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J Biol Chem. 2016 Nov 18;291(47):24431-24448. Epub 2016 Aug 23.

Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease.

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  • 1From the Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, California 92093-0601 edennis@ucsd.edu.

Abstract

In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A2 (PLA2) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral information-containing signaling molecules; for example, PLA2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

KEYWORDS:

allosteric regulation; cell signaling; eicosanoid biosynthesis; enzyme mechanism; inflammation; lipid signaling; lipid-protein interaction; lipidomics; membrane enzyme; phospholipase

PMID:
27555328
PMCID:
PMC5114399
DOI:
10.1074/jbc.X116.723791
[PubMed - in process]
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