Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets
Methionine Aminopeptidases from Mycobacterium tuberculosis as Novel Antimycobacterial Targets
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DOI：
10.1016/j.chembiol.2009.12.014
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发表时间：
2010-01-29
影响因子：
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通讯作者：
Liu, Jun O.
中科院分区：
文献类型：
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作者：
Olaleye, Omonike;Raghunand, Tirumalai R.;Liu, Jun O.
蛋氨酸氨肽酶（MetAP）是一种金属蛋白酶，在蛋白质合成过程中去除N-末端蛋氨酸。为了评估这两种MetAP在结核分枝杆菌中的重要性，我们过表达并纯化了每种MetAP至接近同质，并显示两者在体外都具有MetAP酶的活性。我们筛选了175，000种针对MtMetAP 1c的化合物的文库，并鉴定了2，3-二氯-1，4-萘醌类化合物作为两种MtMetAP的抑制剂。发现MtMetAP抑制剂对复制和老化的非生长M.结核MtMetAP 1a或MtMetAP 1c在M.结核病赋予细菌细胞对抑制剂的抗性。此外，敲低MtMetAP 1a，而不是MtMetAP 1c，导致M的活力降低。结核这些结果表明，MtMetAP 1a是一个有前途的目标，为开发抗结核药物。
Methionine aminopeptidase (MetAP) is a metalloprotease that removes the N-terminal methionine during protein synthesis. To assess the importance of the two MetAPs in Mycobacterium tuberculosis, we overexpressed and purified each of the MetAPs to near homogeneity and showed that both were active as MetAP enzymes in vitro. We screened a library of 175,000 compounds against MtMetAP1c and identified 2,3-dichloro-1,4-naphthoquinone class of compounds as inhibitors of both MtMetAPs. It was found that the MtMetAP inhibitors were active against replicating and aged nongrowing M. tuberculosis. Overexpression of either MtMetAP1a or MtMetAP1c in M. tuberculosis conferred resistance of bacterial cells to the inhibitors. Moreover, knockdown of MtMetAP1a, but not MtMetAP1c, resulted in decreased viability of M. tuberculosis. These results suggest that MtMetAP1a is a promising target for developing antituberculosis agents.