The influence of active site conformations on the hydride transfer step of the thymidylate synthase reaction mechanism

Literature Information

Publication Date 2015-04-02
DOI 10.1039/C5CP01239B
Impact Factor 3.676
Authors

Amnon Kohen, Vicent Moliner


View Original

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.

Related Literature

Improving the antifouling property of polysulfone ultrafiltration membrane by incorporation of isocyanate-treated graphene oxide

Haiyang Zhao, Liguang Wu, Zhijun Zhou, Lin Zhang, Huanlin Chen

2013-04-08 Paper

DOI: 10.1039/C3CP50955A

Screening metal–organic frameworks for selective noble gasadsorption in air: effect of pore size and framework topology

Marie V. Parkes, Chad L. Staiger, John J. Perry IV, Mark D. Allendorf, Jeffery A. Greathouse

2013-05-03 Paper

DOI: 10.1039/C3CP50774B

Contributions of magnetic properties in epitaxial copper-doped ZnO

Hongyan Liu, Fei Zeng, Shuang Gao, Guangyue Wang, Cheng Song, Feng Pan

2013-07-03 Paper

DOI: 10.1039/C3CP51894A

Orbital-based insights into parallel-displaced and twisted conformations in π–π interactions

Patricia B. Lutz, Craig A. Bayse

2013-03-21 Paper

DOI: 10.1039/C3CP51077H

Copper(ii)–human amylin complex protects pancreatic cells from amylin toxicity‡

Elizabeth C. Lee, Emmeline Ha, Sanghamitra Singh, Linda Legesse, Sana Ahmad, Elena Karnaukhova, Robert P. Donaldson, Aleksandar M. Jeremic

2013-06-13 Paper

DOI: 10.1039/C3CP44542A

Antioxidant activity of propyl gallate in aqueous and lipid media: a theoretical study

Manuel E. Medina, Cristina Iuga, Juan Raúl Alvarez-Idaboy

2013-06-04 Paper

DOI: 10.1039/C3CP51644J

Excitation energies of a water-bridged twisted retinal structure in the bacteriorhodopsin proton pump: a theoretical investigation

Tino Wolter, Kai Welke, Prasad Phatak, Ana-Nicoleta Bondar, Marcus Elstner

2013-05-24 Paper

DOI: 10.1039/C3CP44280B

Linking electronic and molecular structure: insight into aqueous chloride solvation

Ling Ge, Leonardo Bernasconi, Patricia Hunt

2013-05-31 Paper

DOI: 10.1039/C3CP50652E

Atomic insight into copper nanostructures nucleation on bending graphene

Yezeng He, Hui Li, Yunfang Li, Kun Zhang, Yanyan Jiang, Xiufang Bian

2013-04-10 Paper

DOI: 10.1039/C3CP50876E

Synthesis and characterization of the crystal structure and magnetic properties of the hydroxyfluoride MnF2−x(OH)x (x ∼ 0.8)

Hamdi Ben Yahia, Masahiro Shikano, Hironori Kobayashi, Maxim Avdeev, Samuel Liu, Chris D. Ling

2013-06-10 Paper

DOI: 10.1039/C3CP50740H

You might also like

Compound Q&A

What are the main uses of 1H-Indazole-6-carbonitrile (CAS: 141290-59-7)?

1H-Indazole-6-carbonitrile finds applications in pharmaceuticals, where it serve...

141290-59-71H-Indazole-6-carbon...
Compound Q&A

How should waste containing Dioctyl (2E)-2-butenedioate (CAS: 2997-85-5) be handled?

Waste containing Dioctyl (2E)-2-butenedioate (CAS: 2997-85-5) should be collecte...

2997-85-5Dioctyl (2E)-2-buten...
Compound Q&A

What industries use Sodium [(1,2-benzoxazol-3-ylmethyl)sulfonyl]azanide (CAS: 68291-98-5)?

Sodium [(1,2-benzoxazol-3-ylmethyl)sulfonyl]azanide is primarily used in pharmac...

68291-98-5Sodium [(1,2-benzoxa...
Compound Q&A

Are there alternatives to Dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-pyridinedicarboxylate (CAS: 741709-66-0) in synthesis?

Dimethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,6-pyridinedicarboxyla...

741709-66-0Dimethyl 4-(4,4,5,5-...
Compound Q&A

How should waste containing 2-Fluoro-6-hydrazinopyridine (CAS: 80714-39-2) be handled?

Waste containing 2-Fluoro-6-hydrazinopyridine (CAS: 80714-39-2) should be manage...

80714-39-22-Fluoro-6-hydrazino...
Compound Q&A

What is 6-Formyl-2-pyridinecarboxylic acid (CAS: 499214-11-8)?

6-Formyl-2-pyridinecarboxylic acid is an organic compound with the molecular for...

499214-11-86-Formyl-2-pyridinec...
900874-91-13-(3,4-dimethoxyphen...
Compound Q&A

How is 9H-Tribenzo[b,d,f]azepine (CAS: 29875-73-8) typically synthesized?

9H-Tribenzo[b,d,f]azepine is typically synthesized via a multi-step process invo...

29875-73-89H-Tribenzo[b,d,f]az...
Compound Q&A

How is 1-Cyclopropyl-7-ethoxy-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (CAS: 1797982-51-4) typically synthesized?

1-Cyclopropyl-7-ethoxy-6-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxyli...

1797982-51-41-Cyclopropyl-7-etho...
Compound Q&A

How should waste containing Methyl 3-oxo-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (CAS: 671820-52-3) be handled?

Waste containing Methyl 3-oxo-1,2,3,4-tetrahydro-6-quinoxalinecarboxylate (CAS: ...

671820-52-3Methyl 3-oxo-1,2,3,4...

Source Journal

Physical Chemistry Chemical Physics

Physical Chemistry Chemical Physics
CiteScore: 5.5
Self-citation Rate: 10.3%
Articles per Year: 3036

Physical Chemistry Chemical Physics (PCCP) is an international journal co-owned by 19 physical chemistry and physics societies from around the world. This journal publishes original, cutting-edge research in physical chemistry, chemical physics and biophysical chemistry. To be suitable for publication in PCCP, articles must include significant innovation and/or insight into physical chemistry; this is the most important criterion that reviewers and Editors will judge against when evaluating submissions. The journal has a broad scope and welcomes contributions spanning experiment, theory, computation and data science. Topical coverage includes spectroscopy, dynamics, kinetics, statistical mechanics, thermodynamics, electrochemistry, catalysis, surface science, quantum mechanics, quantum computing and machine learning. Interdisciplinary research areas such as polymers and soft matter, materials, nanoscience, energy, surfaces/interfaces, and biophysical chemistry are welcomed if they demonstrate significant innovation and/or insight into physical chemistry. Joined experimental/theoretical studies are particularly appreciated when complementary and based on up-to-date approaches.

Recommended Compounds

Recommended Suppliers

Disclaimer
This page provides academic journal information for reference and research purposes only. We are not affiliated with any journal publishers and do not handle publication submissions. For publication-related inquiries, please contact the respective journal publishers directly.
If you notice any inaccuracies in the information displayed, please contact us at support@chemtradehub.com. We will promptly review and address your concerns.