br Conclusion The past few years have witnessed substantial
Conclusion The past few years have witnessed substantial progress in understanding the structural mechanisms of substrate recognition and the reactions catalyzed by the O-GlcNAc-cycling enzymes, but more work remains. In particular, future research will be needed to establish how OGT and OGA interact with protein substrates and to advance understanding of substrate specificity. Structural work that reveals new binding modes and guides the design of cellular experiments to deconvolute OGT and OGA’s functions will continue to play a crucial role in linking in vitro biochemistry to cellular function. In addition, regulatory mechanisms of OGT and OGA that limit futile O-GlcNAc cycling remain to be uncovered.
Conflict of interest statement
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as:
Introduction A prime example of bioactive fatty DASA-58 is arachidonic acid (20:4n-6, AA), an omega-6 fatty acid that is found at relatively high levels in cells involved in innate immunity reactions, such as monocytes, macrophages and dendritic cells [, , ]. AA is the common precursor of the eicosanoids, a family of lipid mediators with fundamental roles in physiology and pathophysiology, particularly in inflammatory reactions [, , ]. The eicosanoids affect immune regulation by modulating cell activation at different points, including differentiation and migration, phagocytic capacity, and cytokine production [, , , ]. Similarly, docosahexaenoic acid (22:6n-3, DHA) and related long-chain omega-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA) and docosapentaenoic acid (22:5n-3, DPA), also found in major inflammatory cells, can be oxygenated to generate biomolecules known as protectins, resolvins, and maresins (collectively called specialized pro-resolving mediators, SPM), which account for much of the biological activity of omega-3 fatty acids, and are involved in the resolution phase of inflammation, clearance of apoptotic cells, tissue repair and regeneration, and anti-nociceptive actions . In addition, omega-3 fatty acids may promote anti-inflammatory reactions by themselves by acting on fatty acid-sensing receptors [12,13]. Fatty acid-derived mediators are produced during inflammation in two temporal waves with opposite effects, when cells switch the type of mediators produced from pro- to anti-inflammatory . Thus, the immediate production of proinflammatory AA-derived eicosanoids after the insult is progressively followed by accumulation of anti-inflammatory lipoxins and other pro-resolving lipid mediators derived from omega-3 fatty acids, a process that initiates resolution of inflammation and the return to homeostasis [11,14]. Thus, cells appear to possess intrinsic mechanisms to dampen inflammation to avoid excessive damage that might lead to irreversible injury. In addition to the expression of polyunsaturated fatty acid-metabolizing enzymes, availability of the fatty acid in free form is well established to constitute a limiting factor for the biosynthesis of eicosanoids and pro-resolving lipid mediators [1,15]. Such free fatty acid availability is provided by phospholipase A2s, the enzymes that cleave the sn-2 position of glycerophospholipids . Multiple PLA2 enzymes co-exist in a single cell, each exhibiting potentially different headgroup and/or fatty acid preferences. Acting frequently in a co-ordinate manner, cellular PLA2s provide a tight regulation of biological processes involving membrane phospholipid fatty acid rearrangement (Fig. 1). PLA2s are found in practically all types of organisms, and in mammals they are ubiquitously expressed throughout most cells and tissues, suggesting their importance in life processes. The variety of functions of PLA2s in physiology, far from being only circumscribed to activated states of immune cells, have become more evident in the last years with the study of the phenotypes of genetically-manipulated mice [16,17].