Abstract
Leukotrienes (LTs) are autacoids derived from the precursor arachidonic acid (AA) via the action of five-lipoxygenase (5-LO). When inflammatory cells are activated, 5-LO translocates to the nuclear membrane to initiate oxygenation of AA released by cytosolic phospholipase A2 (cPLA2) into leukotriene A4 (LTA4). LTA4 can also be exported from an activated donor cell into an acceptor cell by the process of transcellular biosynthesis. When thimerosal is added to cells, the level of free AA increases by inhibition of lysophospholipid acyltransferases of the Lands pathway of phospholipid remodeling. Another arachidonate phospholipid cycle involves phosphatidylinositol (PI) in the plasma membrane that undoubtedly intersects with the Lands pathway of phospholipid remodeling. The highest abundance of PI occurs between the ER and the plasma membrane and is probably a result of the importance of the PI signaling cascade in cellular biochemistry. Because transport proteins mediate the rapid intracellular movement of phospholipids, largely as result of physical membrane contact, 5-LO-dependent production of LTA4 could be mediated by the disappearance of free AA from the nuclear membrane, transfer to the ER for Lands cycle reesterification into PI, and population of PI(18:0/20:4) for cell membrane signaling.
Highlights
Leukotrienes (LTs) are autacoids derived from the precursor arachidonic acid (AA) via the action of five-lipoxygenase (5-LO)
Considerable information is available concerning the complexity of biochemical events that take place leading to the synthesis of leukotrienes (LTs), which are lipid mediators derived from arachidonic acid (AA)
A rather unexpected mechanism by which leukotrienes appear in a tissue is that of movement of newly synthesized leukotriene A4 (LTA4) from the activated cell that expressed 5-LO into a cell that contains one of the auxiliary enzymes, such as leukotriene C4 (LTC4) synthase or LTA4 hydrolase [23]
Summary
A rather unexpected mechanism by which leukotrienes appear in a tissue is that of movement of newly synthesized LTA4 from the activated cell that expressed 5-LO into a cell that contains one of the auxiliary enzymes, such as LTC4 synthase or LTA4 hydrolase [23]. This is the process of transcellular biosynthesis. The substrate specificity of these enzymes was investigated using a novel substrate competition assay that involved incubation of a mutant yeast (Ale deficient) engineered to express each of these human MBOATs with six different fatty acyl CoA esters and eight different lysophospholipid substrates in a single in vitro assay. The results were fascinating in that two enzymes were found to be rather specific for AA incorporation into phospholipids, LPCAT3/MBOAT5 and MBOAT7 [39]
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