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    • sphingosine 1-phosphate receptor modulator In general terms

    2021-05-11

    In general terms, PLA2s participate in the Lands cycle of phospholipid fatty sphingosine 1-phosphate receptor modulator 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. First of all, it should be emphasized that, although cPLA2α manifests a marked selectivity for phospholipids that contain AA at the sn-2 position, this does not mean in any way that, in cells, the enzyme cannot hydrolyze other fatty acyl residues to a significant extent even if this occurs at a lower rate [24]. This points out the importance of cellular compartmentalization in the regulation of biological activity, i.e. the phospholipid fatty acid composition of the membrane to which the enzyme translocates during cell activation. In this regard, it has been recently shown that cPLA2α is not only instrumental in effecting AA mobilization for eicosanoid production during inflammation reactions, but also regulates membrane phospholipid remodeling leading to the formation of phospholipid molecules with defined composition that participate in the execution of other responses such as generation of reactive oxygen species and secretion of bactericidal hydrolases [54]. One of such molecules is an unusual PI species which contains arachidonate at both the sn-1 and sn-2 positions of glycerol [55,56]. In addition to its biological roles in innate immune reactions mentioned above [54], this is a short-lived species that may also act as a transient acceptor for the incorporation of arachidonic acid into various cellular phospholipid classes [56]. Owing to its high arachidonic acid content, PI is also a major source for the release of this fatty acid via cPLA2α in activated immune cells [55,57].