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Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids.

ABSTRACT: The fatty acid ethanolamides (FAEs) are lipid mediators present in all organisms and involved in highly conserved biological functions, such as innate immunity, energy balance, and stress control. They are produced from membrane N-acylphosphatidylethanolamines (NAPEs) and include agonists for G protein-coupled receptors (e.g., cannabinoid receptors) and nuclear receptors (e.g., PPAR-?). Here, we report the crystal structure of human NAPE-hydrolyzing phospholipase D (NAPE-PLD) at 2.65 Å resolution, a membrane enzyme that catalyzes FAE formation in mammals. NAPE-PLD forms homodimers partly separated by an internal ? 9-Å-wide channel and uniquely adapted to associate with phospholipids. A hydrophobic cavity provides an entryway for NAPE into the active site, where a binuclear Zn(2+) center orchestrates its hydrolysis. Bile acids bind with high affinity to selective pockets in this cavity, enhancing dimer assembly and enabling catalysis. These elements offer multiple targets for the design of small-molecule NAPE-PLD modulators with potential applications in inflammation and metabolic disorders.

SUBMITTER: Magotti P

PROVIDER: S-EPMC4351732 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids.

Magotti Paola P Bauer Inga I Igarashi Miki M Babagoli Masih M Marotta Roberto R Piomelli Daniele D Garau Gianpiero G

Structure (London, England : 1993) 20150212 3

The fatty acid ethanolamides (FAEs) are lipid mediators present in all organisms and involved in highly conserved biological functions, such as innate immunity, energy balance, and stress control. They are produced from membrane N-acylphosphatidylethanolamines (NAPEs) and include agonists for G protein-coupled receptors (e.g., cannabinoid receptors) and nuclear receptors (e.g., PPAR-α). Here, we report the crystal structure of human NAPE-hydrolyzing phospholipase D (NAPE-PLD) at 2.65 Å resolutio ...[more]

PMID: 25684574

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Project description:Background: The concentrations of three N-acylethanolamines (NAEs), anandamide (AEA), N-oleoylethanolamide (OEA), and N-palmitylethanolamide (PEA) are increased in the endometria of women with endometrial cancer (EC). It is widely accepted that plasma levels of these three NAEs are regulated by the actions of the rate-limiting enzymes N-acylphoshatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), which are synthesizing and degradative, respectively. The expression and activity of these enzymes have not previously been studied in EC. Methods: FAAH activity in peripheral blood lymphocytes, and transcript and protein expression for FAAH and NAPE-PLD in EC tissues were measured using enzyme, quantitative RT-PCR, and histomorphometry (of immunoreactive tissue sections), respectively. Samples were from 6 post-menopausal women with atrophic endometria (controls) and 34 women with histologically diagnosed EC. Concentrations of the three NAEs also measured in plasma and tissues were correlated with lymphocytic FAAH activity and the NAPE-PLD and FAAH transcript and protein levels. Results: Peripheral lymphocyte FAAH activity was unaffected in women with EC compared to controls. The FAAH transcript expression level was significantly (p < 0.0001) 75% lower in EC whilst NAPE-PLD levels were not significantly (p = 0.798) increased. In line with the transcript data, a significant (p < 0.0001) tumor type-dependent 70-90% decrease in FAAH protein and significant 4- to 14-fold increase in NAPE-PLD protein (p < 0.0001) was observed in the malignant tissue with more advanced disease having lower FAAH and higher NAPE-PLD expression than less advanced disease. Correlation analyses also confirmed that tissue NAE concentrations were inversely related to FAAH expression and directly correlated to NAPE-PLD expression and the NAPE-PLD/FAAH ratio. Conclusion: These data support our previous observation of tissue levels of AEA, OEA, and PEA and a role for NAE metabolism in the pathogenesis of EC.

Dataset Information

Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids.

Publications

Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids.

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