title: Membrane and inhibitor interactions of intracellular phospholipases A2.
abstract: Studying phospholipases A2 (PLA2s) is a challenging task since they act on membrane-like aggregated substrates and not on monomeric phospholipids. Multidisciplinary approaches that include hydrogen/deuterium exchange mass spectrometry (DXMS) and computational techniques have been employed with great success in order to address important questions about the mode of interactions of PLA2 enzymes with membranes, phospholipid substrates and inhibitors. Understanding the interactions of PLA2s is crucial since these enzymes are the upstream regulators of the eicosanoid pathway liberating free arachidonic acid (AA) and other polyunsaturated fatty acids (PUFA). The liberation of AA by PLA2 enzymes sets off a cascade of molecular events that involves downstream regulators such as cyclooxygenase (COX) and lipoxygenase (LOX) metabolites leading to inflammation. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) work by inhibiting COX, while Zileuton inhibits LOX and both rely on PLA2 enzymes to provide them with AA. That means PLA2 enzymes can potentially also be targeted to diminish inflammation at an earlier point in the process. In this review we describe extensive efforts reported in the past to define the interactions of PLA2 enzymes with membranes, substrate phospholipids and inhibitors using DXMS, molecular docking, and molecular dynamics (MD) simulations.
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Varnavas D
authors.initials: VD
authors.lastname: Mouchlis
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: edennis@ucsd.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001241:Aspirin / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D008084:Lipoxygenase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D054467:Phospholipases A2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010743:Phospholipids; D016718:Arachidonic Acid; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D054467:Phospholipases A2; D001241:Aspirin; C063449:zileuton; D006918:Hydroxyurea
keywords: Allosteric regulation; Catalytic cycle; DXMS; Eicosanoid pathway; Molecular dynamics simulations; PAPC; Phospholipase A(2)