ArticleJournal of the American Chemical Society2014
Concerted versus stepwise mechanism in thymidylate synthase.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- FOXM1 induces therapy resistance and inhibits apoptosis in a variety of human cancers.Cell death & disease · 2026Review
- Discovery of 5'-Substituted 5-Fluoro-2'-deoxyuridine Monophosphate Analogs: A Novel Class of Thymidylate Synthase Inhibitors.ACS pharmacology & translational science · 2023Article
- Engineering an efficient and enantioselective enzyme for the Morita-Baylis-Hillman reaction.Nature chemistry · 2022Article
- Advanced Spectroscopy and APBS Modeling for Determination of the Role of His190 and Trp103 in Mouse Thymidylate Synthase Interaction with Selected dUMP Analogues.International journal of molecular sciences · 2021Article
- Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS).Molecules (Basel, Switzerland) · 2019Review
- Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer for E. coli Thymidylate Synthase.ACS catalysis · 2018Article
- Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Chemo-enzymatic synthesis of the exocyclic olefin isomer of thymidine monophosphate.Bioorganic & medicinal chemistry · 2018Article
- Loss of ABCB4 attenuates the caspase-dependent apoptosis regulating resistance to 5-Fu in colorectal cancer.Bioscience reports · 2018Article
- Article
- Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.Journal of chemical theory and computation · 2017Article
- Article
- Noncovalent Intermediate of Thymidylate Synthase: Fact or Fiction?Journal of the American Chemical Society · 2016Article
- 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
- The influence of active site conformations on the hydride transfer step of the thymidylate synthase reaction mechanism.Physical chemistry chemical physics : PCCP · 2015Article
- Activation of Two Sequential H-transfers in the Thymidylate Synthase Catalyzed Reaction.ACS catalysis · 2015Article
- Role of dynamics in enzyme catalysis: substantial versus semantic controversies.Accounts of chemical research · 2015Review
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4 authors at 1 institution in 1 country.
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Abstract
Thymidylate synthase (TSase) catalyzes the intracellular de novo formation of thymidylate (a DNA building block) in most living organisms, making it a common target for chemotherapeutic and antibiotic drugs. Two mechanisms have been proposed for the rate-limiting hydride transfer step in TSase catalysis: a stepwise mechanism in which the hydride transfer precedes the cleavage of the covalent bond between the enzymatic cysteine and the product and a mechanism where both happen concertedly. Striking similarities between the enzyme-bound enolate intermediates formed in the initial and final step of the reaction supported the first mechanism, while QM/MM calculations favored the concerted mechanism. Here, we experimentally test these two possibilities using secondary kinetic isotope effect (KIE), mutagenesis study, and primary KIEs. The findings support the concerted mechanism and demonstrate the critical role of an active site arginine in substrate binding, activation of enzymatic nucleophile, and the hydride transfer studied here. The elucidation of this reduction/substitution sheds light on the critical catalytic step in TSase and may aid future drug or biomimetic catalyst design.
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