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Palermo G, Campomanes P, Neri M, et al. Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis. J Chem Theory Comput. 2013;9(2):1202-13doi: 10.1021/ct300611q.
Palermo, G., Campomanes, P., Neri, M., Piomelli, D., Cavalli, A., Rothlisberger, U., & De Vivo, M. (2013). Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis. Journal of chemical theory and computation, 9(2), 1202-13. https://doi.org/10.1021/ct300611q
Palermo, Giulia, et al. "Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis." Journal of chemical theory and computation vol. 9,2 (2013): 1202-13. doi: https://doi.org/10.1021/ct300611q
Palermo G, Campomanes P, Neri M, Piomelli D, Cavalli A, Rothlisberger U, De Vivo M. Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis. J Chem Theory Comput. 2013 Feb 12;9(2):1202-13. doi: 10.1021/ct300611q. Epub 2013 Jan 15. PMID: 26588763.
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J Chem Theory Comput. 2013 Feb 12;9(2):1202-13. doi: 10.1021/ct300611q. Epub 2013 Jan 15.

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

Journal of chemical theory and computation

Giulia Palermo, Pablo Campomanes, Marilisa Neri, Daniele Piomelli, Andrea Cavalli, Ursula Rothlisberger, Marco De Vivo

Affiliations

  1. Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy.
  2. Laboratory of Computational Chemistry and Biochemistry, Institute of Chemical Sciences and Engineering, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
  3. Department of Anatomy and Neurobiology, University of California, Irvine, California 92697, United States.
  4. Department of Pharmaceutical Sciences, University of Bologna, via Belmeloro 6, I-40126 Bologna, Italy.

PMID: 26588763 DOI: 10.1021/ct300611q

Abstract

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 "membrane-access" (MA) channel and position its flexible fatty acyl chain in a highly hydrophobic "acyl chain-binding" (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 "dynamic paddle." The results identify structural flexibility as a key determinant by which FAAH recognizes its primary lipid substrate.

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