ArticlePhysical chemistry chemical physics : PCCP2015
The influence of active site conformations on the hydride transfer step of the thymidylate synthase reaction mechanism.
Article in Physical chemistry chemical physics : PCCP, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 15 citations in OpenAlex.
- Cooperative Conformational Transitions Underpin the Activation Heat Capacity in the Temperature Dependence of Enzyme Catalysis.ACS catalysis · 2024Article
- Transfer hydrogenations catalyzed by streptavidin-hosted secondary amine organocatalysts.Chemical communications (Cambridge, England) · 2021Article
- A host dTMP-bound structure of T4 phage dCMP hydroxymethylase mutant using an X-ray free electron laser.Scientific reports · 2019Article
- Article
- Experimental and Computational Studies Delineate the Role of Asparagine 177 in Hydride Transfer for E. coli Thymidylate Synthase.ACS catalysis · 2018Article
- Benchmarking Quantum Mechanics/Molecular Mechanics (QM/MM) Methods on the Thymidylate Synthase-Catalyzed Hydride Transfer.Journal of chemical theory and computation · 2017Article
- Widespread Perturbation of Function, Structure, and Dynamics by a Conservative Single-Atom Substitution in Thymidylate Synthase.Biochemistry · 2016Article
- Article
- Activation of Two Sequential H-transfers in the Thymidylate Synthase Catalyzed Reaction.ACS catalysis · 2015Article
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Authors and funding
3 authors at 3 institutions in 3 countries.
Funding
Abstract
The hydride transfer from C6 of tetrahydrofolate to the reaction's exocyclic methylene-dUMP intermediate is the rate limiting step in thymidylate synthase (TSase) catalysis. This step has been studied by means of QM/MM molecular dynamics simulations to generate the corresponding free energy surfaces. The use of two different initial X-ray structures has allowed exploring different conformational spaces and the existence of chemical paths with not only different reactivities but also different reaction mechanisms. The results confirm that this chemical conversion takes place preferentially via a concerted mechanism where the hydride transfer is conjugated to thiol-elimination from the product. The findings also confirm the labile character of the substrate-enzyme covalent bond established between the C6 of the nucleotide substrate and a conserved cysteine residue. The calculations also reproduce and rationalize a normal H/T 2° kinetic isotope effect measured for that step. From a computational point of view, the results demonstrate that the use of an incomplete number of coordinates to describe the real reaction coordinate can render biased results.
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