<i>N</i>-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons

Rimmerman, Neta; Bradshaw, Heather B.; Hughes, H. Velocity; Chen, Jay Shih Chieh; Hu, Sherry Shu Jung; McHugh, Douglas; Vefring, Eivind; Jahnsen, Jan Anker; Thompson, Eric L.; Masuda, Kim; Cravatt, Benjamin F.; Burstein, Sumner; Vasko, Michael R.; Prieto, Anne L.; O'Dell, David K.; Walker, J. Michael

doi:10.1124/mol.108.045997

Cited by 79 publications

(83 citation statements)

References 44 publications

(59 reference statements)

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“…This strategy has been developed for identifying and quantifying such molecular entities in tissue extracts at high efficiency and sensitivity (13,14). This screening confirmed the presence of several known compounds, such as anandamide and oleoyl ethanolamide, as well as a previously unexplored constituent, OS (Figs.…”

Section: Os Occurs Naturally In Bonementioning

confidence: 63%

“…Quantification of OS by HPLC/ MS/MS was similar to methods previously described (13). Exceptions to this protocol were that the chromatographic methods were optimized to the OS standard in which multiple reaction monitoring measured the OS 368[H − ] parent mass paired to the 104[H − ] fragment, and the gradients were optimized to OS peak retention parameters.…”

Section: Methodsmentioning

confidence: 99%

“…Methods used previously for the isolation and identification of N-palmitoyl glycine were employed (13), with the exception that the optimization parameters were based on the retention times and molecular weight of OS. In brief, a modified Folch extraction was performed on the reported tissues.…”

Section: Methodsmentioning

confidence: 99%

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Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-L-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-κB ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.fatty acyl amides I n mammals, including humans, bone mass is determined by an unremitting remodeling process whereby the mineralized matrix is continuously removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. This process is regulated by autocrine/paracrine factors, such as receptor activator of nuclear-κB ligand (RANKL), osteoprotegerin (OPG), bone morphogenetic proteins, and Wnt, as well as circulating hormones (e.g., sex steroids, parathyroid hormone) and brain-derived signals (e.g., sympathetic, pituitary) (1-3). Imbalanced bone remodeling leads to skeletal pathologies, mainly osteoporosis, the most common degenerative disorder in affluent societies, which results from a net increase in bone resorption (4). Identification of endogenous constituents, which regulate bone remodeling and skeletal mass, contributes to the elucidation of the mechanisms involved in this process and offers promise for developing novel antiosteoporotic pharmacotherapy.Amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) represent a major group of endogenous lipids. In mammalian tissues they have numerous physiological functions. For example, anandamide (arachidonoyl ethanolamide) is the first identified endogenous psychoactive ligand of cannabinoid receptors (5); arachidonoyl serine is an endogenous vasodilator, which does not bind to the cannabinoid receptors (6); and oleoyl ethanolamide is an endogenous structural analog to anandamide that regulates food intake through the activation of GPR 119 (7, 8). The well-established biosynthetic tendency to follow existing p...

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Section: Os Occurs Naturally In Bonementioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

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Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Smoum

Bar²,

Tan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…G2A has been implicated in autoimmune disease and atherosclerosis, which are both diseases where host-microbial interactions are thought to play a role (31)(32)(33). The structural similarity between commendamide and a broad class of eukaryotic signaling molecules is striking and suggests that chemical mimicry may be a mechanism used by commensal bacteria to facilitate interactions with their human host (34,35).…”

Section: Significancementioning

confidence: 99%

“…The best studied of these is N-arachidonylethanolamide (anandamide), an endogenous ligand for the cannabinoid GPCR CB1 (57). Other endogenous long-chain N-acyl glycines and ethanolamines are reported to activate diverse receptors including many GPCRs (34,35,58,59). For example, N-arachidonyl-glycine activates GPR18 and T-type calcium channels; N-palmitoyl-ethanolamide activates GPR119, GPR55, and PPARα; and N-palmitoyl-glycine is believed to act through an unidentified GPCR in sensory nerves (Fig.…”

Section: Comparative Phylogenetic and Functional Analysis Of Effectormentioning

confidence: 99%

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Cohen

Kang

Chu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

151

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The trillions of bacteria that make up the human microbiome are believed to encode functions that are important to human health; however, little is known about the specific effectors that commensal bacteria use to interact with the human host. Functional metagenomics provides a systematic means of surveying commensal DNA for genes that encode effector functions. Here, we examine 3,000 Mb of metagenomic DNA cloned from three phenotypically distinct patients for effectors that activate NF-κB, a transcription factor known to play a central role in mediating responses to environmental stimuli. This screen led to the identification of 26 unique commensal bacteria effector genes (Cbegs) that are predicted to encode proteins with diverse catabolic, anabolic, and ligand-binding functions and most frequently interact with either glycans or lipids. Detailed analysis of one effector gene family (Cbeg12) recovered from all three patient libraries found that it encodes for the production of N-acyl-3-hydroxypalmitoyl-glycine (commendamide). This metabolite was also found in culture broth from the commensal bacterium Bacteroides vulgatus, which harbors a gene highly similar to Cbeg12. Commendamide resembles long-chain N-acyl-amides that function as mammalian signaling molecules through activation of G-protein–coupled receptors (GPCRs), which led us to the observation that commendamide activates the GPCR G2A/GPR132. G2A has been implicated in disease models of autoimmunity and atherosclerosis. This study shows the utility of functional metagenomics for identifying potential mechanisms used by commensal bacteria for host interactions and outlines a functional metagenomics-based pipeline for the systematic identification of diverse commensal bacteria effectors that impact host cellular functions.

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Enzymatic Strategies for the Biosynthesis of N‐Acyl Amino Acid Amides

Kua,

Nguyen,

2024

ChemBioChem

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Amide bond‐containing biomolecules are functionally significant and useful compounds with diverse applications. For example, N‐acyl amino acids (NAAAs) are an important class of lipoamino acid amides with extensive use in food, cosmetic and pharmaceutical industries. Their conventional chemical synthesis involves the use of toxic chlorinating agents for carboxylic acid activation. Enzyme‐catalyzed biotransformation for the green synthesis of these amides is therefore highly desirable. Here, we review a range of enzymes suitable for the synthesis of NAAA amides and their strategies adopted in carboxylic acid activation. Generally, ATP‐dependent enzymes for NAAA biosynthesis are acyl‐adenylating enzymes that couple the hydrolysis of phosphoanhydride bond in ATP with the formation of an acyl‐adenylate intermediate. In contrast, ATP‐independent enzymes involve hydrolases such as lipases or aminoacylases, which rely on the transient activation of the carboxylic acid. This occurs either through an acyl‐enzyme intermediate or by favorable interactions with surrounding residues to anchor the acyl donor in a suitable orientation for the incoming amine nucleophile. Recently, the development of an alternative pathway involving ester‐amide interconversion has unraveled another possible strategy for amide formation through esterification‐aminolysis cascade reactions, potentially expanding the substrate scope for enzymes to catalyze the synthesis of a diverse range of NAAA amides.

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N-Palmitoyl Glycine, a Novel Endogenous Lipid That Acts As a Modulator of Calcium Influx and Nitric Oxide Production in Sensory Neurons

Cited by 79 publications

References 44 publications

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Oleoyl serine, an endogenous N -acyl amide, modulates bone remodeling and mass

Functional metagenomic discovery of bacterial effectors in the human microbiome and isolation of commendamide, a GPCR G2A/132 agonist

Enzymatic Strategies for the Biosynthesis of N‐Acyl Amino Acid Amides

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