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

55 Pages Posted: 3 Nov 2019 Sneak Peek Status: Review Complete

See all articles by Euna Yoo

Euna Yoo

Stanford University - Department of Pathology

Christopher J. Schulze

Stanford University - Department of Pathology

Barbara H. Stokes

Columbia University - Department of Microbiology and Immunology

Ouma Onguka

Stanford University - Department of Pathology

Tomas Yeo

Columbia University - Department of Microbiology and Immunology

Sachel Mok

Columbia University - Department of Microbiology and Immunology

Nina F. Gnädig

Columbia University - Department of Microbiology and Immunology

Yani Zhou

Boston College - Department of Chemistry

Kenji Kurita

Simon Fraser University (SFU) - Department of Chemistry

Ian T. Foe

Stanford University - Department of Pathology

Stephanie M. Terrell

Stanford University - Department of Pathology

Michael J. Boucher

Stanford University - Department of Microbiology and Immunology

Piotr Cieplak

Sanford Burnham Prebys Medical Discovery Institute - Infectious & Inflammatory Disease Center

Roger G. Linington

Simon Fraser University (SFU) - Department of Chemistry

Jonathan Z. Long

Stanford University - Department of Pathology

Anne-Catrin Uhlemann

Columbia University - Division of Infectious Diseases

Eranthie Weerapana

Boston College - Department of Chemistry

David A. Fidock

Columbia University - Department of Microbiology and Immunology

Matthew Bogyo

Stanford University - Department of Pathology

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Abstract

Salinipostin A (Sal A) is a potent antimalarial 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 high 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 and produces disorganized and stalled schizonts similar to Sal A. Resistance selections yielded parasites that showed only minor reductions in sensitivity and that acquired mutations in a 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: Malaria, natural products, salinipostin A, serine hydrolyses, lipid metabolism, Plasmodium falciparum, chemical proteomics, activity-based probes

Suggested Citation

Yoo, Euna and Schulze, Christopher J. and Stokes, Barbara H. and Onguka, Ouma and Yeo, Tomas and Mok, Sachel and Gnädig, Nina F. and Zhou, Yani and Kurita, Kenji and Foe, Ian T. and Terrell, Stephanie M. and Boucher, Michael J. and Cieplak, Piotr and Linington, Roger G. and Long, Jonathan Z. and Uhlemann, Anne-Catrin and Weerapana, Eranthie and Fidock, David A. and Bogyo, Matthew, The Antimalarial Natural Product Salinipostin a Identifies Essential α/β Serine Hydrolases Involved in Lipid Metabolism in P. Falciparum Parasites (November 2, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00423. Available at SSRN: https://ssrn.com/abstract=3479442 or http://dx.doi.org/10.2139/ssrn.3479442
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Euna Yoo

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Christopher J. Schulze

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Barbara H. Stokes

Columbia University - Department of Microbiology and Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Ouma Onguka

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Tomas Yeo

Columbia University - Department of Microbiology and Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Sachel Mok

Columbia University - Department of Microbiology and Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Nina F. Gnädig

Columbia University - Department of Microbiology and Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Yani Zhou

Boston College - Department of Chemistry

United States

Kenji Kurita

Simon Fraser University (SFU) - Department of Chemistry

Burnaby, British Columbia V5A 1S6
Canada

Ian T. Foe

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Stephanie M. Terrell

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Michael J. Boucher

Stanford University - Department of Microbiology and Immunology

Stanford, CA 94305
United States

Piotr Cieplak

Sanford Burnham Prebys Medical Discovery Institute - Infectious & Inflammatory Disease Center

United States

Roger G. Linington

Simon Fraser University (SFU) - Department of Chemistry

Burnaby, British Columbia V5A 1S6
Canada

Jonathan Z. Long

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Anne-Catrin Uhlemann

Columbia University - Division of Infectious Diseases

United States

Eranthie Weerapana

Boston College - Department of Chemistry

United States

David A. Fidock

Columbia University - Department of Microbiology and Immunology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Matthew Bogyo (Contact Author)

Stanford University - Department of Pathology

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

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