Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford ChEM-H, Stanford University, Stanford, United States
Stephanie M Terrell
Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford ChEM-H, Stanford University, Stanford, United States
Veronica L Li
Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford ChEM-H, Stanford University, Stanford, United States
Wei Wei
Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford ChEM-H, Stanford University, Stanford, United States; Department of Biology, Stanford University, Stanford, United States
Department of Pathology, Stanford University School of Medicine, Stanford, United States; Stanford ChEM-H, Stanford University, Stanford, United States
The N-acyl amino acids are a family of bioactive lipids with pleiotropic physiologic functions, including in energy homeostasis. Their endogenous levels are regulated by an extracellular mammalian N-acyl amino acid synthase/hydrolase called PM20D1 (peptidase M20 domain containing 1). Using an activity-guided biochemical approach, we report the molecular identification of fatty acid amide hydrolase (FAAH) as a second intracellular N-acyl amino acid synthase/hydrolase. In vitro, FAAH exhibits a more restricted substrate scope compared to PM20D1. In mice, genetic ablation or selective pharmacological inhibition of FAAH bidirectionally dysregulates intracellular, but not circulating, N-acyl amino acids. Dual blockade of both PM20D1 and FAAH reveals a dramatic and non-additive biochemical engagement of these two enzymatic pathways. These data establish FAAH as a second intracellular pathway for N-acyl amino acid metabolism and underscore enzymatic division of labor as an enabling strategy for the regulation of a structurally diverse bioactive lipid family.
