ArticleBiochemistry2013
QM/MM calculations suggest a novel intermediate following the proton abstraction catalyzed by thymidylate synthase.
Article in Biochemistry, 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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Who cites it
17 citing papers in PubMed, 22 citations in OpenAlex.
- Caught in Action: X-ray Structure of Thymidylate Synthase with Noncovalent Intermediate Analog.Biochemistry · 2021Article
- 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
- 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
- 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
- The general base in the thymidylate synthase catalyzed proton abstraction.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
- Linking protein motion to enzyme catalysis.Molecules (Basel, Switzerland) · 2015Review
- Substrate activation in flavin-dependent thymidylate synthase.Journal of the American Chemical Society · 2014Article
- Concerted versus stepwise mechanism in thymidylate synthase.Journal of the American Chemical Society · 2014Article
- Mg2+ binds to the surface of thymidylate synthase and affects hydride transfer at the interior active site.Journal of the American Chemical Society · 2013Article
- Isotope effects as probes for enzyme catalyzed hydrogen-transfer reactions.Molecules (Basel, Switzerland) · 2013Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
The cleavage of covalent C-H bonds is one of the most energetically demanding, yet biologically essential, chemical transformations. Two C-H bond cleavages are involved in the reaction catalyzed by thymidylate synthase (TSase), which provides the sole de novo source of thymidylate (i.e., the DNA base T) for most organisms. Our QM/MM free energy calculations show that the C-H → O proton transfer has three transition states that are energetically similar but structurally diverse. These characteristics are different from our previous calculation results on the C-H → C hydride transfer, providing an explanation for differences in temperature dependences of KIEs on these two C-H bond activation steps. The calculations also suggest that the traditionally proposed covalent bond between the protein and substrate (the C6-S bond) is very labile during the multistep catalytic reaction. Collective protein motions not only assist cleavage of the C6-S bond to stabilize the transition state of the proton transfer step but also rearrange the H-bond network at the end of this step to prepare the active site for subsequent chemical steps. These computational results illustrate functionalities of specific protein residues that reconcile many previous experimental observations and provide guidance for future experiments to examine the proposed mechanisms. The synchronized conformational changes in the protein and ligands observed in our simulations demonstrate participation of protein motions in the reaction coordinate of enzymatic reactions. Our computational findings suggest the existence of new reaction intermediates not covalently bound to TSase, which may lead to a new class of drugs targeting DNA biosynthesis.
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