Chair of Theoretical Chemistry, Department of Chemistry, University of Munich (LMU), D-81377 Munich, Germany.
Max Planck Institute for Solid State Research, Heisenbergstr. 1, D-70569 Stuttgart, Germany.
J Chem Theory Comput. 2021 Jan 12;17(1):96-104. doi: 10.1021/acs.jctc.0c00616. Epub 2020 Dec 24.
Dynamic regulation of DNA methylation is an important process for the control of gene expression in mammals. It is believed that in the demethylation pathway of 5-methyl cytosine, the intermediate 5-carboxy cytosine () can be actively decarboxylated alongside the substitution in the base excision repair. For the active decarboxylation of , a decarboxylase has not been identified so far. Due to the similar chemistry of the decarboxylation of 5-carboxy uracil () to uracil () in the pyrimidine salvage pathway catalyzed by the iso-orotate decarboxylase (IDCase), the study of this reaction might give valuable insights into the active decarboxylation process. In this work, we employ quantum chemical and molecular mechanic calculations and find that the catalytic mechanism of IDCase proceeds via a direct decarboxylation mechanism. Detailed investigations on the reaction coordinate reveal that it is a one-step mechanism with concerted proton transfer and C-C bond opening.
DNA 甲基化的动态调控是哺乳动物基因表达调控的一个重要过程。人们认为在 5-甲基胞嘧啶的去甲基化途径中，碱基切除修复过程中 5-羧基胞嘧啶（）可以与碱基的取代同时发生，被积极脱羧。到目前为止，还没有发现能够使 发生有效脱羧的脱羧酶。由于嘧啶补救途径中由异乳清酸脱羧酶（IDCase）催化的 5-羧基尿嘧啶（）和尿嘧啶（）的脱羧反应具有相似的化学性质，因此对该反应的研究可能会为了解有效的脱羧过程提供有价值的见解。在这项工作中，我们采用量子化学和分子力学计算，发现 IDCase 的催化机制通过直接脱羧机制进行。对反应坐标的详细研究表明，这是一个具有协同质子转移和 C-C 键断裂的一步反应机制。
