Streptococcus pneumoniae isoprenoid biosynthesis is downregulated by diphosphomevalonate:: An antimicrobial target
Streptococcus pneumoniae isoprenoid biosynthesis is downregulated by diphosphomevalonate:: An antimicrobial target
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DOI：
10.1021/bi048075t
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发表时间：
2004-12-28
期刊：
影响因子：
2.9
通讯作者：
Leyh, TS
中科院分区：
文献类型：
--
作者：
Andreassi, JL;Dabovic, K;Leyh, TS
肺炎链球菌对人类福祉造成的损失是巨大的。这种微生物每天夺走3700人的生命，其中大多数是5岁以下的儿童，而且由于有害的、多重抗生素耐药菌株的发病率不断增加，情况可能会恶化。在这里，我们报告了一个新的变抗位点的发现和特征，显示在人类中不存在，可以用来关闭肺炎链球菌的一个基本途径，甲羟戊酸途径。二磷酰戊酸钠（DPM）是该途径的中间体，与该途径的第一个酶甲戊酸激酶（mevalonate kinase）具有高亲和力（K-d = 530 nM），并使其失活。稳态和平衡结合测量表明，DPM结合对底物是非竞争性的。DPM在变构位点结合，抑制不能通过增加底物浓度来克服。dpm结合位点是开发新型抗菌药物的一个有希望的靶点。
The toll that Streptococcus pneumoniae exacts on the welfare of humanity is enormous. This organism claims the lives of similar to3700 people daily, the majority of whom are children below the age of 5, and the situation could worsen due to the increasing incidence of pernicious, multiple-antibiotic-resistant strains. Here we report the discovery and characterization of a new allosteric site, shown to be absent in humans, that can be used to switch off an essential pathway in S. pneumoniae, the mevalonate pathway. Diphosphomevalonate (DPM), an intermediate in the pathway, binds with high affinity (K-d = 530 nM) to mevalonate kinase, the first enzyme in the pathway, and inactivates it. Steady-state and equilibrium binding measurements reveal that DPM binding is noncompetitive versus substrates. DPM binds at an allosteric site, and inhibition cannot be overcome by an increasing substrate concentration. The DPM-binding site is a promising target for the development of new antimicrobial agents.