ArticleJournal of the American Chemical Society2015
Bacterial Thymidylate Synthase Binds Two Molecules of Substrate and Cofactor without Cooperativity.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Disordered N-Terminal Tail "Wags the Dog" in Human Thymidylate Synthase.Biochemistry · 2026Article
- Advances in uncovering the mechanisms of macromolecular conformational entropy.Nature chemical biology · 2025Review
- Isolation and characterization of 24 phages infecting the plant growth-promoting rhizobacterium Klebsiella sp. M5al.PloS one · 2025Article
- Article
- Early Life Stage Folic Acid Deficiency Delays the Neurobehavioral Development and Cognitive Function of Rat Offspring by Hindering De Novo Telomere Synthesis.International journal of molecular sciences · 2022Article
- Positive Cooperativity in Substrate Binding by Human Thymidylate Synthase.Biophysical journal · 2019Article
- Inter-Active Site Communication Mediated by the Dimer Interface β-Sheet in the Half-the-Sites Enzyme, Thymidylate Synthase.Biochemistry · 2019Article
- Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS).Molecules (Basel, Switzerland) · 2019Review
- Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors.Molecules (Basel, Switzerland) · 2019Article
- Structural Comparison ofMolecules (Basel, Switzerland) · 2019Article
- A Single Mutation Traps a Half-Sites Reactive Enzyme in Midstream, Explaining Asymmetry in Hydride Transfer.Biochemistry · 2018Article
- A novel thymidylate synthase from thePeerJ · 2018Article
- Thermodynamic and NMR Assessment of Ligand Cooperativity and Intersubunit Communication in Symmetric Dimers: Application to Thymidylate Synthase.Frontiers in molecular biosciences · 2018Review
- Widespread Perturbation of Function, Structure, and Dynamics by a Conservative Single-Atom Substitution in Thymidylate Synthase.Biochemistry · 2016Article
- Chemical shift imprint of intersubunit communication in a symmetric homodimer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
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3 authors.
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Abstract
Thymidylate synthase (TSase) is a clinically important enzyme because it catalyzes synthesis of the sole de novo source of deoxy-thymidylate. Without this enzyme, cells die a "thymineless death" since they are starved of a crucial DNA synthesis precursor. As a drug target, TSase is well studied in terms of its structure and reaction mechanism. An interesting mechanistic feature of dimeric TSase is that it is "half-the-sites reactive", which is a form of negative cooperativity. Yet, the basis for this is not well-understood. Some experiments point to cooperativity at the binding steps of the reaction cycle as being responsible for the phenomenon, but the literature contains conflicting reports. Here we use ITC and NMR to resolve these inconsistencies. This first detailed thermodynamic dissection of multisite binding of dUMP to E. coli TSase shows the nucleotide binds to the free and singly bound forms of the enzyme with nearly equal affinity over a broad range of temperatures and in multiple buffers. While small but significant differences in ΔC°P for the two binding events show that the active sites are not formally equivalent, there is little-to-no allostery at the level of ΔG°bind. In addition NMR titration data reveal that there is minor intersubunit cooperativity in formation of a ternary complex with the mechanism based inhibitor, 5F-dUMP, and cofactor. Taken together, the data show that functional communication between subunits is minimal for both binding steps of the reaction coordinate.
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