In the search for enzyme inhibitors of compounds such as anandamide, oleamide and palmitoylethanolamide the group of dr Palermo et al tested new structural enzymatic frameworks to regulate substrate specificity in lipid-degrading enzymes such as fatty acid amide hydrolase (FAAH).
They identified novel mechanism and key features for lipid selection in FAAH and analysed these in the context of other relevant lipid-degrading enzymes.
Here the FAAH protein (pdb 1MT5) is seen, in complex with anandamide, embedded in a 1-palmitoyl-2-oleoyl-phosphatidylethanolamine(POPE) lipid bilayer.
This comparative study revealed that FAAH selectively accommodates anandamide into a multi-pocket binding site, and properly orients it in pre-reactive conformations for efficient hydrolysis. The authors suggested that these results could also be extended to other lipid-processing enzymes where the presence of multiple binding cavities and gating residues have been indicated to be relevant for enzyme selectivity and function.
Palermo G, Bauer I, Campomanes P, Cavalli A, Armirotti A, Girotto S, Rothlisberger U, De Vivo M. Keys to Lipid Selection in Fatty Acid Amide Hydrolase Catalysis: Structural Flexibility, Gating Residues and Multiple Binding Pockets. PLoS Comput Biol. 2015 Jun 25;11(6):e1004231.