PXD017586-1

PXD017586 is an original dataset announced via ProteomeXchange.

Title	Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice
Description	N‑acylethanolamines (NAEs), which include the endocannabinoid anandamide, represent an important family of signaling lipids in the brain. The lack of chemical probes that modulate NAE biosynthesis in living systems hamper the understanding of the biological role of these lipids. Using a high-throughput screen, chemical proteomics and targeted lipidomics, we report here the discovery and characterization of LEI-401 as the first CNS-active N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD) inhibitor. LEI-401 reduced NAE levels in neuroblastoma cells and in the brain of freely moving mice, but not in NAPE-PLD KO cells and mice, respectively. LEI-401 activated the hypothalamus-pituitary-adrenal axis and impaired fear extinction, thereby emulating the effect of a cannabinoid CB1 receptor antagonist, which could be reversed by a fatty acid amide hydrolase inhibitor. Our findings highlight the distinctive role of NAPE-PLD in NAE biosynthesis in the brain and suggest the presence of an endogenous NAE tone controlling emotional behavior.
HostingRepository	PRIDE
AnnounceDate	2020-05-15
AnnouncementXML	Submission_2020-05-15_04:13:51.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Bogdan Florea
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	SYNAPT G2-Si

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-18 05:47:46	ID requested
⏵ 1	2020-05-15 04:13:52	announced

Mock ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN, Kantae V, Di X, Ogasawara D, Varga ZV, Paloczi J, Miliano C, Donvito G, van Esbroeck ACM, van der Gracht AMF, Kotsogianni I, Park JK, Martella A, van der Wel T, Soethoudt M, Jiang M, Wendel TJ, Janssen APA, Bakker AT, Donovan CM, Castillo LI, Florea BI, Wat J, van den Hurk H, Wittwer M, Grether U, Holmes A, van Boeckel CAA, Hankemeier T, Cravatt BF, Buczynski MW, Hill MN, Pacher P, Lichtman AH, van der Stelt M, Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nat Chem Biol, 16(6):667-675(2020) [pubmed]

submitter keyword: lipids, chemical biology, drug discovery, endocannabinoids

Mario van der Stelt
contact affiliation	Department of Molecular Physiology, Leiden University
contact email	m.van.der.stelt@chem.leidenuniv.nl
lab head
Bogdan Florea
contact affiliation	Leiden Institute for Chemistry
contact email	b.florea@chem.leidenuniv.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD017586
     1. Label: PRIDE project
     2. Name: Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice