthases
Author(s) -
Calò Sanuele,
Tondi Donatella,
Ferrari Stefania,
Venturelli Alberto,
Ghelli Stefano,
Costi Maria Paola
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700524
Subject(s) - thymidylate synthase , lactobacillus casei , biochemistry , enzyme , escherichia coli , biology , computational biology , chemistry , stereochemistry , genetics , gene , fluorouracil , chemotherapy , fermentation
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.