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...

ceramides and sphingolipids ( 1, 2 ). Primary fatty acid amides (PFAM), R-CO-NH 2 with R being a long-chain fatty acid, were fi rst identifi ed from a biological source in 1989 with the identifi cation of palmitamide, palmitoleamide, oleamide, elaidamide, and linoleamide in luteal phase plasma ( 3 ). At the time of their discovery, the biological function of these mammalian PFAMs was unknown. Interest in the PFAMs dramatically intensifi ed with the discoveries that oleamide accumulated in the cerebrospinal fl uid (CSF) of sleep-deprived cats, that it is a natural component of the CSF in the cat, rat, and human, and that the administration of synthetic oleamide induced physiological sleep in rats ( 4 ). Intriguingly, later studies found that oleamide levels in the brain of the ground squirrel were ‫ف‬ 2.5-fold higher in hibernating animals relative to those found in nonhibernating animals ( 5 ). Other functions ascribed to oleamide, since its discovery as a sleep-inducing PFAM, include the ability to modulate gap junction communication in glial cells ( 6, 7 ), tracheal epithelial cells ( 8 ), seminiferous tubule cells ( 9 ), and fi broblasts ( 10 ); to allosterically activate the GABA A receptors and specifi c subtypes of the serotonin receptor ( 11-13 ); to affect memory processes ( 14 ); to increase food intake ( 15 ); to reduce anxiety and pain ( 16,17 ); to depress body temperature and locomotor activity ( 17,18 ); to stimulate Ca(II) release ( 19 ); and to relax blood vessels ( 20,21 ).Although much of the research regarding the PFAMs has focused on oleamide, studies show that some of the other known PFAMs are bioactive. Palmitamide is weakly anticonvulsant ( 22 ); linoleamide regulates Ca(II) fl ux ( 23 ) and inhibits the erg current ( 24 ); and erucamide stimulates Abstract Primary fatty acid amides (PFAM) are important signaling molecules in the mammalian nervous system, binding to many drug receptors and demonstrating control over sleep, locomotion, angiogenesis, and many other processes. Oleamide is the best-studied of the primary fatty acid amides, whereas the other known PFAMs are signifi cantly less studied. Herein, quantitative assays were used to examine the endogenous amounts of a panel of PFAMs, as well as the amounts produced after incubation of mouse neuroblastoma N 18 TG 2 and sheep choroid plexus (SCP) cells with the corresponding fatty acids or N -tridecanoylethanolamine. Although fi ve endogenous primary amides were discovered in the N 18 TG 2 and SCP cells, a different pattern of relative amounts were found between the two cell lines. Higher amounts of primary amides were found in SCP cells, and the conversion of N -tridecanoylethanolamine to tridecanamide was observed in the two cell lines. The data reported here show that the N 18 TG 2 and SCP cells are excellent model systems for the study of PFAM metabolism. Furthermore, the data support a role for the N -acylethanolamines as precursors for the PFAMs and provide valuable new kinetic results useful in modeling the metabolic fl ux throug...

Alginate lyase (AlgL) catalyzes the cleavage of the polysaccharide alginate through a β-elimination reaction. In Pseudomonas aeruginosa algL is part of the alginate biosynthetic operon, and although it is required for alginate biosynthesis, it is not clear why. Steady-state kinetic studies were performed to characterize its substrate specificity, and revealed that AlgL operates preferentially on non-acetylated alginate or its precursor mannuronan. Mature alginate is secreted as a partially acetylated polysaccharide, so this observation is consistent with suggestions that AlgL serves to degrade mislocalized alginate that is trapped in the periplasmic space. The kcat/Km for the reaction increased linearly with the number of residues in the substrate, from 2.1×105 M−1s−1 for substrate containing 16 residues to 7.9×106 M−1s−1 for substrate with 280 residues. Over the same substrate size range, kcat varied between 10 s−1 and 30 s−1. The variation in kcat/Km with substrate length suggests that AlgL operates in a processive manner. AlgL displayed a surprising lack of stereospecificity, in that it was able to catalyze cleavage adjacent to either mannuronate or guluronate residues in alginate. Thus, the enzyme is able to remove the C5 proton from both mannuronate and guluronate, which are C5 epimers. Exhaustive digestion of alginate by AlgL generated dimeric and trimeric products, which were characterized by 1H NMR spectroscopy and mass spectrometry. Rapid-mixing chemical quench studies revealed that there was no lag in dimer or trimer production, indicating that AlgL operates as an exopolysaccharide lyase.

The long-chain fatty acid amides are an emerging family of bioactive lipids with members that include N-acyl amino acids, primary fatty acid amides (PFAMs), N-acylarylalkylamides, N-acylethanolamines, and N-monoacylpolyamines. Fatty acid amides were first identified from biological sources over 50 years ago with the isolation and identification of N-palmitoylethanolamine from egg yolk in 1957 (1) and, in 1965, N-palmitoylethanolamine and N-stearoylethanolamine in several tissues from rat and guinea pig (2). The discovery of N-arachidonoylethanolamine (anandamide) as the endogenous ligand for the mammalian brain cannabinoid receptor CB 1 sparked a dramatic interest in the fatty acid amides (3). Since these early discoveries, a diversity of long-chain fatty acid amides have been identified in mammals and, more recently, in invertebrates as well (4)(5)(6)(7)(8).The N-fatty acylglycines, a subclass of the N-fatty acyl amino acids, are an important class of cell signaling lipids that are distributed throughout the central nervous system and the rest of the body (6, 7, 9). Identification of glycine conjugates dates back to the 1820s with the identification of N-benzoylglycine (hippurate) as a mammalian metabolite (10). N-arachidonoylglycine was the first longchain N-acylglycine identified from a mammalian source and was determined to have anti-nociceptive and antiinflammatory effects in rat models of pain (11). Since

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