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  • Because of the lack of

    2019-08-02

    Because of the lack of sequence, current knowledge on the cellular regulation of CoA-IT is scarce. However, recent work has suggested an interesting new role for CoA-IT in regulating the extent of the AA mobilization response in primed macrophages. Bacterial lipopolysaccharide (LPS) is a poor trigger of AA mobilization in macrophages but has the capacity to greatly increase the response upon a subsequent cellular stimulation. Gil-de-Gómez et al. [197] recently showed that LPS priming of macrophages is strikingly associated with an increased hydrolysis of ethanolamine plasmalogens by cPLA2α, which is due, at least in part, to diminished recycling of AA into this particular species via CoA-IT-mediated transacylation reactions. Reduced CoA-IT activity after LPS priming could bear important pathological consequences because it may lead to excessive damage arising from an exacerbated production of eicosanoids subsequent to the increased availability of free AA [197]. An important unanswered question that stems from these observations is whether the priming effect is exerted directly on the CoA-IT enzyme itself or rather by impacting on an unrecognized Alamethicin that regulates upstream events such as the proper access of the enzyme to its substrate. The latter scenario would be analogous to that described for CoA-IT regulation of platelet-activating factor synthesis in human neutrophils, which depended upon substrate availability, not increased enzyme activity [198]. Another important regulator of CoA-IT-mediated reactions that has recently been unveiled is the cellular level of esterified AA in membranes. It has been known for some time that phospholipid AA remodeling is much faster in cell lines than that in their counterpart physiologic cells. For example, complete AA transfer from PC to PE generally takes hours in murine macrophages or human monocytes, while it takes only minutes in the murine macrophage-like cell line P388D1 or the human monocyte-like cell line U937 [15,25,189,197,199,200]. Astudillo et al. [189] demonstrated that cellular AA levels determine the amount of CoA-independent transacylase activity expressed by cells; the lower the levels of cellular AA, the higher the extent of cellular CoA-IT activity [189]. The mechanism through which this occurs remains to be elucidated but, since simply enriching the cells with AA reduces the measurable CoA-IT activity of homogenates, it seems likely that an unidentified AA metabolite or AA-containing phospholipid that is present in the AA-enriched cells may act to regulate the expression levels of CoA-IT [189].
    Concluding remarks Much progress has been made in recent years to understand the cellular regulation of the selective hydrolysis of membrane phospholipids by PLA2s. Still, the different activation conditions and the accessibility to different pools in the cell may lead to the production of yet unidentified lipid mediators that participate in crucial pathophysiological events. It is important to emphasize that PLA2 represents the very first step of signaling pathways that involve lipid mediators which act per se or may be further metabolized to other bioactive compounds. The definition of molecular mechanisms governing the catalytic activity and substrate preference of the various cellular PLA2s under stimulation conditions is a very significant yet still unexplored field.
    Transparency document
    Acknowledgments Work in the authors\' laboratory was supported by Grants SAF2016-80883-R and SAF2015-73000-EXP from the Spanish Ministry of Economy, Industry and Competitiveness, and Grant CSI073U16 from the Education Department of the Regional Government of Castile and Leon. CIBERDEM is an initiative of Instituto de Salud Carlos III.
    Introduction Precise detection of enzyme activity has been of constant interest due to the essential roles of enzymes in various biological and physiological processes. Abnormal enzyme activity is closely related to the pathology of many human diseases [1]. For instance, up-regulation of matrix metalloproteinase (MMP) activity has been implicated in tumor invasiveness, metastasis, and angiogenesis 2., 3.. A high level of β-galactosidase has been demonstrated as an important biomarker for cell senescence and primary ovarian cancers 4., 5.. Hence, direct monitoring of the activity in vivo in real time is crucial to unravel their functional roles, which could greatly aid in the early detection of diseases and the rapid assessment of disease progression during treatment. However, the complex and dynamic physiological environment in vivo presents a significant challenge to determine enzyme activity within the context of the natural biological environment in living subjects.