Phosphatidic acids (PA) are a class of anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.
Structure
Phosphatidic acid consists of a glycerol backbone, with, in general, a saturated fatty acid bonded to carbon-1, an unsaturated fatty acid bonded to carbon-2, and a phosphate group bonded to carbon-3.
Formation and degradation Besides de novo synthesis, PA can be formed in three ways:
By phospholipase D (PLD), via the hydrolysis of the P-O bond of phosphatidylcholine (PC) to produce PA and choline. By the phosphorylation of diacylglycerol (DAG) by DAG kinase (DAGK). By the acylation of lysophosphatidic acid by lysoPA-acyltransferase (LPAAT); this is the most common pathway. The glycerol 3-phosphate pathway for de novo synthesis of PA is shown here: In addition, PA can be converted into DAG by lipid phosphate phosphohydrolases (LPPs) or into lyso-PA by phospholipase A (PLA).
Roles in the cell The role of PA in the cell can be divided into three categories:
PA is the precursor for the biosynthesis of many other lipids. The physical properties of PA influence membrane curvature. PA acts as a signaling lipid, recruiting cytosolic proteins to appropriate membranes (e.g., sphingosine kinase 1). PA plays very important role in phototransduction in Drosophila. PA is a lipid ligand that gates ion channels. See also lipid-gated ion channels. The first three roles are not mutually exclusive. For example, PA may be involved in vesicle formation by promoting membrane curvature and by recruiting the proteins to carry out the much more energetically unfavourable task of neck formation and pinching.
Roles in biosynthesis PA is a vital cell lipid that acts as a biosynthetic precursor for the formation (directly or indirectly) of all acylglycerol lipids in the cell. In mammalian and yeast cells, two different pathways are known for the de novo synthesis of PA, the glycerol 3-phosphate pathway or the dihydroxyacetone phosphate pathway. In bacteria, only the former pathway is present, and mutations that block this pathway are lethal, demonstrating the importance of PA. In mammalian and yeast cells, where the enzymes in these pathways are redundant, mutation of any one enzyme is not lethal. However, it is worth noting that in vitro, the various acyltransferases exhibit different substrate specificities with respect to the acyl-CoAs that are incorporated into PA. Different acyltransferases also have different intracellular distributions, such as the endoplasmic reticulum (ER), the mitochondria or peroxisomes, and local concentrations of activated fatty acids. This suggests that the various acyltransferases present in mammalian and yeast cells may be responsible for producing different pools of PA. The conversion of PA into diacylglycerol (DAG) by LPPs is the commitment step for the production of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS). In addition, DAG is also converted into CDP-DAG, which is a precursor for phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphoinositides (PIP, PIP2, PIP3). PA concentrations are maintained at extremely low levels in the cell by the activity of potent LPPs. These convert PA into DAG very rapidly and, because DAG is the precursor for so many other lipids, it too is soon metabolised into other membrane lipids. This means that any upregulation in PA production can be matched, over time, with a corresponding upregulation in LPPs and in DAG metabolising enzymes. PA is, therefore, essential for lipid synthesis and cell survival, yet, under normal conditions, is maintained at very low levels in the cell.
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