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Handmade painting representing FAAH bound to the membrane.

This is a handmade painting of the membrane-bound fatty acid amide hydrolase (FAAH), a key enzyme for the endocannabinoid lipid signaling pathway that hydrolyzes a variety of lipids with different catalytic rates. Through the integration of microsecond-long molecular dynamics simulations with mutagenesis and kinetic experiments, Palermo et al. describe a novel mechanism and mechanistic features for lipid selection in FAAH.

Key contributions include exploitation of structural flexibility, gating residues and multiple cavities in one catalytic site to selectively hydrolyze the main substrate anandamide. Palermo et al. also discuss how this structural framework could likely be a general enzymatic strategy of other lipiddegrading enzymes to select the preferred lipid substrate within a broad spectrum of biologically active lipids.

These findings encourage additional experimental verifications of the role of ligand and structural flexibility for lipid-selection in several other lipid-degrading enzymes.

Image Credit: Painting by Giulia Palermo with digital manipulation by O'Reilly Science Art, LLC