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

Euna Yoo, Christopher J. Schulze, Barbara H. Stokes, Ouma Onguka, Tomas Yeo, Sachel Mok, Nina F. Gnädig, Yani Zhou, Kenji Kurita, Ian T. Foe, Stephanie M. Terrell, Michael J. Boucher, Piotr Cieplak, Krittikorn Kumpornsin, Marcus C.S. Lee, Roger G. Linington, Jonathan Z. Long, Anne Catrin Uhlemann, Eranthie Weerapana, David A. FidockMatthew Bogyo (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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/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.

Original languageEnglish
Pages (from-to)143-157
Number of pages15
JournalCell Chemical Biology
Volume27
Issue number2
DOIs
Publication statusPublished - 23 Jan 2020

Keywords

  • activity-based probes
  • chemical proteomics
  • lipid metabolism
  • malaria
  • natural products
  • Plasmodium falciparum
  • Salinipostin A
  • serine hydrolases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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