Fatty acid amide hydrolase (FAAH) is a membrane-bound serine hydrolase responsible for the intracellular degradation of anandamide and a wide range of other bioactive fatty acid ethanolamides involved in the regulation of pain, inflammation and other pathophysiological processes. Other relevant FAAH substrates are the anti-inflammatory factor N-palmytoyl ethanolamine (PEA) and the sleeping-inducing factor oleamide (OA). The catalytic site of FAAH is composed of multiple cavities with mixed hydrophobic and hydrophilic properties, the role of which remains elusive. Using microsecond molecular dynamics (MD) simulations of FAAH embedded in a realistic membrane/water environment, we performed a comparative MD study of three FAAH/ligand complexes, namely FAAH in complex with AEA, PEA or OA. This provided a rational for substrate selectivity and relative rates of hydrolysis of the considered substrates. Overall, these findings complement existing experimental results and identify structural flexibility as a key determinant by which FAAH recognizes its main lipid substrates.

Fatty acid amide hydrolase (FAAH) substrate specificity understood via molecular dynamics

245th National Meeting (2013)

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