The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.
The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.
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DOI：
10.1016/j.chembiol.2020.01.001
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发表时间：
2020-02-20
影响因子：
8.6
通讯作者：
Bogyo M
中科院分区：
文献类型：
--
作者：
Yoo E;Schulze CJ;Stokes BH;Onguka O;Yeo T;Mok S;Gnädig NF;Zhou Y;Kurita K;Foe IT;Terrell SM;Boucher MJ;Cieplak P;Kumpornsin K;Lee MCS;Linington RG;Long JZ;Uhlemann AC;Weerapana E;Fidock DA;Bogyo M
Salinipostin A（Sal A）是一种有效的抗疟原虫海洋天然产物，其作用机制尚未明确。使用Sal A衍生的基于活性的探针，我们确定其在恶性疟原虫寄生虫的目标。所有鉴定的蛋白质都含有α/β丝氨酸水解酶结构域，其中几种是寄生虫生长所必需的。其中一个基本靶标与人单酰基甘油脂酶（MAGL）具有高度同源性，并能够加工包括MAGL酰基甘油酯底物在内的脂质酯。这种Sal A靶点被抗肥胖药物奥利司他抑制，奥利司他破坏脂质代谢。抗性选择产生的寄生虫仅表现出轻微的敏感性降低，并且获得了与弓形虫耐药性相关的含有PRELI结构域的蛋白质的突变。这种无法进化出有效的耐药机制，加上人类同源物的非必要性，使得这里鉴定的丝氨酸水解酶成为有希望的抗疟疾靶点。Yoo等人使用抗疟疾天然产物Sal A的探针类似物，将其靶点鉴定为多种必需丝氨酸水解酶，包括人单酰基甘油脂酶的同系物。由于寄生虫无法在体外产生强大的耐药性Sal A，这些酶代表抗疟药物的有前途的目标。
Salinipostin A (Sal A) is a potent antiplasmodial marine natural product with an undefined mechanism of action. Using a Sal A-derived activity-based probe, we identify its targets in the Plasmodium falciparum parasite. All of the identified proteins contain α/β serine hydrolase domains and several are essential for parasite growth. One of the essential targets displays a high degree of homology to human monoacylglycerol lipase (MAGL) and is able to process lipid esters including a MAGL acylglyceride substrate. This Sal A target is inhibited by the anti-obesity drug Orlistat, which disrupts lipid metabolism. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a PRELI domain-containing protein linked to drug resistance in Toxoplasma gondii. This inability to evolve efficient resistance mechanisms combined with the non-essentiality of human homologs makes the serine hydrolases identified here promising antimalarial targets. Using a probe analog of the antimalarial natural product Sal A, Yoo et al. identify its targets as multiple essential serine hydrolases, including a homolog of human monoacylglycerol lipase. Because parasites were unable to generate robust in vitro resistance to Sal A, these enzymes represent promising targets for antimalarial drugs.
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影响因子：
--
作者：
Corvi MM;Alonso AM;Caballero MC
通讯作者：
Caballero MC
DOI：
10.1073/pnas.0504679102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Balu, B;Shoue, DA;Adams, JH
通讯作者：
Adams, JH
影响因子：
5.6
作者：
Bertrand, T.;Auge, F.;Mathieu, M.
通讯作者：
Mathieu, M.
影响因子：
6.7
作者：
Gisselberg JE;Dellibovi-Ragheb TA;Matthews KA;Bosch G;Prigge ST
通讯作者：
Prigge ST
影响因子：
120.1
作者：
Bachovchin, Daniel A.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.