Fig. 2.

MBOAT7 plays a unique role in PI homeostasis by esterifying LPI to several PUFA acyl-CoAs including arachidonyl-CoA (20:4) to generate the most abundant PI species (PI 38:4; where the sn-1 position harbors a stearate 18:0 and the sn-2 position harbors arachidonic acid 20:4). Within the Land’s cycle, MBOAT7-dependent esterification opposes the actions of cytosolic PLA₂, which instead cleaves PUFAs such as AA from 38:4 PI to generate downstream AA-derived lipid mediators including leukotrienes, prostanoids, thromboxanes, lipoxins, and epoxyeicosatrienoic acids. In parallel to MBOAT7-driven synthesis of 38:4 PI, the de novo “Kennedy” pathway can also generate large amounts of PI 38:4 using CDP-DAG as a substrate. Although MBOAT7 specifically regulates reacylation in the Land’s cycle, it could indirectly impact the substrate availability of 38:4 PI to the arachidonate PI cycle, which is initiated by a parallel pathway where inositol is added to CDP-DAG (18:0/20:4) by phosphatidylinositol synthase (PIS) to also form 38:4 PI. Current evidence suggests that both PIS-generated as well as MBOAT7-generated 38:4 can serve as substrate for phosphatidylinositol kinases to form the key second messengers known as PIPs (including PI [18:0/20:4]-4P, PI [18:0/20:4]-4,5P₂) and lipid mediators downstream of phospholipase C in the arachidonate PI cycle (IP3, DAG [18:0/20:4], PA [18:0/20:4], and CDP-DAG [18:0/20:4]). CL, cardiolipin; G3P, glycerol-3-phosphate; IP3, inositol trisphosphate; LPA, lysophosphatidic acid, PG, phosphatidylglycerol; PIS, phosphatidylinositol synthase; PI4P, phosphatidylinositol-4-phosphate; PI4,5-P, phosphatidylinositol 4,5-bisphosphate; PS, phosphatidylserine.