Review of four major distinct types of human phospholipase A2

Abstract

The phospholipase A superfamily of enzymes plays a significant role in the development and progression of numerous inflammatory diseases. Through their catalytic action on membrane phospholipids, phospholipases are the upstream regulators of the eicosanoid pathway releasing free fatty acids for cyclooxygenases, lipoxygenases, and cytochrome P450 enzymes which produce various well-known inflammatory mediators including leukotrienes, thromboxanes and prostaglandins. Elucidating the association of phospholipases A with the membrane, the extraction and binding of phospholipid substrates, and their interactions with small-molecule inhibitors is crucial for the development of new anti-inflammatory therapeutics. Studying phospholipases has been challenging because they act on the surface of cellular membranes and micelles. Multidisciplinary approaches including hydrogen/deuterium exchange mass spectrometry, molecular dynamics simulations, and other computer-aided drug design techniques have been successfully employed by our laboratory to study interactions of phospholipases with membranes, phospholipid substrates and inhibitors. This review summarizes the application of these techniques to study four human recombinant phospholipases A.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…Computational studies have been also employed to simulate the interactions of PLA 2 s with substrates and cell membrane for the membrane-associated members [134]. The binding mode of a phospholipid into the active site of GIVA cPLA 2 and GVIA iPLA 2 has been explored using MD simulations driven by DXMS data [135].…”

A method for the quantitative determination of glycerophospholipid regioisomers by UPLC-ESI-MS/MS

“…PLA 2 hydrolyzes the sn-2 ester bond with high specificity, resulting in the formation of free fatty acids and the corresponding lyso-glycerophospholipid species [7]. For the standard PC 16:0/18:1, we found the opposite regioisomer PC 18:1/16:0 to contribute with 16.4%, while the standard PC 18:1/16:0 contained 11.9% of its opposite regioisomer (Table 1).…”

“…First attempts to discriminate between GP regioisomers made use of phospholipases that stereospecifically hydrolyze at either sn-1 or sn-2 position [7]. Quantification of the released lyso-GP species hereby allows deducing the relative abundance of each regioisomer in a GP of interest.…”

Toll/IMD signal pathways mediate cellular immune responses via induction of intracellular PLA2 expression

“…PLA 2 s play diverse roles in various biological functions, including digestion of lipids, remodeling of cellular membrane, signal transduction, immune defense of host, and production of various lipid mediators in mammals (Valentin & Lambeau, ). These PLA 2 genes are classified into at least 16 groups (GI–GXVI) based on amino acid sequence, molecular size, number of disulfide bond, and Ca 2+ requirement (Vasquez, Mouchlis, & Dennis, ). However, these PLA 2 s are traditionally classified as secretory PLA 2 (sPLA 2 ), cellular calcium‐dependent PLA 2 (cPLA 2 ), and cellular calcium‐independent PLA 2 (iPLA 2 ) depending on their function and cellular location (Burke & Dennis, ).…”