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

  • Cell Chem Biol. 2020 Feb 20;27(2):143-157.e5. doi: 10.1016/j.chembiol.2020.01.001.
Euna Yoo  1 ,  Christopher J Schulze  1 ,  Barbara H Stokes  2 ,  Ouma Onguka  1 ,  Tomas Yeo  2 ,  Sachel Mok  2 ,  Nina F Gnädig  2 ,  Yani Zhou  3 ,  Kenji Kurita  4 ,  Ian T Foe  1 ,  Stephanie M Terrell  5 ,  Michael J Boucher  6 ,  Piotr Cieplak  7 ,  Krittikorn Kumpornsin  8 ,  Marcus C S Lee  8 ,  Roger G Linington  4 ,  Jonathan Z Long  5 ,  Anne-Catrin Uhlemann  9 ,  Eranthie Weerapana  3 ,  David A Fidock  10 ,  Matthew Bogyo  11
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 2. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 3. Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.
  • 4. Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • 5. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • 6. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 7. Infectious & Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • 8. Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
  • 9. Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 10. Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 11. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 31978322 DOI: 10.1016/j.chembiol.2020.01.001
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.

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