Acylation and deacylation mechanism and kinetics of penicillin G reaction with Streptomyces R61 DD ‐peptidase,Journal of Computational Chemistry

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Acylation and deacylation mechanism and kinetics of penicillin G reaction with Streptomyces R61 DD ‐peptidase
Journal of Computational Chemistry ( IF 3.4 ) Pub Date : 2020-04-23 , DOI: 10.1002/jcc.26210
Qianyi Cheng ₁ , Nathan J DeYonker ₁

Affiliation

Two quantum mechanical (QM)‐cluster models are built for studying the acylation and deacylation mechanism and kinetics of Streptomyces R61 DD‐peptidase with the penicillin G at atomic level detail. DD‐peptidases are bacterial enzymes involved in the cross‐linking of peptidoglycan to form the cell wall, necessary for bacterial survival. The cross‐linking can be inhibited by antibiotic beta‐lactam derivatives through acylation, preventing the acyl‐enzyme complex from undergoing further deacylation. The deacylation step was predicted to be rate‐limiting. Transition state and intermediate structures are found using density functional theory in this study, and thermodynamic and kinetic properties of the proposed mechanism are evaluated. The acyl‐enzyme complex is found lying in a deep thermodynamic sink, and deacylation is indeed the severely rate‐limiting step, leading to suicide inhibition of the peptidoglycan cross‐linking. The usage of QM‐cluster models is a promising technique to understand, improve, and design antibiotics to disrupt function of the Streptomyces R61 DD‐peptidase.

中文翻译：

青霉素G与链霉菌R61 DD-肽酶反应的酰化和脱酰机理及动力学

建立了两个量子力学 (QM) 簇模型，用于在原子级细节上研究链霉菌 R61 DD-肽酶与青霉素 G 的酰化和脱酰化机制和动力学。DD-肽酶是细菌酶，参与肽聚糖交联以形成细胞壁，是细菌存活所必需的。抗生素β-内酰胺衍生物可以通过酰化抑制交联，防止酰基酶复合物进一步脱酰。预计脱酰步骤是限速的。在本研究中使用密度泛函理论发现了过渡态和中间结构，并评估了所提出机制的热力学和动力学性质。发现酰基酶复合物位于深热力学水槽中，脱酰确实是严重的限速步骤，导致肽聚糖交联的自杀抑制。QM-cluster 模型的使用是一种很有前途的技术，可以理解、改进和设计抗生素来破坏链霉菌 R61 DD-肽酶的功能。

更新日期：2020-04-23

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