Selective
            <i>N</i>
            -acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation

Solórzano, Carlos Ortiz de; Zhu, Chenggang; Battista, Natalia; Astarita, Giuseppe; Lodola, Alessio; Rivara, Silvia; Mor, Marco; Russo, Roberto; Maccarrone, Mauro; Antonietti, Francesca; Duranti, Andrea; Tontini, Andrea; Cuzzocrea, Salvatore; Tarzia, Giorgio; Piomelli, Daniele

doi:10.1073/pnas.0907417106

Cited by 210 publications

(328 citation statements)

References 52 publications

Supporting

Mentioning

297

Contrasting

Order By: Relevance

“…7 -9 Other endocannabinoid-like compounds have been described to date, such as N -palmitoylethanolamine (PEA) and oleoylethanolamide, which are unable to bind with significant affinity to either CB1 and CB2. 11 Endocannabinoid signaling is terminated by specific degradation systems involving their cellular uptake by a facilitated transport mechanism and their hydrolysis by fatty acid amide hydrolase (FAAH) for AEA, monoacylglycerol lipase for 2-AG, and N -acylethanolamine-hydrolyzing acid amidase for PEA. 7,11 Although AEA synthesis might be because of several metabolic routes, N -acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) is currently considered the major enzyme responsible for AEA production, 12 whereas 2-AG synthesis is mainly mediated by diacylglycerol lipase.…”

Section: Introductionmentioning

confidence: 99%

“…11 Endocannabinoid signaling is terminated by specific degradation systems involving their cellular uptake by a facilitated transport mechanism and their hydrolysis by fatty acid amide hydrolase (FAAH) for AEA, monoacylglycerol lipase for 2-AG, and N -acylethanolamine-hydrolyzing acid amidase for PEA. 7,11 Although AEA synthesis might be because of several metabolic routes, N -acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) is currently considered the major enzyme responsible for AEA production, 12 whereas 2-AG synthesis is mainly mediated by diacylglycerol lipase. 7,13 Several synthetic compounds have been shown to efficiently block either endocannabinoid uptake or degradation, thus providing…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

et al. 2011

View full text Add to dashboard Cite

Activation of cannabinoid receptors (CBs) by endocannabinoids impacts on a number of gastrointestinal functions. Recent data indicate that CB1 agonists improve 2,4-dinitrobenzene sulfonic acid-induced colitis in mice, thus suggesting a role for the endocannabinoid agonist anandamide (AEA) in protecting the gut against inflammation. We here examined the gut endocannabinoid system in inflammatory bowel disease (IBD) patients, and investigated the ex vivo and in vitro effects of the non-hydrolysable AEA analog methanandamide (MAEA) on the mucosal proinflammatory response. The content of AEA, but not of 2-arachidonoyl-glycerol and N-palmitoylethanolamine, was significantly lower in inflamed than uninflamed IBD mucosa, and this was paralleled by lower activity of the AEA-synthesizing enzyme N-acyl-phosphatidylethanolamine-specific phospholipase D and higher activity of the AEA-degrading enzyme fatty acid amide hydrolase. MAEA significantly downregulated interferon-γ and tumor necrosis factor-α secretion by both organ culture biopsies and lamina propria mononuclear cells. Although these results are promising, further studies are needed to determine the role of cannabinoid pathways in gut inflammation.[...

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

et al. 2011

View full text Add to dashboard Cite

show abstract

mentioning

confidence: 99%

“…Processing of NAAA renders a cysteine residue (Cys131 in mice and rats and Cys126 in humans) the N-terminal amino acid and catalytic nucleophile. 18,21,22 Pharmacological blockade of intracellular NAAA activity results in a normalization of OEA and PEA levels, which are markedly reduced in inflammatory states, 18,23,24 and exerts profound anti-inflammatory effects in animal models. 18 These findings suggest that NAAA inhibition might represent a novel mechanistic approach to control inflammation.…”

mentioning

confidence: 99%

“…18,25,26 Among them is a class of substituted β-lactones, which shows promising potency and target selectivity. 18,26 The prototype of this class, (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropanamide [(S)-OOPP, Figure 1], is a potent noncompetitive NAAA inhibitor that is highly effective at preventing PEA and OEA hydrolysis in activated inflammatory cells and at reducing tissue reactions to various proinflammatory stimuli. 18 We have recently used the structure of (S)-OOPP as a starting point to discover β-lactone-based NAAA inhibitors with improved potency.…”

mentioning

confidence: 99%

See 1 more Smart Citation

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

Armirotti

Romeo

Ponzano

et al. 2012

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

ABSTRACT:The cysteine amidase N-acylethanolamine acid amidase (NAAA) is a member of the N-terminal nucleophile class of enzymes and a potential target for anti-inflammatory drugs. We investigated the mechanism of inhibition of human NAAA by substituted β-lactones. We characterized pharmacologically a representative member of this class, ARN077, and showed, using high-resolution liquid chromatography−tandem mass spectrometry, that this compound forms a thioester bond with the N-terminal catalytic cysteine in human NAAA. KEYWORDS: NAAA, cysteine amidase, covalent inhibitors, high resolution mass spectrometry, proteomics T he fatty acid ethanolamides (FAEs) are a family of bioactive lipid molecules that have attracted considerable interest due to their potential role in the control of pain, inflammation, and energy metabolism. Two structurally and functionally distinct classes of FAEs have been described. Polyunsaturated FAEs, such as arachidonoylethanolamide (anandamide) and eicosapentaenoylethanolamide, are endogenous agonists of G protein-coupled cannabinoid receptors. 1,2 These compounds are thought to act as retrograde messengers at synapses of the central nervous system and as local mediators in peripheral tissues. In the brain, anandamide-mediated signaling at CB 1 type cannabinoid receptors has been implicated in the regulation of anxiety, 3 depression, 4,5 stress-induced analgesia, 6 and nausea. 7 Outside the brain, anandamide released at sites of tissue injury is thought to control the initiation of emerging pain signals, 8,9 presumably by reducing the local release of proalgesic and proinflammatory factors from nociceptive nerve terminals. 10 The biological actions of anandamide are interrupted by a two-step deactivation process consisting of carriermediated transport into cells 11,12 followed by intracellular hydrolysis, which is catalyzed by the membrane-bound serine hydrolase, fatty acid amide hydrolase (FAAH). Inhibitors of this enzyme protect anandamide from deactivation and selectively magnify its intrinsic actions, producing an array of pharmacological effects that include reduced anxiety, depression, and pain. 13 Saturated and monounsaturated FAEs, which include oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), do not productively interact with cannabinoid receptors. These compounds are, however, potent or moderately potent agonists of nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is responsible for most of their analgesic and anti-inflammatory properties. 14−16 OEA and PEA are produced in many mammalian tissues, including neurons 17 and innate immune cells, 18 where a selective phospholipase D releases them by cleaving the membrane precursor, N-acyl-phosphatidylethanolamine. 19 They are deactivated either by FAAH, which prefers anandamide and OEA over PEA, or by NAAA, which conversely prefers PEA and OEA over anandamide. 20 Despite its functional similarity with FAAH, NAAA shares no homology with this or other enzymes of the same "amidase signature" family. Rather,...

show abstract

Metabolism of N ‐Acylethanolamines: To Phase II and Back Again

Karlsson

Fowler

2017

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Selective N -acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation

Abstract: Identifying points of control in inflammation isNAAA ͉ oleoylethanolamide ͉ PPAR-␣

Cited by 210 publications

References 52 publications

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease

β-Lactones Inhibit N-acylethanolamine Acid Amidase by S-Acylation of the Catalytic N-Terminal Cysteine

Metabolism of N ‐Acylethanolamines: To Phase II and Back Again

Contact Info

Product

Resources

About