دورية أكاديمية
Preorganized Internal Electric Field Promotes a Double-Displacement Mechanism for the Adenine Excision Reaction by Adenine DNA Glycosylase.
| العنوان: | Preorganized Internal Electric Field Promotes a Double-Displacement Mechanism for the Adenine Excision Reaction by Adenine DNA Glycosylase. |
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| المؤلفون: | Diao W; Center for Advanced Materials Research, Beijing Normal University, Zhuhai 519087, China.; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.; School of Physical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China., Farrell JD; School of Physical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.; Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.; Songshan Lake Materials Laboratory, Dongguan, Guangdong 523808, China., Wang B; State Key Laboratory of Physical Chemistry of Solid Surfaces and Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China., Ye F; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang 325000, China.; School of Physical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.; Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China.; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325000, China., Wang Z; Center for Advanced Materials Research, Beijing Normal University, Zhuhai 519087, China. |
| المصدر: | The journal of physical chemistry. B [J Phys Chem B] 2023 Oct 12; Vol. 127 (40), pp. 8551-8564. Date of Electronic Publication: 2023 Oct 02. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, D.C. : American Chemical Society, c1997- |
| مواضيع طبية MeSH: | N-Glycosyl Hydrolases*/chemistry , DNA Glycosylases*/metabolism, Adenine/chemistry ; DNA Repair ; DNA/chemistry ; Water |
| مستخلص: | Adenine DNA glycosylase (MutY) is a monofunctional glycosylase, removing adenines (A) misinserted opposite 8-oxo-7,8-dihydroguanine (OG), a common product of oxidative damage to DNA. Through multiscale calculations, we decipher a detailed adenine excision mechanism of MutY that is consistent with all available experimental data, involving an initial protonation step and two nucleophilic displacement steps. During the first displacement step, N-glycosidic bond cleavage is accompanied by the attack of the carboxylate group of residue Asp144 at the anomeric carbon (C1'), forming a covalent glycosyl-enzyme intermediate to stabilize the fleeting oxocarbenium ion. After departure of the excised base, water nucleophiles can be recruited to displace Asp144, completing the catalytic cycle with retention of stereochemistry at the C1' position. The two displacement reactions are found to mostly involve the movement of the oxocarbenium ion, occurring with large charge reorganization and thus sensitive to the internal electric field (IEF) exerted by the polar protein environment. Intriguingly, we find that the negatively charged carboxylate group is a good nucleophile for the oxocarbenium ion, yet an unactivated water molecule is not, and that the electric field catalysis strategy is used by the enzyme to enable its unique double-displacement reaction mechanism. A strong IEF, pointing toward 5' direction of the substrate sugar ring, greatly facilitates the second displacement reaction at the expense of elevating the barrier of the first one, thereby allowing both reactions to occur. These findings not only increase our understanding of the strategies used by DNA glycosylases to repair DNA lesions, but also have important implications for how internal/external electric field can be applied to modulate chemical reactions. |
| المشرفين على المادة: | EC 3.2.2.- (N-Glycosyl Hydrolases) JAC85A2161 (Adenine) EC 3.2.2.- (DNA Glycosylases) 9007-49-2 (DNA) 059QF0KO0R (Water) |
| تواريخ الأحداث: | Date Created: 20231002 Date Completed: 20231101 Latest Revision: 20231111 |
| رمز التحديث: | 20231111 |
| DOI: | 10.1021/acs.jpcb.3c04928 |
| PMID: | 37782825 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-5207 |
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| DOI: | 10.1021/acs.jpcb.3c04928 |