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The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites

ABSTRACT: Salinipostin A (Sal A) is a bicyclic phosphotriester natural product isolated from the marine bacterium Salinospora sp. that exhibits potent antimalarial activity. However, the direct targets and mechanisms by which it exerts its effects are poorly understood. Here, we use semi-synthesis to generate a Sal A-derived activity-based probe, enabling the identification of its targets in the human malaria parasite Plasmodium falciparum. All of the identified proteins contain an / serine hydrolase domain and several have been reported as essential for growth of the parasite. One of the essential targets is an uncharacterized protein (PF3D7_1038900, referred to as PfMAGLLP) that displays a high degree of homology to human monoacylglycerol lipase (MAGL). Recombinant expression of this protein confirms that it processes lipid esters as well as a bona fide MAGL acylglyceride substrate. PfMAGLLP is potently inhibited by Sal A, as well as by human MAGL inhibitors and by the anti-obesity drug Orlistat that disrupts lipid metabolism and induces a similar death phenotype in parasites as Sal A. Resistance selection studies with Sal A yielded parasites that showed only a mild reduction in sensitivity. Multiple whole-genome sequenced Sal A-selected clones displayed nonsynonymous mutations in a gene coding for a putative PRELI domain-containing protein (PF3D7_1324400) related to a mitochondrial protein linked to multidrug resistance in Toxoplasma gondii. Together, these data suggest that the antimalarial activity of Sal A results from inhibition of multiple essential serine hydrolases, leading to disruption of lipid metabolism pathways. The combination of the non-essentiality of many of these serine hydrolases in humans and the lack of parasite resistance pathways to fully overcome inhibitor treatment suggest that this class of enzymes represent promising targets for development of next-generation antimalarial agents.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Plasmodium Falciparum 58.1

DISEASE(S): Plasmodium Falciparum Malaria

SUBMITTER: Eranthie Weerapana

LAB HEAD: Eranthie Weerapana

PROVIDER: PXD016835 | Pride | 2020-01-24

REPOSITORIES: Pride

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			Action	DRS
	DTASelect-filter_YZ_Bogyo_tryptic_Neg_1_1.txt	Txt
	DTASelect-filter_YZ_Bogyo_tryptic_Neg_1_2.txt	Txt
	DTASelect-filter_YZ_Bogyo_tryptic_Neg_1_3.txt	Txt
	DTASelect-filter_YZ_Bogyo_tryptic_Pos_1_1.txt	Txt
	DTASelect-filter_YZ_Bogyo_tryptic_Pos_1_2.txt	Txt

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The Antimalarial Natural Product Salinipostin A Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. falciparum Parasites.

Yoo Euna E Schulze Christopher J CJ Stokes Barbara H BH Onguka Ouma O Yeo Tomas T Mok Sachel S Gnädig Nina F NF Zhou Yani Y Kurita Kenji K Foe Ian T IT Terrell Stephanie M SM Boucher Michael J MJ Cieplak Piotr P Kumpornsin Krittikorn K Lee Marcus C S MCS Linington Roger G RG Long Jonathan Z JZ Uhlemann Anne-Catrin AC Weerapana Eranthie E Fidock David A DA Bogyo Matthew M

Cell chemical biology 20200123 2

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 acylglyce ...[more]

PMID: 31978322

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