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Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools
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Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools
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Journal Article
Parallel reaction pathways and noncovalent intermediates in thymidylate synthase revealed by experimental and computational tools
2018
Overview
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.
Publisher
National Academy of Sciences
Subject
