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J Am Chem Soc. 2017 Apr 5;139(13):4943-4947. doi: 10.1021/jacs.7b01269. Epub 2017 Mar 28.

Stereochemistry of Endogenous Palmitic Acid Ester of 9-Hydroxystearic Acid and Relevance of Absolute Configuration to Regulation.

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Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California-San Diego , 9500 Gilman Drive, La Jolla, California 92093-0934, United States.
Department of Chemistry, University of Texas at Austin , 105 East 24th Street, A5300, Austin, Texas 78712-1224, United States.
School of Medicine, University of Texas Medical Branch , 301 University Boulevard, Galveston, Texas 77555, United States.
Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies , 10010 North Torrey Pines Road, La Jolla, California 92037-1002, United States.
Division of Endocrinology, Diabetes, Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts 02215, United States.


Lipids have fundamental roles in the structure, energetics, and signaling of cells and organisms. The recent discovery of fatty acid esters of hydroxy fatty acids (FAHFAs), lipids with potent antidiabetic and anti-inflammatory activities, indicates that our understanding of the composition of lipidome and the function of lipids is incomplete. The ability to synthesize and test FAHFAs was critical in elucidating the roles of these lipids, but these studies were performed with racemic mixtures, and the role of stereochemistry remains unexplored. Here, we synthesized the R- and S- palmitic acid ester of 9-hydroxystearic acid (R-9-PAHSA, S-9-PAHSA). Access to highly enantioenriched PAHSAs enabled the development of a liquid chromatography-mass spectrometry (LC-MS) method to separate and quantify R- and S-9-PAHSA, and this approach identified R-9-PAHSA as the predominant stereoisomer that accumulates in adipose tissues from transgenic mice where FAHFAs were first discovered. Furthermore, biochemical analysis of 9-PAHSA biosynthesis and degradation indicate that the enzymes and pathways for PAHSA production are stereospecific, with cell lines favoring the production of R-9-PAHSA and carboxyl ester lipase (CEL), a PAHSA degradative enzyme, selectively hydrolyzing S-9-PAHSA. These studies highlight the role of stereochemistry in the production and degradation of PAHSAs and define the endogenous stereochemistry of 9-PAHSA in adipose tissue. This information will be useful in the identification and characterization of the pathway responsible for PAHSA biosynthesis, and access to enantiopure PAHSAs will elucidate the role of stereochemistry in PAHSA activity and metabolism in vivo.

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