Stable Analogues of OSB-AMP: Potent Inhibitors of MenE, the o-Succinylbenzoate-CoA Synthetase from Bacterial Menaquinone Biosynthesis
Stable Analogues of OSB-AMP: Potent Inhibitors of MenE, the o-Succinylbenzoate-CoA Synthetase from Bacterial Menaquinone Biosynthesis
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DOI：
10.1002/cbic.201100585
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发表时间：
2012-01-02
期刊：
影响因子：
3.2
通讯作者：
Tan, Derek S.
中科院分区：
文献类型：
--
作者：
Lu, Xuequan;Zhou, Rong;Tan, Derek S.
MenE是由细菌甲萘醌生物合成的邻琥珀酰苯甲酸（OSB）辅酶A合成酶，是一种很有前途的抗菌新靶点。同源反应中间体OSB-AMP的磺酰腺苷类似物已被开发为来自结核分枝杆菌（mtMenE）、金黄色葡萄球菌（saMenE）和大肠杆菌（ecMenE）的MenE酶的抑制剂。OSB侧链上的游离羧酸酯和酮部分都是有效抑制活性所需的。OSB-AMS（4）是mtMenE相对于ATP的竞争性抑制剂（Ki=5.4 +/- 0.1 nM）和相对于OSB的非竞争性抑制剂（Ki=11.2 +/- 0.9 nM）。这些数据与这些酶的Bi Uni Uni Bi乒乓动力学机制一致。此外，OSB-AMS抑制saMenE的${\rm app}\hfill \atop {\rm i}\hfill}}$=22 +/- 8 nM，抑制ecMenE的${\rm OSB}\hfill \atop {\rm i}\hfill}}$=128 +/- 5 nM。推定的活性位点残基，Arg 222，这可能与OSB芳香羧酸，和Ser 302，这可能会结合OSB酮氧，已被确定通过计算对接的OSB-AMP与未配体的晶体结构的saMenE。还描述了抑制剂的游离酮酸和内半缩醛形式的pH依赖性相互转化，沿着对抑制剂设计的影响。
MenE, the o-succinylbenzoate (OSB)-CoA synthetase from bacterial menaquinone biosynthesis, is a promising new antibacterial target. Sulfonyladenosine analogues of the cognate reaction intermediate, OSB-AMP, have been developed as inhibitors of the MenE enzymes from Mycobacterium tuberculosis (mtMenE), Staphylococcus aureus (saMenE) and Escherichia coli (ecMenE). Both a free carboxylate and a ketone moiety on the OSB side chain are required for potent inhibitory activity. OSB-AMS (4) is a competitive inhibitor of mtMenE with respect to ATP (Ki=5.4 +/- 0.1 nM) and a noncompetitive inhibitor with respect to OSB (Ki=11.2 +/- 0.9 nM). These data are consistent with a Bi Uni Uni Bi Ping-Pong kinetic mechanism for these enzymes. In addition, OSB-AMS inhibits saMenE with ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$=22 +/- 8 nM and ecMenE with ${K{{{\rm OSB}\hfill \atop {\rm i}\hfill}}}$=128 +/- 5 nM. Putative active-site residues, Arg222, which may interact with the OSB aromatic carboxylate, and Ser302, which may bind the OSB ketone oxygen, have been identified through computational docking of OSB-AMP with the unliganded crystal structure of saMenE. A pH-dependent interconversion of the free keto acid and lactol forms of the inhibitors is also described, along with implications for inhibitor design.