ArticleJournal of the American Chemical Society2013
Mg2+ binds to the surface of thymidylate synthase and affects hydride transfer at the interior active site.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 23 citations in OpenAlex.
- Mechanistic Insights into SAM-Dependent Methyltransferases: A Review of Computational Approaches.International journal of molecular sciences · 2025Review
- The genetic landscape of a metabolic interaction.Nature communications · 2024Article
- The Catalysis Mechanism ofInternational journal of molecular sciences · 2024Article
- MgACS catalysis · 2020Article
- Inter-Active Site Communication Mediated by the Dimer Interface β-Sheet in the Half-the-Sites Enzyme, Thymidylate Synthase.Biochemistry · 2019Article
- Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer for E. coli Thymidylate Synthase.ACS catalysis · 2018Article
- Article
- Widespread Perturbation of Function, Structure, and Dynamics by a Conservative Single-Atom Substitution in Thymidylate Synthase.Biochemistry · 2016Article
- Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?Journal of the American Chemical Society · 2016Article
- Article
- Preserved hydride transfer mechanism in evolutionarily divergent thymidylate synthases.Current topics in biochemical research · 2016Article
- Examinations of the Chemical Step in Enzyme Catalysis.Methods in enzymology · 2016Article
- Role of long-range protein dynamics in different thymidylate synthase catalyzed reactions.International journal of molecular sciences · 2015Article
- Role of dynamics in enzyme catalysis: substantial versus semantic controversies.Accounts of chemical research · 2015Review
- Linking protein motion to enzyme catalysis.Molecules (Basel, Switzerland) · 2015Review
- Kinetic isotope effects as a probe of hydrogen transfers to and from common enzymatic cofactors.Archives of biochemistry and biophysics · 2014Review
- Development and binding mode assessment of N-[4-[2-propyn-1-yl[(6S)-4,6,7,8-tetrahydro-2-(hydroxymethyl)-4-oxo-3H-cyclopenta[g]quinazolin-6-yl]amino]benzoyl]-l-γ-glutamyl-D-glutamic acid (BGC 945), a novel thymidylate synthase inhibitor that targets tumor cells.Journal of medicinal chemistry · 2013Article
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8 authors at 4 institutions in 1 country.
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Abstract
Thymidylate synthase (TSase) produces the sole intracellular de novo source of thymidine (i.e., the DNA base T) and thus is a common target for antibiotic and anticancer drugs. Mg(2+) has been reported to affect TSase activity, but the mechanism of this interaction has not been investigated. Here we show that Mg(2+) binds to the surface of Escherichia coli TSase and affects the kinetics of hydride transfer at the interior active site (16 Å away). Examination of the crystal structures identifies a Mg(2+) near the glutamyl moiety of the folate cofactor, providing the first structural evidence for Mg(2+) binding to TSase. The kinetics and NMR relaxation experiments suggest that the weak binding of Mg(2+) to the protein surface stabilizes the closed conformation of the ternary enzyme complex and reduces the entropy of activation on the hydride transfer step. Mg(2+) accelerates the hydride transfer by ~7-fold but does not affect the magnitude or temperature dependence of the intrinsic kinetic isotope effect. These results suggest that Mg(2+) facilitates the protein motions that bring the hydride donor and acceptor together, but it does not change the tunneling ready state of the hydride transfer. These findings highlight how variations in cellular Mg(2+) concentration can modulate enzyme activity through long-range interactions in the protein, rather than binding at the active site. The interaction of Mg(2+) with the glutamyl tail of the folate cofactor and nonconserved residues of bacterial TSase may assist in designing antifolates with polyglutamyl substitutes as species-specific antibiotic drugs.
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