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Chiral discrimination in a mutated IDH enzymatic reaction in cancer: a computational perspective.
European Biophysics Journal ( IF 2 ) Pub Date : 2020-09-03 , DOI: 10.1007/s00249-020-01460-x
Masthan Thamim 1 , Krishnan Thirumoorthy 1
Affiliation  

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.

Graphic Abstract



中文翻译:

癌症中突变的 IDH 酶促反应的手性鉴别:计算视角。

摘要

生物系统中的手性区分,例如蛋白质中的l-氨基酸和核酸中的d-糖,已被提议依赖于各种机制,并且介导癌细胞信号传导的突变酶的手性区分在当前研究中很重要。我们已经探索了突变的异柠檬酸脱氢酶 (IDH) 如何催化异柠檬酸氧化脱羧为 α-酮戊二酸,α-酮戊二酸又转化为d -2-羟基戊二酸 ( d -2HG) 作为首选产物,而不是l -2-羟基戊二酸 ( l - 2HG) 根据量子化学计算。使用过渡态结构建模,我们描绘了d的首选产品形式-2HG在 IDH 活性位点模型中超过l -2HG。通过识别气相和溶液相中的过渡态结构和活化能势垒来评估在l -2HG 上形成d -2HG的机制。对于形成的所计算出的反应能量分布d -2HG和-2HG代谢物显示了较高的29倍值相比-2HG d -2HG。二阶 Møller-Plesset 微扰理论 (MP2) 的结果不会改变基于密度泛函理论 (DFT) 的观察趋势。观察到的反应能量分布趋势解释了为什么D -2HG的形成优于l-2HG 并揭示为什么突变导致形成d -2HG 而不是l -2HG。为了更好地理解观察到的形成两种替代产品的激活势垒差异,我们进行了自然键轨道分析、非共价相互作用分析和能量分解分析。我们基于计算计算的发现清楚地表明手性区分在癌症生物学中突变酶途径中的作用。

图形摘要

更新日期:2020-09-03
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