The Antimalarial Natural Product Salinipostin A Identifies Essential α/ß Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.
Cell Chem Biol
; 27(2): 143-157.e5, 2020 02 20.
Article
em En
| MEDLINE
| ID: mdl-31978322
ABSTRACT
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/ß 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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas de Protozoários
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Compostos Bicíclicos Heterocíclicos com Pontes
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Metabolismo dos Lipídeos
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Hidrolases
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Antimaláricos
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article