More than thirty enzymes with PLA activity

More than thirty enzymes with PLA2 activity have been described and, based on sequence similarities, they are currently classified in 16 groups, each containing several sub-groups [16]. However, based on biochemical features these enzymes are frequently grouped into six major families: secreted phospholipase A2s (sPLA2), calcium-independent phospholipase A2s (iPLA2), cytosolic phospholipase A2s (cPLA2), platelet activating factor acetylhydrolases (PAF-AH, also known as lipoprotein-associated phospholipase A2, Lp-PLA2), lysosomal phospholipase A2 (L-PLA2) and the adipose phospholipase A (AdPLA2) [[16], [17], [18], [19], [20]]. Extensive in vitro kinetic studies have been recently carried out with most of these enzymes. Many of the studies have taken advantage of the analytical power of mass spectrometry-based lipidomics [[21], [22], [23], [24]], which provided valuable information as to the substrate preference of these enzymes. Nevertheless, factors that take part in the microenvironment of the enzymes, such as the complex membrane composition, compartmentalization of the enzyme and the different physiological and pathophysiological scenarios of the cell (including cross-talk between PLA2 forms), may produce as a result a variety of lipid molecules that orchestrate global responses and cannot be easily reproduced in in vitro assays. In general terms, PLA2s participate in the Lands cycle of phospholipid fatty Benzoylhypaconitine recycling [1,15,25], whereby the fatty acid composition at the sn-2 position of phospholipids is tightly controlled by a balance between hydrolytic reactions mediated by PLA2s versus activation of the free fatty acid by acyl-CoA synthetases and subsequent incorporation into phospholipids by lysophospholipid:acyl-CoA acyltransferases. Further remodeling reactions also occur that are catalyzed primarily by CoA-independent transacylase (CoA-IT) [15,26,27]. In resting cells the reacylation reactions dominate, but in stimulated cells the dominant reaction is the PLA2-mediated deacylation step, which results in a dramatic increase in the levels of free fatty acids, notably AA and omega-3 fatty acids, which will now be available for eicosanoid [1,14,15,28,29] or SPM [[30], [31], [32]] synthesis, depending on the temporal phase of the activation process (Fig. 1). While our current knowledge on the mechanisms governing the expression levels of PLA2s both at gene and protein level is still scarce for the majority of members of this superfamily of enzymes, much information has accumulated on the cellular regulation of their enzymatic activities and in vitro substrate preferences. This review is aimed at relating recent findings on the ability of PLA2s to selectively hydrolyze different phospholipid substrates in cells with the generation of bioactive lipid mediators. Key current studies are discussed, focusing primarily on cPLA2α, iPLA2-VIA, sPLA2-V and sPLA2-X, as these are the PLA2 forms classically involved in the production of fatty acid-derived mediators [15,[33], [34], [35], [36]].
Group IVA PLA2, also known as cytosolic phospholipase A2α (cPLA2α), is long known to exhibit marked preference for phospholipid substrates containing AA at the sn-2 position. The aromatic residues of cPLA2α interact with the double bonds of AA, making the enzyme selective for this fatty acid. cPLA2α also displays significant activity towards EPA but, very remarkably, it shows little or no activity towards DHA [21,24,37]. This may be related to the fact that, unlike AA or EPA, DHA does not have a double bond at C5; thus the fatty acid does not adjust well within the cPLA2α\'s active site [16,24,37,38]. cPLA2α is widely accepted as the critical enzyme regulating AA mobilization in cells under a wide variety of activation conditions [[39], [40], [41], [42]]. Various cross-talk mechanisms involving cPLA2α and sPLA2 have been described that result in amplified AA mobilization responses [[43], [44], [45], [46], [47], [48], [49], [50]]. A number of recent reviews are available that cover in a comprehensive manner different aspects of cPLA2α biochemistry and cell regulation, and the reader is kindly referred to these for specific details [15,16,33,[51], [52], [53]]. In the following we focus on recent studies that have unveiled previously unrecognized cellular roles and modes of regulation of cPLA2α activity.