Fatty Acid Amide Hydrolase

In collaboration with the Cravatt Laboratory, Department of Cell Biology, we solved the structure of fatty acid amide hydrolase (FAAH), a degradative integral membrane enzyme responsible for setting intracellular levels of endocannabinoids, to 2.8 Å. FAAH is intimately associated with CNS signaling processes such as retrograde synaptic transmission, a process that is also modulated by the illicit substance d-9-tetrahydrocannabinol. FAAH is a dimer capable of monotopic membrane insertion; it has an active site structure consistent with the capacity for hydrolysis of hydrophobic fatty acid amides and structural features amenable to structure-based drug design. With our knowledge of the 3-dimensional structure, we are trying to understand how the enzyme works at a basic level and how it might be the basis for potential drug discovery. More recently in a collaboration with Pfizer, the rat enzyme active site has been converted into the human residues allowing for drug development for both the rat and human species (PNAS, 2008).