PXD016835

PXD016835 is an original dataset announced via ProteomeXchange.

Title	The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites
Description	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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:00:25.249.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eranthie Weerapana
SpeciesList	scientific name: Plasmodium falciparum 58.1; NCBI TaxID: 1245012;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2019-12-19 05:39:47	ID requested
1	2020-01-24 07:19:29	announced
2	2020-02-17 03:22:24	announced	2020-02-17: Updated publication reference for PubMed record(s): 31978322.
⏵ 3	2024-10-22 05:00:31	announced	2024-10-22: Updated project metadata.

10.1016/j.chembiol.2020.01.001;

Yoo E, Schulze CJ, Stokes BH, Onguka O, Yeo T, Mok S, Gn, ä, dig 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, falciparum Parasites. Cell Chem Biol, 27(2):143-157.e5(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: salinipostin A, serine hydrolase

Eranthie Weerapana
contact affiliation	Associate Professor
contact email	eranthie@bc.edu
lab head
Eranthie Weerapana
contact affiliation	Boston College
contact email	eranthie@bc.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016835
     1. Label: PRIDE project
     2. Name: The antimalarial natural product salinipostin A identifies essential alpha/beta serine hydrolases involved in lipid metabolism in P. falciparum parasites