Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools
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Other documents of the author: Kholodar, Svetlana; Ghosh, Ananda K; Świderek, Katarzyna; Moliner, Vicent; Kohen, Amnon
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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Title
Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational toolsDate
2018Publisher
National Academy of SciencesISSN
0027-8424; 1091-6490Bibliographic citation
KHOLODAR, Svetlana A., et al. Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools. Proceedings of the National Academy of Sciences, 2018, vol. 115, no 41, p. 10311-10314.Type
info:eu-repo/semantics/articlePublisher version
https://www.pnas.org/content/115/41/10311Version
info:eu-repo/semantics/publishedVersionAbstract
Thymidylate synthase was one of the most studied enzymes due
to its critical role in molecular pathogenesis of cancer. Nevertheless, many atomistic details of its chemical mechanism remain
unknown or debated, thereby ... [+]
Thymidylate synthase was one of the most studied enzymes due
to its critical role in molecular pathogenesis of cancer. Nevertheless, many atomistic details of its chemical mechanism remain
unknown or debated, thereby imposing limits on design of novel
mechanism-based anticancer therapeutics. Here, we report unprecedented isolation and characterization of a previously proposed intact noncovalent bisubstrate intermediate formed in the
reaction catalyzed by thymidylate synthase. Free-energy surfaces
of the bisubstrate intermediates interconversions computed with
quantum mechanics/molecular mechanics (QM/MM) methods and
experimental assessment of the corresponding kinetics indicate
that the species is the most abundant productive intermediate
along the reaction coordinate, whereas accumulation of the covalent bisubstrate species largely occurs in a parallel nonproductive pathway. Our findings not only substantiate relevance of the
previously proposed noncovalent intermediate but also support
potential implications of the overstabilized covalent intermediate
in drug design targeting DNA biosynthesis. [-]
Is part of
PNAS, October 9, 2018, vol. 115, no. 41Investigation project
R01 GM65368 ; CTQ2015-66223-C2 and UJI·B2017-31.Rights
info:eu-repo/semantics/openAccess
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