Publication

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

Résumé

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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Proximité ontologique
Concepts associés (34)
N-Acylethanolamine
An N-acylethanolamine (NAE) is a type of fatty acid amide where one of several types of acyl groups is linked to the nitrogen atom of ethanolamine, and highly metabolic formed by intake of essential fatty acids through diet by 20:4, n-6 and 22:6, n-3 fatty acids, and when the body is physically and psychologically active,.
Site actif
Le site actif désigne en catalyse la partie du catalyseur qui va interagir avec le(s) substrat(s) pour former le(s) produit(s). Cette notion concerne tous les types de catalyseurs, mais on l'associe généralement aux enzymes. Le site actif des catalyseurs fait l'objet d'études poussées dans le cadre de la recherche de nouveaux catalyseurs et de l'étude des mécanismes réactionnels en biochimie.. Or, si la structure du site actif est modifié, la catalyse ne peut avoir lieu.
Hydrolase des amides d'acides gras
Fatty-acid amide hydrolase 1 or FAAH-1(, oleamide hydrolase, anandamide amidohydrolase) is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA), an N-acylethanolamine (NAE) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of NAE's in Dictyostelium discoideum, as they modulate their NAE levels in vivo through the use of a semispecific FAAH inhibitor.
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