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

Structure. 2015 Mar 3;23(3):598-604. doi: 10.1016/j.str.2014.12.018. Epub 2015 Feb 12.

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.

Publication types

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

MeSH terms

  • Bile Acids and Salts / physiology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Hydrolysis
  • Models, Molecular
  • Phosphatidylethanolamines / biosynthesis
  • Phospholipase D / chemistry*
  • Phospholipase D / physiology
  • Protein Interaction Domains and Motifs
  • Protein Structure, Quaternary

Substances

  • Bile Acids and Salts
  • Phosphatidylethanolamines
  • Phospholipase D
  • NAPEPLD protein, human

Associated data

  • PDB/4QN9