Edward A. Dennis
University of California at San Diego, USA
Title: Phospholipase A2 Substrate and Inhibitor Specificity Revealed at the Molecular Level
Biography
Biography: Edward A. Dennis
Abstract
The phospholipase A2 (PLA2) superfamily exhibits a large array of functions, but of special interest is the inflammatory cascade which is initiated by the release of free arachidonic acid by some types of phospholipase A2, all of which interact with membrane phospholipids [Chem Rev, 111, 6130-85 (2011)]. However, different PLA2 types have unique three-dimensional structures and unique catalytic residues as well as specific tissue localization, distinct biological functions, and with which membrane phospholipids have unique allosteric interactions. Understanding how the different PLA2s associate with phospholipid membranes, specific phospholipid substrate molecules, and inhibitors on a structural and molecular basis has advanced in recent years due to the introduction of hydrogen/deuterium exchange mass spectrometry approaches [Annu Rev Biochem, 80, 301-25 (2011)]. We will emphasize recent results utilyzing hydrogen/deuterium exchange approaches and molecular dynamics [J Biol Chem, 288, 1806-13 (2013)] on the major types of PLA2, including secretory s-PLA2, cytosolic c-PLA2, lipoprotein-associated LpPLA2, and calcium-independent iPLA2 with inhibitors [J Am Chem Soc, 135, 1330-37 2013)] and substrates. We will also discuss new results on the precise nature and molecular dynamics of the interaction of these enzymes with specific substrate phospholipids pulled into the catalytic site from membranes [Proc Natl Acad Sci U S A, 112, E516-25 (2015)] and how new potent specific inhibitors block substrate phospholipid binding. Phospholipase A2 is the initiator of eicosanoid formation in inflammatory processes, so it is a critical enzyme and inhibitors could provide new approaches to disease treatment. [Nature Immunology Reviews, 15, 511-523 (2015)] [NIH GM 20,508-40]