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Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition Reveals a Key Role for Endogenous Palmitoylethanolamide in Inflammation

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Selective N-Acylethanolamine-Hydrolyzing Acid Amidase Inhibition Reveals a Key Role for Endogenous Palmitoylethanolamide in Inflammation Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation Carlos Solorzanoa,1, Chenggang Zhub,1, Natalia Battistaa,c,d, Giuseppe Astaritaa, Alessio Lodolae, Silvia Rivarae, Marco More, Roberto Russob,2, Mauro Maccarronec,d, Francesca Antoniettif, Andrea Durantif, Andrea Tontinif, Salvatore Cuzzocreag, Giorgio Tarziaf, and Daniele Piomellia,b,h,3 Departments of aPharmacology and bBiological Chemistry, University of California, Irvine, CA 92697-4624; cDepartment of Biomedical Sciences, University of Teramo, I-64100 Teramo, Italy; dEuropean Center for Brain Research/Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) S. Lucia Foundation, I-00179 Rome, Italy; ePharmaceutical Department, University of Parma, I-43100 Parma, Italy; fInstitute of Medicinal Chemistry, University of Urbino ‘‘Carlo Bo’’, I-61029 Urbino, Italy; gIRCSS Centro Neurolesi ‘‘Bonino-Pulejo,’’ I-98100 Messina, Italy; and hDrug Discovery and Development, Italian Institute of Technology, I-161631 Genova, Italy Edited by L. L. Iversen, University of Oxford, Oxford, United Kingdom, and approved October 6, 2009 (received for review July 7, 2009) Identifying points of control in inflammation is essential to dis- in the midmicromolar range (median effective concentration, covering safe and effective antiinflammatory medicines. Palmi- EC50, 2–20 ␮M) (10); oxygenated fatty acids, such as (8S)- toylethanolamide (PEA) is a naturally occurring lipid amide that, hydroxy-eicosatetraenoic acid (11) and (8R)-hydroxy- when administered as a drug, inhibits inflammatory responses by 11(R),12(R)-epoxyeicosa-5Z,9E,14Z-trienoic acid (12) (EC50 engaging peroxisome proliferator-activated receptor-␣ (PPAR-␣). 0.3–1 ␮M); and lipid amides such as PEA and its analog PEA is preferentially hydrolyzed by the cysteine amidase N- oleoylethanolamide (OEA) (EC50 0.1–3 ␮M) (6, 13). Innate acylethanolamine-hydrolyzing acid amidase (NAAA), which is immune cells produce significant amounts of PEA and OEA (14) highly expressed in macrophages. Here we report the discovery of and express a selective phospholipase D (PLD) that releases a potent and selective NAAA inhibitor, N-[(3S)-2-oxo-3-oxetanyl]- these endogenous PPAR-␣ agonists from their membrane phos- 3-phenylpropanamide [(S)-OOPP], and show that this inhibitor pholipid precursor, N-acylphosphatidylethanolamine (NAPE) increases PEA levels in activated leukocytes and blunts responses (15). Inflammatory cells also express 2 intracellular amidases induced by inflammatory stimuli both in vitro and in vivo. These that have been implicated in lipid amide degradation: fatty-acid effects are stereoselective, mimicked by exogenous PEA, and amide hydrolase (FAAH) (16) and N-acylethanolamine- abolished by PPAR-␣ deletion. (S)-OOPP also attenuates inflamma- hydrolyzing acid amidase (NAAA) (17, 18). Potent FAAH tion and tissue damage and improves recovery of motor function inhibitors, such as the compound URB597 (19), have been used in mice subjected to spinal cord trauma. The results suggest that to unmask the functions of the substrate preferred by FAAH, the PEA activation of PPAR-␣ in leukocytes serves as an early stop endogenous cannabinoid agonist anandamide (20, 21). By con- signal that contrasts the progress of inflammation. The PEA- trast, effective inhibitors of intracellular NAAA activity, which hydrolyzing amidase NAAA may provide a previously undescribed preferentially recognizes PEA (17), have not been reported yet, target for antiinflammatory medicines. and the roles played by endogenous PEA in the control of inflammatory responses remain unknown. NAAA ͉ oleoylethanolamide ͉ PPAR-␣ Results oon after its isolation from plant tissues (1), palmitoyleth- Discovery of a Potent and Selective NAAA Inhibitor. NAAA is a Sanolamide (PEA) was shown to reduce allergic reactions and cysteine hydrolase that belongs to the N-terminal nucleophile inflammation in animals (2) and was briefly used to treat (Ntn) family of enzymes (17, 22). To discover new NAAA influenza symptoms in humans. Interest in the properties of this inhibitors, we generated a 3-dimensional model of the catalytic lipid amide lessened, however, until the characterization of its site of NAAA (Fig. 1A) using the crystallographic coordinates antiinflammatory (3), analgesic (4), and neuroprotective (5) of conjugated bile acid hydrolase (CBAH), another Ntn cysteine effects and the identification of peroxisome proliferator- hydrolase that shares with NAAA a highly conserved sequence activated receptor-␣ (PPAR-␣) as its primary molecular target in the catalytic N-terminal region (Fig. S1) (23–26). According (6, 7). Like other members of the nuclear receptor superfamily, to our model, the tetrahedral intermediate formed through PPAR-␣ is activated through ligand binding, which promotes attack of catalytic cysteine 131 (17) on PEA is stabilized by heterodimer formation with the 9-cis-retinoic acid receptor, electrostatic interactions between the carbonyl oxygen of PEA recruitment of coactivators into a multiprotein complex, and and the enzyme oxyanion hole, which includes the side-chain regulated expression of responsive genes. PPAR-␣ controls transcriptional programs involved in the development of inflam- mation through mechanisms that include direct interactions with Author contributions: C.S., C.Z., M. Mor, G.T., and D.P. designed research; C.S., C.Z., N.B., ␬ A.L., S.R., R.R., F.A., A.D., A.T., and S.C. performed research; G.A. and M. Maccarrone the proinflammatory transcription factors NF- B and AP1, and contributed new reagents/analytic tools; C.S., C.Z., N.B., A.L., S.R., M. Mor, R.R., S.C., G.T., modulation of I␬B function (8). Pharmacologic studies have and D.P. analyzed data; and C.S., C.Z., M. Mor, G.T., and D.P. wrote the paper. ␣ demonstrated that PPAR- agonists are therapeutically effec- Conflict of interest: D.P., G.T., A.D., A.T., and M. Mor are coinventors on a patent application tive in rodent models of inflammatory and autoimmune diseases filed by the Universities of California, Parma, and Urbino ‘‘Carlo Bo.’’ (9). Furthermore, mutant PPAR-␣-deficient mice seem to be This article is a PNAS Direct Submission. vulnerable to various inflammatory stimuli (9), suggesting that 1C.S and C.Z. contributed equally to this work. ␣ endogenous PPAR- activity negatively regulates the initiation 2Present address: Department of Experimental Pharmacology, University of Naples, Naples of acute inflammatory responses. 80131, Italy. The multifunctional ligand-binding pocket of PPAR-␣ allows 3To whom correspondence should be addressed. E-mail: [email protected]. this protein to recognize 3 distinct classes of natural agonists: This article contains supporting information online at www.pnas.org/cgi/content/full/ nonesterified fatty acids, which activate PPAR-␣ with potencies 0907417106/DCSupplemental. 20966–20971 ͉ PNAS ͉ December 8, 2009 ͉ vol. 106 ͉ no. 49 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0907417106 Downloaded by guest on October 1, 2021 A C 0.12 A B ## 120 100 URB597 cells) 75 6 80 0.06 50 (S)-OOPP 1 (R)-OOPP 25 ** 40 *** NAAA Activity of(% control) PEA (pmol/10 PEA 0 0 -8 -7 -6 -5 -4 Carr - - - + + + NAAA Activity (% of control) NAAA 0 *** *** *** *** *** Agent (log[M]) Comp - (S) (R) - (S) (R) S A G .t. 1 2 A 6 w 3 9 1 1 B D 0.8 C131AC N2 Y15 Y151F D150EA1 7 5000 Vehicle ### V =4062, K =14.69 Fig. 1. Properties of the active site of NAAA. (A) Computational model 4000 max m 0.6 illustrating the tetrahedral intermediate of PEA (green) within the active site of rat NAAA (gray). Red, oxygen; fuchsia, nitrogen; blue, hydrogen. Hydrogen 3000 0.4 ** bonds are symbolized by orange lines. (B) Site-directed mutagenesis of rat 2000 (S)-OOPP V =2549, K =14.50 NAAA; NAAA activity is expressed as percentage of wild-type control (w.t.). max m 0.2 Ͻ 1000 ***, P 0.001 vs. wild-type. (pmol/mg protein) PEA NAAA Activity NAAA (pmol/min/mg protein) 0 0 0 1 2 3 LPS - - - + + + [Substrate] (mM) Comp - (S) (R) - (S) (R) amide of the conserved asparagine 292 and the backbone amide of asparagine 209. Aspartate 150 is involved in the stabilization Fig. 2. Characterization of the NAAA inhibitor (S)-OOPP. (A) Concentration- of C131, whereas a hydrophobic pocket lined by tyrosine 151, dependent inhibition of NAAA activity by (S)-OOPP (filled triangles), com- among other residues, accommodates the flexible acyl chain of pound 1 (filled squares), (R)-OOPP (open triangles), and URB597 (filled circles). (B) Kinetic analysis of NAAA inhibition by (S)-OOPP (1 ␮M). Maximal reaction PEA. Site-directed mutagenesis experiments confirmed that Ϫl velocity (Vmax) and Michaelis constant are expressed in pmol⅐min ⅐mg pro- C131, N292, and D150 are essential for NAAA function because teinϪ1 and ␮mol/L, respectively. Vehicle, open squares; (S)-OOPP, filled the mutants C131A, C131S, N292A, and D150E were devoid of squares. (C and D) Effects of (S)-OOPP (S) and its enantiomer (R)-OOPP (R)on enzyme activity (Fig. 1B). Moreover, the negative impact of (C) carrageenan (Carr)-induced (0.1 mL, 1%) reduction in PEA levels in infil- mutations targeting Y151 (Y151A and Y151F) supports a con- trating leukocytes in vivo; and (D) LPS-induced reduction in PEA levels in tribution of the presumptive acyl chain-binding pocket to en- RAW264.7 macrophages in vitro. **, P Ͻ 0.01 vs. vehicle/vehicle; ##, P Ͻ 0.01 zyme function (Fig. 1B). Control mutations distal to the active vs. carrageenan/vehicle; ###, P Ͻ 0.001 vs. LPS/vehicle (n ϭ 3–8). site, such as alanine 176 (A176G), had no effect on NAAA activity (Fig. 1B). We used the active-site properties predicted by our model to select a set of commercial molecules, which were by implanting s.c. polyethylene sponges instilled with the proin- then tested for their ability to inhibit NAAA. Although the flammatory polysaccharide carrageenan. Three days after sur- enzyme was insensitive to most agents—including the FAAH gery, we collected infiltrating cells—mostly neutrophils (90.3% Ϯ 2.0%) and macrophages (6.1% Ϯ 0.9%, mean Ϯ SEM; inhibitor URB597 (Fig.
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