Chiral discrimination in a mutated IDH enzymatic reaction in cancer: a computational perspective
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ORIGINAL ARTICLE
Chiral discrimination in a mutated IDH enzymatic reaction in cancer: a computational perspective Masthan Thamim1 · Krishnan Thirumoorthy1 Received: 30 July 2020 / Accepted: 24 August 2020 © European Biophysical Societies’ Association 2020
Abstract Chiral discrimination in biological systems, such as l-amino acids in proteins and d-sugars in nucleic acids, has been proposed to depend on various mechanisms, and chiral discrimination by mutated enzymes mediating cancer cell signaling is important in current research. We have explored how mutated isocitrate dehydrogenase (IDH) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate which in turn is converted to d-2-hydroxyglutatrate (d-2HG) as a preferred product instead of l-2-hydroxyglutatrate (l-2HG) according to quantum chemical calculations. Using transition state structure modeling, we delineate the preferred product formation of d-2HG over l-2HG in an IDH active site model. The mechanisms for the formation of d-2HG over l-2HG are assessed by identifying transition state structures and activation energy barriers in gas and solution phases. The calculated reaction energy profile for the formation of d-2HG and l-2HG metabolites shows a 29 times higher value for l-2HG as compared to d-2HG. Results for second-order Møller–Plesset perturbation theory (MP2) do not alter the observed trend based on Density Functional Theory (DFT). The observed trends in reaction energy profile explain why the formation of D-2HG is preferred over l-2HG and reveal why mutation leads to the formation of d-2HG instead of l-2HG. For a better understanding of the observed difference in the activation barrier for the formation of the two alternative products, we performed natural bond orbital analysis, non-covalent interactions analysis and energy decomposition analysis. Our findings based on computational calculations clearly indicate a role for chiral discrimination in mutated enzymatic pathways in cancer biology. Keywords Chiral discrimination · IDH enzyme · Cancer · Transition state structure · Biophysical chemistry · Computational chemistry
Introduction One of the most important issues in biology is chiral selectivity as observed in various biochemical events such as ribosomal protein synthesis (Banik and Nandi 2013; Tsuji et al. 2013; Dubois et al. 2011; Gal 2013), nucleic acid recognition (Hein et al. 2011; D’Alonzo et al. 2011; Corradini et al. 2007; Urata 1999; Tamura 2008a, b 2015), and interactions of metabolites with cell signaling receptors Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00249-020-01460-x) contains supplementary material, which is available to authorized users. * Krishnan Thirumoorthy [email protected] 1
Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu 632014, India
(Dong et al. 2019; Wei et al. 2019; Fan et al. 2018; Dennis 2016; Ahmad et al. 2013), and so on (Barron 2008; Mason 1988; Fujii and Saito 2004)
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