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  • Mammalian cells contain significant amounts of a relatively

    2020-09-15

    Mammalian cells contain significant amounts of a relatively lesser known enzyme that shows marked specifity for ether lipids containing AA and other 20–22 carbon fatty acids. This enzyme is called CoA-independent transacylase (CoA-IT), and transfers polyunsaturated moieties of 20–22 carbons, typically AA, from diacyl PC species to ether phospholipids, particularly the ethanolamine plasmalogens. This reaction is considered of special relevance not only for the maintenance of membrane homeostasis but also for ensuring the appropriate distribution of AA among the various phospholipid pools for the execution of PLA2-dependent responses during immune cell activation [15,25,93,178,[180], [181], [182], [183], [184], [185], [186], [187]]. Thus, CoA-IT is regarded as a key enzyme for the regulation of polyunsaturated fatty bioactive synthesis mobilization reactions in major immunoinflammatory cells. The rapid remodeling of AA moieties to ethanolamine plasmalogens during cell stimulation explains why in many instances, when measuring AA mobilization by mass in activated cells, no changes in the AA content of PE molecular species is observed, despite PE constituting the richest AA-containing class. The CoA-IT reaction prevents a decline of AA in the cellular amount of PE during cellular stimulation by channeling AA to PE from PC [2,54,55,57]. The CoA-IT sequence is presently unknown, making it one of the 1078 orphan enzymes currently listed in the ORENZA database (EC 2.3.2.147) [188]. Thus, presently the only way to study of CoA-IT is by measuring its enzyme activity or by pharmacological means [57,[189], [190], [191], [192]]. The importance of CoA-IT in regulating the proper distribution of AA within phospholipids appears so relevant that, when its activity is blunted, the profile of eicosanoids generated by mouse peritoneal macrophages under activation conditions changes [57]. By directing AA from PC towards PE, CoA-IT modulates the relative amount of lipoxygenase products formed, thus suggesting that certain cellular AA phospholipid pools are selectively linked to the formation of specific eicosanoids [57]. This concept, first suggested by the work of Chilton in neutrophils [193] implies the existence of a third regulatory step of the eicosanoid biosynthetic response, i.e. at the level of fatty acid compartmentalization within the cell. CoA-IT, by helping to place precursor fatty acids in the appropriate cellular pools decisively influences the eicosanoid response because not all these pools may be equally accessible to the relevant PLA2 involved. CoA-IT is not a PLA2 in a strict sense because it does not generate a free fatty acid as a product, but it does cleave the sn-2 position of a phospholipid. This has led to the consideration of whether CoA-IT is actually a PLA2 “in disguise”, i.e. that the CoA-IT reaction represents just an uncharacterized activity of an otherwise described PLA2 enzyme. As a matter of fact, some well characterized PLA2s, e.g. cPLA2α or iPLA2-VIA, exhibit Ca2+-independent transacylase activity in vitro [16]. Early work in macrophages utilizing PLA2 inhibitors of known specificity failed to relate CoA-IT activity to any of the PLA2 group types that had been characterized at that time (iPLA2-VIA, cPLA2α, or sPLA2-V) [93]. Consistent with these results, a subsequent study confirmed that neither cPLA2α, nor iPLA2-VIA nor sPLA2-V were involved in AA phospholipid remodeling in peripheral blood T cells [181]. More recent studies have contemplated the possibility that CoA-IT activity may belong to cPLA2γ (group IVC PLA2) [[194], [195], [196]]. Despite being a group IV enzyme, cPLA2γ is actually Ca2+-independent because it lacks the C2 domain present in the other group IV members [16]. However, the lysophospholipase activity of cPLA2γ is considerably higher than its CoA-independent transacylation activity, which casts doubt as to whether this enzyme is actually responsible for moving AA from PC to PE in cells [194,195].