Functional annotation of serine hydrolases in the asexual erythrocytic stage of Plasmodium falciparum

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dc.contributor.authorElahi, Rubayeten
dc.contributor.authorRay, W. Keithen
dc.contributor.authorDapper, Christieen
dc.contributor.authorDalal, Seemaen
dc.contributor.authorHelm, Richard F.en
dc.contributor.authorKlemba, Michaelen
dc.contributor.departmentBiochemistryen
dc.date.accessioned2020-02-05T17:47:32Zen
dc.date.available2020-02-05T17:47:32Zen
dc.date.issued2019-11-26en
dc.description.abstractEnzymes of the serine hydrolase superfamily are ubiquitous, highly versatile catalysts that mediate a wide variety of metabolic reactions in eukaryotic cells, while also being amenable to selective inhibition. We have employed a fluorophosphonate-based affinity capture probe and mass spectrometry to explore the expression profile and metabolic roles of the 56-member P. falciparum serine hydrolase superfamily in the asexual erythrocytic stage of P. falciparum. This approach provided a detailed census of active serine hydrolases in the asexual parasite, with identification of 21 active serine hydrolases from ei/0 hydrolase, patatin, and rhomboid protease families. To gain insight into their functional roles and substrates, the pan-lipase inhibitor isopropyl dodecylfluorophosphonate was employed for competitive activity-based protein profiling, leading to the identification of seven serine hydrolases with potential lipolytic activity. We demonstrated how a chemoproteomic approach can provide clues to the specificity of serine hydrolases by using a panel of neutral lipase inhibitors to identify an enzyme that reacts potently with a covalent monoacylglycerol lipase inhibitor. In combination with existing phenotypic data, our studies define a set of serine hydrolases that likely mediate critical metabolic reactions in asexual parasites and enable rational prioritization of future functional characterization and inhibitor development efforts.en
dc.description.notesThis work was supported by National Institute of Allergy and Infectious Diseases grant AI133136 and by HATCH project VA-160082 from the USDA National Institute of Food and Agriculture. The funding agencies had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. We are grateful to Dr. Ken Hsu, University of Virginia, for helpful discussions.en
dc.description.sponsorshipNational Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [AI133136]; USDA National Institute of Food and AgricultureUnited States Department of Agriculture (USDA) [VA-160082]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-019-54009-0en
dc.identifier.issn2045-2322en
dc.identifier.other17532en
dc.identifier.pmid31772212en
dc.identifier.urihttp://hdl.handle.net/10919/96722en
dc.identifier.volume9en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleFunctional annotation of serine hydrolases in the asexual erythrocytic stage of Plasmodium falciparumen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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