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

Antimalarials / chemistry Biological Products / chemical synthesis Bridged Bicyclo Compounds, Heterocyclic / chemistry Click Chemistry Drug Resistance / drug effects Humans Hydrolases / antagonists & inhibitors Lipid Metabolism / drug effects Malaria, Falciparum / drug therapy Monoacylglycerol Lipases / antagonists & inhibitors Orlistat / chemistry Plasmodium falciparum / drug effects Protozoan Proteins / antagonists & inhibitors
Plasmodium falciparum Salinipostin A activity-based probes chemical proteomics lipid metabolism malaria natural products serine hydrolases

Journal

Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030

Informations de publication

Date de publication:
20 02 2020
Historique:
received: 28 10 2019
revised: 11 12 2019
accepted: 03 01 2020
pubmed: 25 1 2020
medline: 14 5 2021
entrez: 25 1 2020
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.chembiol.2020.01.001 PMID: 31978322 PMC: PMC8027986
pubmed: 31978322
pii: S2451-9456(20)30001-5
doi: 10.1016/j.chembiol.2020.01.001
pmc: PMC8027986
mid: NIHMS1678834
pii:
doi:

Substances chimiques

Antimalarials 0
Biological Products 0
Bridged Bicyclo Compounds, Heterocyclic 0
Protozoan Proteins 0
salinipostin A 0
Orlistat 95M8R751W8
Hydrolases EC 3.-
Monoacylglycerol Lipases EC 3.1.1.23

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

143-157.e5

Subventions

Organisme : NIDDK NIH HHS
ID : R00 DK105203
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI106711
Pays : United States
Organisme : NIAID NIH HHS
ID : R33 AI127581
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM117004
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM118431
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK105203
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Euna Yoo (E)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Christopher J Schulze (CJ)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Barbara H Stokes (BH)

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Ouma Onguka (O)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Tomas Yeo (T)

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Sachel Mok (S)

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Nina F Gnädig (NF)

Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.

Yani Zhou (Y)

Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.

Kenji Kurita (K)

Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.

Ian T Foe (IT)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Stephanie M Terrell (SM)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.

Michael J Boucher (MJ)

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.

Piotr Cieplak (P)

Infectious & Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.

Krittikorn Kumpornsin (K)

Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

Marcus C S Lee (MCS)

Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.

Roger G Linington (RG)

Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.

Jonathan Z Long (JZ)

Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford ChEM-H, Stanford University, Stanford, CA 94305, USA.

Anne-Catrin Uhlemann (AC)

Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Eranthie Weerapana (E)

Department of Chemistry, Boston College, Chestnut Hill, MA 02467, USA.

David A Fidock (DA)

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.

Matthew Bogyo (M)

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.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiparasitaires › Antiprotozoaires › Antipaludiques › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Mélanges complexes › Produits biologiques › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques, cycle ponté › Composés hétérocycliques bicycliques › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Technologie, industrie et agriculture › Technologie › Technologie pharmaceutique › Techniques de chimie synthétique › Chimie click › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Métabolisme › Métabolisme lipidique › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Infection › Maladies vectorielles › Paludisme › Paludisme à Plasmodium falciparum › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Carboxylic ester hydrolases › Acylglycerol lipase › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Composés chimiques organiques › Lactones › Orlistat › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Eucaryotes › Alveolata › Apicomplexa › Haemosporida › Plasmodium › Plasmodium falciparum › The Antimalarial Natural Product Salinipostin...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de protozoaire › The Antimalarial Natural Product Salinipostin...