Phosphatidic Acid - PA As A Biosynthetic Precursor

PA As A Biosynthetic Precursor

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.