The proposed research represents an interdisciplinary effort to understand the pathways for the biosynthesis and metabolism of the fatty acid amide family of bioactive lipids, with a particular focus on a novel set of N-acyltransferases. The N-acyltransferases catalyze the following reaction: acyl-CoA + amine -> N-acylamine + CoA-SH. We have largely completed an evaluation of the endogenous fatty acid amidome in neuroblastoma cells and in Drosophila and need to complete our measurements of fatty acid amidome in choroid plexus cells. Once the baseline fatty acid amide lipidome is understood in these model systems, we will eliminate specific enzymes of fatty acid amide metabolism and measure the corresponding changes fatty acid amides - subtraction lipidomics. More detailed information will come from competitive pulse chase experiments. Over the past 20 years, it has become increasingly clear that the fatty acid amides are a broad family of cell-signaling lipids tremendously important to human health. The members of the fatty acid amide family include the N-acylethanolamines (NAEs), the N-acyldopamines (NADAs), the N-acyltaurines (NATs), N-acylamino acids (NAMAs), and the primary fatty acid amides (PFAMs). Recent studies have suggested that members of the fatty acid amide family are metabolically linked. Our goal is to better define the metabolic relationships between the members of the fatty acid amide family and elaborate the enzymes catalyzing these conversions. A full understanding of fatty acid amide metabolism and the enzymes involved is essential to ultimately developing new drugs and diagnostic strategies to treat human diseases related to fatty acid amide dysfunction.
Fatty acid amides are an emerging class of cell signaling lipids that are intimately involved in a number of human diseases, particular neurological disorders and chronic pain. The biosynthetic pathway for many of the fatty acid amides is not fully understood. We propose that novel N-acyltransferases have an important role in fatty acid amide production in vivo. The goal of this research is to better define the cellular spectrum of fatty acid amides (the fatty acid amidome) found in vivo, to develop a platform strategy to characterize novel N-acyltransferases in vitro, to elaborate the contribution of the characterized N-acyltransferases to fatty acid amidome, and to dissect the divergent pathways of fatty acid amide metabolism. A full understanding of fatty acid amide metabolism and the enzymes involved is essential to ultimately developing new drugs and diagnostic strategies to treat the human diseases related to fatty acid amide dysfunction.
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