Deacylation Mechanism and Kinetics of Acyl-Enzyme Complex of Class C β-Lactamase and Cephalothin.
Deacylation Mechanism and Kinetics of Acyl-Enzyme Complex of Class C β-Lactamase and Cephalothin.
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C类β-内酰胺酶和头孢噻吩酰基酶复合物的脱酰基机制和动力学。
DOI：
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发表时间：
2016
影响因子：
3.3
通讯作者：
N. N. Nair
中科院分区：
文献类型：
--
作者：
R. Tripathi;N. N. Nair
了解细菌酶β-内酰胺酶的抗生素耐药性的分子细节对于开发新的抗生素和抑制剂至关重要。基于此，本文采用量子力学/分子力学分子动力学方法研究了头孢噻吩与C类β-内酰胺酶形成的酰基-酶复合物的脱酰机理。阐明了各种活性位点残基和底物在脱酰反应中的作用。我们确定了激活水解水分子的碱基和使催化丝氨酸（Ser 64）质子化的残基。的活性位点和质子转移，增强脱酰反应的效率的构象变化。我们还表征了含氧阴离子空穴和其他稳定反应中间体的氢键相互作用。结合酰化反应的动力学和机理细节，我们分析了药物水解的完整机理和总体动力学。最后，在药物水解的表观速率决定步骤进行审查。
Understanding the molecular details of antibiotic resistance by the bacterial enzymes β-lactamases is vital for the development of novel antibiotics and inhibitors. In this spirit, the detailed mechanism of deacylation of the acyl-enzyme complex formed by cephalothin and class C β-lactamase is investigated here using hybrid quantum-mechanical/molecular-mechanical molecular dynamics methods. The roles of various active-site residues and substrate in the deacylation reaction are elucidated. We identify the base that activates the hydrolyzing water molecule and the residue that protonates the catalytic serine (Ser64). Conformational changes in the active sites and proton transfers that potentiate the efficiency of the deacylation reaction are presented. We have also characterized the oxyanion holes and other H-bonding interactions that stabilize the reaction intermediates. Together with the kinetic and mechanistic details of the acylation reaction, we analyze the complete mechanism and the overall kinetics of the drug hydrolysis. Finally, the apparent rate-determining step in the drug hydrolysis is scrutinized.
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影响因子：
2.9
作者：
LOBKOVSKY, E;BILLINGS, EM;KNOX, JR
通讯作者：
KNOX, JR
影响因子：
4.1
作者：
Majiduddin, FK;Materon, IC;Palzkill, TG
通讯作者：
Palzkill, TG
影响因子：
56.3
作者：
Laxminarayan, Ramanan;Duse, Adriano;Cars, Otto
通讯作者：
Cars, Otto
DOI：
10.1080/07391102.1999.10508297
发表时间：
1999-02-01
影响因子：
4.4
作者：
Cheatham, TE;Cieplak, P;Kollman, PA
通讯作者：
Kollman, PA
影响因子：
7.3
作者：
Powers, RA;Shoichet, BK
通讯作者：
Shoichet, BK