Fatty Acid Amide Hydrolase: From Characterization to Therapeutics

Labar, Geoffray; Michaux, Catherine

doi:10.1002/cbdv.200790157

Cited by 78 publications

(45 citation statements)

References 103 publications

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“…[12,13,109,110] for recent reviews). Potential drug targets include the enzymes involved in fatty acid amide biosynthesis and degradation [111,112], transporters responsible for moving the fatty acid amides across the cell membranes [110], and analogs of the fatty acid amides themselves as agonists or antagonists for their respective receptors (Table 2) [13,113]. As detailed by Felder et al [110], the potential existence of specific transporters for anandamide and the other fatty acid amides is controversial, but accumulating evidence suggests that the simple passive diffusion of the these hydrophobic compounds across the membrane driven by FAAH-hydrolysis is insufficient to account for published anandamide uptake data.…”

Section: Pharmacological Importance Of the Fatty Acid Amidesmentioning

confidence: 99%

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Farrell

Merkler

2008

Drug Discovery Today

115

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The identification of two biologically active fatty acid amides, N-arachidonoylethanolamine (anandamide) and oleamide, has generated a great deal of excitement and stimulated considerable research. However, anandamide and oleamide are merely the best-known and best-understood members of a much larger family of biologically-occurring fatty acid amides. In this review, we will outline which fatty acid amides have been isolated from mammalian sources, detail what is known about how these molecules are made and degraded in vivo, and highlight their potential for the development of novel therapeutics. Keywords N-acylamino acid; N-acyldopamine; N-acylethanolamine; primary fatty acid amide; N-acylamideThe fatty acid amide bond has long been recognized in nature, being important in the structure of the ceramides [1] and the sphingolipids [2]. The first non-sphingosine based fatty acid amide isolated from a natural source was N-palmitoylethanolamine from egg yolk in 1957 [3]. Interest in the N-acylethanolamines (NAEs) dramatically increased upon the identification of Narachidonoylethanolamine (anandamide) as the endogenous ligand for the cannabinoid receptors in the mammalian brain [4]. It is now known that a family of NAEs is found in the brain and in other tissues [5,6].In addition to the NAEs, other classes of fatty acid amides have been characterized, namely the N-acylamino acids (NAAs) [7], the N-acyldopamines (NADAs) [8] and the primary fatty acid amides (PFAMs) [9,10] (Figure 1). Relative to NAEs, much less is currently known about the NAAs, the NADAs and the PFAMs, except that they are found in biological systems. The goal of this review is to summarize the current state of knowledge regarding the different classes of endogenous fatty acid amides and highlight their potential for drug discovery (see refs. [11-13] for earlier reviews) © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Merkler, D.J (E-mail: merkler@cas.usf.edu) phone 813-974-3579; fax 813-974-1733. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Teaser SentenceFatty acid amides are a family of mammalian bioactive compounds. These molecules and the enzymes involved in their metabolism provide an opportunity to develop new drugs to treat human disease. -palmitoyl-, N-stearoyl-and N-oleoylethanolamine [5,11], each compromising ≥25% of total brain NAEs. Other less abundant NAEs found in the brain are anandamide, N-linoleoyl-, N-linolenoyl-, N-dihomo-γ-linolenoyl-and N-docosatetraenoylethanolamine [11]. In addition to the brain, the NAEs are widespread in the peripheral tissues [5]. The mos...

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Section: Pharmacological Importance Of the Fatty Acid Amidesmentioning

confidence: 99%

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Farrell

Merkler

2008

Drug Discovery Today

115

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“…1 FAAH has a relatively wide substrate selectivity, as it also catalyzes the hydrolysis of other fatty acid ethanolamides (FAE)s including oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which are agonists of the peroxisome proliferator-activated receptor (PPAR) subtype alpha. 2 Multiple studies have shown that inactivation of FAAH by active-site directed inhibitors significantly increases the level of FAEs in vivo, leading to analgesic, anti-anxiety and anti-inflammatory effects, 3 without producing the unwanted side effects observed with direct CB 1 agonists, including hypothermia, cognitive and motor dysfunctions. 4 FAAH inhibition therefore represents an attractive therapeutic strategy for the treatment of several central nervous system disorders.…”

Section: Introductionmentioning

confidence: 99%

Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors

et al. 2013

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Carbamate and urea derivatives are important classes of fatty acid amide hydrolase (FAAH) inhibitors that carbamoylate the active-site nucleophile Ser241. In the present work, the reactivation mechanism of carbamoylated FAAH is investigated by means of a quantum mechanics/molecular mechanics (QM/MM) approach. The potential energy surfaces for decarbamoylation of FAAH covalent adducts, deriving from the O-aryl carbamate URB597 and from the N-piperazinylurea JNJ1661610, were calculated and compared to that for deacylation of FAAH acylated by the substrate oleamide. Calculations show that a carbamic group bound to Ser241 prevents efficient stabilization of transition states of hydrolysis, leading to large increments in the activation barrier. Moreover, the energy barrier for the piperazine carboxylate was significantly lower than that for the ciclohexyl carbamate derived from URB597. This is consistent with experimental data showing slowly reversible FAAH inhibition for the N-piperazinylurea inhibitor and irreversible inhibition for URB597.

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“…Toward this goal, two principal endocannabinoid enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL), are promising candidates for drug discovery, by modulating the effects of the two principal endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG), respectively, at the cannabinoid receptors 1 and 2 (CB1 and CB2) [4], [5]. Other important bioactive fatty acid amides, such as N -palmitoylethanolamine (PEA), N -oleoylethanolamine (OEA) and oleamide (OA), with no or very low affinity for the cannabinoid receptors, are potential substrates in FAAH and N -acylethanolamine-hydrolyzing acid amidase (NAAA) regulated metabolism.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Mass Spectrometric Characterization of Human N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition

et al. 2012

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The mechanism of inactivation of human enzyme N-acylethanolamine-hydrolyzing acid amidase (hNAAA), with selected inhibitors identified in a novel fluorescent based assay developed for characterization of both reversible and irreversible inhibitors, was investigated kinetically and using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). 1-Isothiocyanatopentadecane (AM9023) was found to be a potent, selective and reversible hNAAA inhibitor, while two others, 5-((biphenyl-4-yl)methyl)-N,N-dimethyl-2H-tetrazole-2-carboxamide (AM6701) and N-Benzyloxycarbonyl-L-serine β-lactone (N-Cbz-serine β-lactone), inhibited hNAAA in a covalent and irreversible manner. MS analysis of the hNAAA/covalent inhibitor complexes identified modification only of the N-terminal cysteine (Cys126) of the β-subunit, confirming a suggested mechanism of hNAAA inactivation by the β-lactone containing inhibitors. These experiments provide direct evidence of the key role of Cys126 in hNAAA inactivation by different classes of covalent inhibitors, confirming the essential role of cysteine for catalysis and inhibition in this cysteine N-terminal nucleophile hydrolase enzyme. They also provide a methodology for the rapid screening and characterization of large libraries of compounds as potential inhibitors of NAAA, and subsequent characterization or their mechanism through MALDI-TOF MS based bottom up-proteomics.

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Fatty Acid Amide Hydrolase: From Characterization to Therapeutics

Cited by 78 publications

References 103 publications

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Quantum Mechanics/Molecular Mechanics Modeling of Fatty Acid Amide Hydrolase Reactivation Distinguishes Substrate from Irreversible Covalent Inhibitors

Biochemical and Mass Spectrometric Characterization of Human N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition

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