FIGURE 2.

Biosynthetic pathways for phosphatidic acid production. Phosphatidic acid (PA) can be generated by three major routes: (a-b) The de novo synthesis via lysophosphatidic acid (LPA) formation that occurs via two different acylation pathways. (a) The first and main synthesis route is the glycerol 3-phosphate (G3P) pathway. G3P is acylated by a glycerol 3-phosphate acyltransferase (GPAT) to form LPA. (b) The second pathway of LPA formation involves acylation of dihydroxyacetone phosphate (DHAP) by DHAP acyltransferase (DHAP AT) via the 1-acylDHAP (Ac-DHAP) pathway followed by Ac-DHAP reductase-mediated reduction. LPA can then be further acylated by the addition of an unsaturated fatty acid (generally arachidonate) to form PA, via a lysophosphatidic acid acyltransferase (LPAAT). The inverse reaction is mediated by phospholipase A₂ (PLA₂), which thus converts PA into LPA. Both of these reactions are of particular significance for the geometry of the membrane bilayers, since cone-shaped PA is converted to inverted-cone-shaped LPA (and vice versa), thus facilitating rapid changes in membrane curvature. (c) PA is also formed by the breakdown of other phospholipids, and in particular by the activity of phosphatidylcholine (PC)-specific phospholipase D (PLD). (d) Finally, PA can be dephosphorylated by PA phosphatases (PAPs), to form diacylglycerol (DAG), a strongly conical component of the bilayer, which due to its small and uncharged headgroup, has spontaneous transbilayer movement (flip-flop). The opposite reaction is catalyzed by diacylglycerol kinases (DAGKs). PA and DAG have been shown to be in dynamic equilibrium, and this mechanism can affect the composition and curvature of both leaflets of the bilayer.