title: 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-α). 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.
authors: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
authors: Paola
authors: P
authors: Magotti
authors: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
authors: Inga
authors: I
authors: Bauer
authors: Department of Anatomy & Neurobiology, University of California - Irvine, Gillespie NRF 3101, Irvine, CA 92697, USA.
authors: Miki
authors: M
authors: Igarashi
authors: Department of Anatomy & Neurobiology, University of California - Irvine, Gillespie NRF 3101, Irvine, CA 92697, USA.
authors: Masih
authors: M
authors: Babagoli
authors: Nanochemistry, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy.
authors: Roberto
authors: R
authors: Marotta
authors: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; Department of Anatomy & Neurobiology, University of California - Irvine, Gillespie NRF 3101, Irvine, CA 92697, USA. Electronic address: piomelli@uci.edu.
authors: Daniele
authors: D
authors: Piomelli
authors: Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy. Electronic address: gianpiero.garau@iit.it.
authors: Gianpiero
authors: G
authors: Garau
mesh_terms: D001647:Bile Acids and Salts / Q000502:physiology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D006868:Hydrolysis; D008958:Models, Molecular; D010714:Phosphatidylethanolamines / Q000096:biosynthesis; D010739:Phospholipase D / Q000737:chemistry* / Q000502:physiology; D054730:Protein Interaction Domains and Motifs; D020836:Protein Structure, Quaternary
chemical_list: D001647:Bile Acids and Salts; D010714:Phosphatidylethanolamines; D010739:Phospholipase D; C581518:NAPEPLD protein, human