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

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

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: mbogyo@stanford.edu.
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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