The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.
The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.
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DOI：
10.1038/s41467-017-02339-w
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发表时间：
2017-12-21
影响因子：
16.6
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Feng H;Liu X;Wang S;Fleming J;Wang DC;Liu W
新德里金属β-内酰胺酶（NDMs）是近年来新发现的一类β-内酰胺酶，由于其对β-内酰胺类抗生素的高效水解作用和在全球范围内的快速传播，对公共卫生构成了严重威胁。与青霉素类和头孢菌素类相比，对碳青霉烯类的MBL水解机制的研究较少。在这里，我们报告了NDM-1与水解亚胺培南和美罗培南复合物的晶体结构，分辨率为1.80-2.32 nm，以及监测美罗培南水解的NMR光谱。三个酶中间体/产物衍生物，EI 1，EI 2和EP，被困在这些晶体。我们的结构数据揭示了从Δ2到Δ1的双键互变异构化，不存在桥接水分子和唯一的β-非对映体产物，所有这些都表明水解中间体被从β-面进入的大体积水分子质子化。这些结果强烈表明，NDM-1催化的碳青霉烯水解的机制与青霉素或头孢菌素水解的机制不同，这可能为基于机制的抑制剂的设计提供新的理论基础。新德里金属β-内酰胺酶（NDM）水解几乎所有的β-内酰胺抗生素并构成主要的公共卫生威胁。本文研究了NDM-1催化碳青霉烯水解的机理，并给出了酶-中间体和产物复合物的晶体结构，这对药物设计具有重要意义。
New Delhi metallo-β-lactamases (NDMs), the recent additions to metallo-β-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of β-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80–2.32 Å, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI1, EI2, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Δ2 to Δ1, absence of a bridging water molecule and an exclusive β-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the β-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors. New Delhi metallo-β-lactamases (NDMs) hydrolyze almost all β-lactam antibiotics and pose a major public health threat. Here, the authors study the mechanism of NDM-1 catalyzed carbapenem hydrolysis and present the crystal structures of the enzyme-intermediate and product complexes, which is important for drug design.
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影响因子：
4.2
作者：
Khan AU;Maryam L;Zarrilli R
通讯作者：
Zarrilli R
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC
影响因子：
16.6
作者：
Ma, Junhe;McLeod, Sarah;Hu, Jun
通讯作者：
Hu, Jun
NDM-1 催化头孢菌素水解的结构和机制见解
影响因子：
15
作者：
Feng, Han;Ding, Jingjin;Liu, Wei
通讯作者：
Liu, Wei
DOI：
10.1098/rstb.1980.0049
发表时间：
1980-01-01
影响因子：
6.3
作者：
AMBLER, RP
通讯作者：
AMBLER, RP