Ground State Destabilization in Uracil DNA Glycosylase (UDG): Let’s Not Forget “Tautomeric Strain” in Substrates,Journal of the American Chemical Society

当前位置： X-MOL 学术 › J. Am. Chem. Soc. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Ground State Destabilization in Uracil DNA Glycosylase (UDG): Let’s Not Forget “Tautomeric Strain” in Substrates
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2019-08-22 , DOI: 10.1021/jacs.9b06447
Ranjita Das ₁ , Erik A Vázquez-Montelongo ₂ , G Andrés Cisneros ₂ , Judy I Wu ₁

Affiliation

Enzymes like uracil DNA glycosylase (UDG) can achieve ground state destabilization, by polarizing substrates to mimic rare tautomers. Based on computed nucleus independent chemical shifts, NICS(1)zz, and harmonic oscillator model of electron delocalization (HOMED) analyses, of QM and QM/MM models of the UDG active site, uracil is strongly polarized when bound to UDG, and resembles a tautomer > 12 kcal/mol higher in energy. Natural resonance theory (NRT) analyses identified a dominant O2 imidate resonance form for residue bound 1-methyl-uracil. This "tautomeric strain" raises the energy of uracil, making uracilate a better than expected leaving group. Computed gas-phase SN2 reactions of free and hydrogen bonded 1-methyl-uracil demonstrate the relationship between degree of polarization in uracil and leaving group ability of uracilate.

中文翻译：

尿嘧啶 DNA 糖基化酶 (UDG) 中的基态不稳定：不要忘记底物中的“互变异构菌株”

像尿嘧啶 DNA 糖基化酶 (UDG) 这样的酶可以通过极化底物来模拟稀有互变异构体来实现基态不稳定。基于 UDG 活性位点的 QM 和 QM/MM 模型的计算核独立化学位移、NICS(1)zz 和电子离域 (HOMED) 分析的谐振子模型，尿嘧啶与 UDG 结合时会强烈极化，并且类似于互变异构体 > 12 kcal/mol 的能量更高。自然共振理论 (NRT) 分析确定了残基结合的 1-甲基-尿嘧啶的主要 O2 亚胺酸酯共振形式。这种“互变异构菌株”提高了尿嘧啶的能量，使尿嘧啶成为比预期更好的离去基团。计算的游离和氢键合 1-甲基-尿嘧啶的气相 SN2 反应证明了尿嘧啶的极化程度与尿嘧啶的离去基团能力之间的关系。

更新日期：2019-08-22

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南