Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis

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• 作者：Giulia Palermo ; Pablo Campomanes ; Marilisa Neri ; Daniele Piomelli ; Andrea Cavalli ; Ursula Rothlisberger ; Marco De Vivo
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2013
• 出版时间：February 12, 2013
• 年：2013
• 卷：9
• 期：2
• 页码：1202-1213
• 全文大小：720K
• 年卷期：v.9,no.2(February 12, 2013)
• ISSN：1549-9626

文摘

The serine hydrolase, fatty acid amide hydrolase (FAAH), is responsible for the intracellular degradation of anandamide and other bioactive fatty acid ethanolamides involved in the regulation of pain, inflammation, and other pathophysiological processes. The catalytic site of FAAH is composed of multiple cavities with mixed hydrophobic and hydrophilic properties, the role of which remains incompletely understood. Anandamide is thought to enter the active site through a 鈥渕embrane-access鈥?(MA) channel and position its flexible fatty acyl chain in a highly hydrophobic 鈥渁cyl chain-binding鈥?(AB) cavity to allow for hydrolysis to occur. Using microsecond molecular dynamics (MD) simulations of FAAH embedded in a realistic membrane/water environment, we show now that anandamide may not lock itself into the AB cavity but may rather assume catalytically significant conformations required for hydrolysis by moving its flexible arachidonoyl tail between the MA and AB cavities. This process is regulated by a phenylalanine residue (Phe432) located at the boundary between the two cavities, which may act as a 鈥?i>dynamic paddle.鈥?The results identify structural flexibility as a key determinant by which FAAH recognizes its primary lipid substrate.