ArticleBiochemistry2007
Cooperative inhibition of human thymidylate synthase by mixtures of active site binding and allosteric inhibitors.
Article in Biochemistry, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 36 citations in OpenAlex.
- Disordered N-Terminal Tail "Wags the Dog" in Human Thymidylate Synthase.Biochemistry · 2026Article
- Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.ACS pharmacology & translational science · 2023Article
- 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
- 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
- Biomolecular study of human thymidylate synthase conformer-selective inhibitors: New chemotherapeutic approach.PloS one · 2018Article
- Crystal structure of the active form of native human thymidylate synthase in the absence of bound substrates.Acta crystallographica. Section F, Structural biology communications · 2017Article
- Chemical shift imprint of intersubunit communication in a symmetric homodimer.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Inhibitory effects of neochamaejasmin B on P-glycoprotein in MDCK-hMDR1 cells and molecular docking of NCB binding in P-glycoprotein.Molecules (Basel, Switzerland) · 2015Article
- Alanine mutants of the interface residues of human thymidylate synthase decode key features of the binding mode of allosteric anticancer peptides.Journal of medicinal chemistry · 2015Article
- Analysis of mRNA recognition by human thymidylate synthase.Bioscience reports · 2014Article
- Virtual screening reveals allosteric inhibitors of the Toxoplasma gondii thymidylate synthase-dihydrofolate reductase.Bioorganic & medicinal chemistry letters · 2014Article
- Selective peptide inhibitors of bifunctional thymidylate synthase-dihydrofolate reductase from Toxoplasma gondii provide insights into domain-domain communication and allosteric regulation.Protein science : a publication of the Protein Society · 2013Article
- Protein-protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Evolution of metamorphism in thymidylate synthases within the primate lineages.Journal of molecular evolution · 2011Article
- Human thymidylate synthase with loop 181-197 stabilized in an inactive conformation: ligand interactions, phosphorylation, and inhibition profiles.Protein science : a publication of the Protein Society · 2011Article
- Structures of human thymidylate synthase R163K with dUMP, FdUMP and glutathione show asymmetric ligand binding.Acta crystallographica. Section D, Biological crystallography · 2011Article
- Variants of human thymidylate synthase with loop 181-197 stabilized in the inactive conformation.Protein science : a publication of the Protein Society · 2009Article
- The R163K mutant of human thymidylate synthase is stabilized in an active conformation: structural asymmetry and reactivity of cysteine 195.Biochemistry · 2008Article
- Role of an invariant lysine residue in folate binding on Escherichia coli thymidylate synthase: calorimetric and crystallographic analysis of the K48Q mutant.The international journal of biochemistry & cell biology · 2008Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Thymidylate synthase (TS) is a target in the chemotherapy of colorectal cancer and some other neoplasms. It catalyzes the transfer of a methyl group from methylenetetrahydrofolate to dUMP to form dTMP. On the basis of structural considerations, we have introduced 1,3-propanediphosphonic acid (PDPA) as an allosteric inhibitor of human TS (hTS); it is proposed that PDPA acts by stabilizing an inactive conformer of loop 181-197. Kinetic studies showed that PDPA is a mixed (noncompetitive) inhibitor versus dUMP. In contrast, versus methylenetrahydrofolate at concentrations lower than 0.25 microM, PDPA is an uncompetitive inhibitor, while at PDPA concentrations higher than 1 microM the inhibiton is noncompetive, as expected. At the concentrations corresponding to uncompetitive inhibition, PDPA shows positive cooperativity with an antifolate inhibitor, ZD9331, which binds to the active conformer. PDPA binding leads to the formation of hTS tetramers, but not higher oligomers. These data are consistent with a model in which hTS exists preferably as an asymmetric dimer with one subunit in the active conformation of loop 181-197 and the other in the inactive conformation.
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Registered trials
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