Identification of an arylalkylamine N‐acyltransferase from Drosophila melanogaster that catalyzes the formation of long‐chain N‐acylserotonins

Dempsey, Daniel R.; Jeffries, Kristen A.; Anderson, Ryan L.; Carpenter, Anne-Marie; Opsina, Santiago Rodriquez; Merkler, David J.

doi:10.1016/j.febslet.2013.12.027

Cited by 32 publications

(73 citation statements)

References 26 publications

(39 reference statements)

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“…Another consideration regarding the presence of long-chain fatty acids in Drosophila is potential variations in the cellular levels of these compounds in different tissues [Table 2 and ref. 14], at different stages of development [24,32,33], and due to differences in their diet [29,31,34], further complicating reports of these trace metabolites. Similar conclusions regarding presence of ≥C 20 fatty acids and their metabolites were reached by Vrablik and Watts in a recent review [35].…”

Section: Resultsmentioning

confidence: 99%

“…Our demonstration that flies fed a diet supplemented with [1- 13 C]-palmitic acid led to the formation of 13 C- N -palmitoyldopamine, 13 C- N -palmitoylglycine, and 13 C-palmitamide is consistent with, but does not prove, that palmitoyl-CoA in a central palmitoyl donor in the biosynthesis of the different classes of palmitoylated fatty acid amides. We have recently identified and characterized an enzyme from D. melanogaster that catalyzes the formation of long-chain N -acylarylalkylamides, notably the N -acylserotonins and the N -acyldopamines, from the corresponding long-chain acyl-CoA thioesters and arylakylamine: acyl-CoA + serotonin (or dopamine) → N -acylserotonin (or N -acyldopamine) + CoA [14]. Importantly, we also found that the expression pattern of this enzyme in D. melanogaster co-localized to the tissues containing measurable levels of the endogenous long-chain N -acylserotonins.…”

Section: Resultsmentioning

confidence: 99%

“…These data are consistent with the formation of palmitoyl-CoA as a palmitoyl donor to other fatty acid amides. Relevant to this suggestion is our recent description of an N -acyltransferase catalyzing long-chain N -acylserotonin and N -acyldopamine production in D. melanogaster [14], acyl-CoA + serotonin (or dopamine) → N -acylserotonin (or N -acyldopamine) + CoA-SH. In sum, these findings reported herein establish that D. melanogaster is a useful and intriguing invertebrate model for the study of long-chain fatty acid amide metabolism.…”

Section: Introductionmentioning

confidence: 99%

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Drosophila melanogaster as a model system to study long‐chain fatty acid amide metabolism

et al. 2014

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Long-chain fatty acid amides are cell-signaling lipids identified in mammals and, recently, in invertebrates, as well. Many details regarding fatty acid amide metabolism remain unclear. Herein, we demonstrate that Drosophila melanogaster is an excellent model system for the study long-chain fatty acid amide metabolism as we have quantified the endogenous levels of N-acylglycines, N-acyldopamines, N-acylethanolamines, and primary fatty acid amides by LC/QTOF-MS. Growth of Drosophila melanogaster on media supplemented with [1-13C]-palmitate lead to a family of 13C-palmitate-labeled fatty acid amides in the fly heads. The [1-13C]-palmitate feeding studies provide insight into the biosynthesis of the fatty acid amides.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drosophila melanogaster as a model system to study long‐chain fatty acid amide metabolism

et al. 2014

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“…The increases in N-acyldopamine levels were unexpected, but could be due to an increase in acyl-CoAs available for conjugation to dopamine by an unidentified arylalkylamine N-acyltransferase-like (AANATL) enzyme. In Drosophila, AANATL2 catalyzes the formation of long-chain N-acyldopamines in vitro (35,36) and we propose that a mammalian AANATL2 ortholog could be responsible for N-acyldopamine formation in the N 18 TG 2 cells.…”

Section: Cells Express Glyatl3 Transcriptsmentioning

confidence: 86%

Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

Jeffries

Dempsey²,

Farrell³

et al. 2016

Journal of Lipid Research

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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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“…1–4 We have proposed that one route for the biosynthesis of the fatty acid amides involves the reaction of an amine with a fatty acyl-CoA in a reaction catalyzed by an N- acyltransferase: R-CO-S-CoA + H 2 N-R′ → R-CO-NH-R′ + CoA-SH. Drosophila melanogaster is an excellent model system for the study of fatty acid amide metabolism because these insects (a) produce fatty acid amides, 2–4 (b) are inexpensive to grow and maintain, (c) possess a genome that has been sequenced, and (d) can be manipulated genetically with relative ease. Intriguingly, we and others have identified the genes of seven putative N -acyltransferases in D. melanogaster by “genome mining” using the DNA sequences of known N- acetyltransferases.…”

mentioning

confidence: 99%

Mechanistic and Structural Analysis of a Drosophila melanogaster Enzyme, Arylalkylamine N-Acetyltransferase Like 7, an Enzyme That Catalyzes the Formation of N-Acetylarylalkylamides and N-Acetylhistamine

et al. 2015

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Arylalkylamine N-acetyltransferase like 7 (AANATL7) catalyzes the formation of N-acetylarylalkylamides and N-acetylhistamine from acetyl-CoA and the corresponding amine substrate. AANATL7 is a member of the GNAT superfamily of >10000 GCN5-related N-acetyltransferases, many members being linked to important roles in both human metabolism and disease. Drosophila melanogaster utilizes the N-acetylation of biogenic amines for the inactivation of neurotransmitters, the biosynthesis of melatonin, and the sclerotization of the cuticle. We have expressed and purified D. melanogaster AANATL7 in Escherichia coli and used the purified enzyme to define the substrate specificity for acyl-CoA and amine substrates. Information about the substrate specificity provides insight into the potential contribution made by AANATL7 to fatty acid amide biosynthesis because D. melanogaster has emerged as an important model system contributing to our understanding of fatty acid amide metabolism. Characterization of the kinetic mechanism of AANATL7 identified an ordered sequential mechanism, with acetyl-CoA binding first followed by histamine to generate an AANATL7·acetyl-CoA·histamine ternary complex prior to catalysis. Successive pH–activity profiling and site-directed mutagenesis experiments identified two ionizable groups: one with a pKa of 7.1 that is assigned to Glu-26 as a general base and a second pKa of 9.5 that is assigned to the protonation of the thiolate of the coenzyme A product. Using the data generated herein, we propose a chemical mechanism for AANATL7 and define functions for other important amino acid residues involved in substrate binding and regulation of catalysis.

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Identification of an arylalkylamine N‐acyltransferase from Drosophila melanogaster that catalyzes the formation of long‐chain N‐acylserotonins

Cited by 32 publications

References 26 publications

Drosophila melanogaster as a model system to study long‐chain fatty acid amide metabolism

Drosophila melanogaster as a model system to study long‐chain fatty acid amide metabolism

Glycine N-acyltransferase-like 3 is responsible for long-chain N-acylglycine formation in N18TG2 cells

Mechanistic and Structural Analysis of a Drosophila melanogaster Enzyme, Arylalkylamine N-Acetyltransferase Like 7, an Enzyme That Catalyzes the Formation of N-Acetylarylalkylamides and N-Acetylhistamine

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