Glycerophosphates (GP10)

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Phosphatidic acid
Phosphatidic acid
Formula: C5H7O8PR1R2

Natural sources



  • Phosphatidic acid
  • Phosphatidate
  • 1,2-Diacyl-sn-glycerol 3-phosphate
  • 3-sn-Phosphatidate

Biophysical properties

Besides the biochemical reactions of the glycerophospholipid metabolism described in the “Kennedy pathway” of phosphatidylcholine synthesis a key pathway of the glycerophospholipid metabolism is related to phosphatidic acid (PA) metabolism (Fig. 27_2).

Figure 27_2. The DAG, PA, LPA conversion cycle
Figure 27_2. The DAG, PA, LPA conversion cycle

Biology / biochemistry

Biochemical synthesis

Phosphatidic acid (PA) can be generated by the hydrolysis of phosphatidylcholine (PC) by phospholipase D (PLD) and the acylation of lyso-PA by lyso-PA acyl transferases. Additionally, DAG-kinase (DAGK) phosphorylates diacylglycerol (DAG) to yield phosphatidic acid (PA). This enzyme initiates resynthesis of phosphoinositides consumed by phospholipase C during cellular signal transduction. A variety of functions have been recently defined for DAGK isozymes, and it has become increasingly clear that each DAGK isozyme is a critical downstream component of the DAG-dependent signalling system. Regulatory functions of DAGK alpha in the downstream signalling pathways linked to cell-surface tyrosine kinase receptors have recently been described for T-lymphocytes (T-cell receptor, Ref. Sanjuan et al. 2001), and epithelial and endothelial cells (hepatocyte growth factor receptor, Cetrupi et al. 2000). The antagonistic enzyme for DAGK action is PA phosphohydrolase (PAP).


PA is an important metabolite involved in phospholipid biosynthesis and membrane remodeling. Recent work has established a direct link between the generation of PA and the regulation of endocytosis. PA and other acidic phospholipids facilitate the binding of dynamin to membranes (Burger et al. 2000). However, the role of PA in vesicle trafficking appears to be much more general than the modulation of endocytosis. PA has also been shown to facilitate the binding of AP-2 and clathrin coats to lysosomal membranes (Arneson et al. 1999). Endophilin A1, a protein that plays a very important role in the recycling of synaptic vesicles, has been shown to have a lyso-PA acyl transferase activity (Schmidt et al. 1999). PA also seems to play a major role in Golgi traffic, whether it is produced by PLD (Bi et al. 1997, Chen et al. 1997) or by acylation of lyso-PA (Weigert et al. 1999). In general, PA appears to facilitate the fission of vesicles. This function of PA appears to be a consequence of the selective interaction of the lipid with specific target proteins, but given the peculiar structure of PA molecules (a lipid with a small head group and two bulky fatty acid chains attached to the glycerol), it has been proposed that PA may facilitate the formation of local regions of negative curvature on cell membranes (Siddhanta et al. 1998, Huttner et al. 2000).

Moreover, recent data have suggested that PA may play a crucial role in the regulation of several important biological events. For instance, PA has been implicated in the regulation of protein phosphorylation (Fang et al. 2001, Ghosh et al 1996, Rizzo et al. 2000), in the activation of oxidative processes (Erickson et al. 1999, Waite et al. 1997), and in the modulation of membrane traffic (Manifava et al. 2001, Williger et al. 1999). Many of these processes are mediated by a previously unsuspected role of PA: the binding of PA in a highly selective and specific manner. Thus, PA appears to function in a manner similar to many other lipid second messengers: by promoting the binding of selected targets to specific regions of the cell membrane.

Beside PA, its lysoproduct lysophosphatidic acid (LPA) is a key intermediate in early steps of neutral lipid and phospholipid synthesis. The glycerophosphate acyltransferase (GPAT), located in both endoplasmic reticulum and mitochondria catalyses the formation of LPA by acylation of glycerol 3-phosphate. LPA may also be synthesised by phospholipase A-catalysed deacylation of PA. LPA is supposed to act through at least four different G protein-mediated signalling cascades (Moolenaar et al .1995, 1997). It seems that activation of a pertussis toxin-sensitive Gi protein by LPA is critical for the mitogenic response to LPA. Additional signalling pathways include a Gi-dependent activation of Ras and the downstream Raf/mitogen-activated protein kinase pathway. This activates a pertussis toxin-insensitive Gq protein causing phosphoinosite hydrolysis leading to Ca2+ mobilization and stimulation of protein kinase C (PKC). Finally, a pertussis toxin-insensitive Gq protein-mediated release of AA by LPA is dependent on the Rho family of guanine nucleotide triphosphatases and independent of prior phosphoinosite hydrolysis cascades (Moolenaar et al .1995, 1997). An initial step of the glycerophospholipid synthesis is catalysed by glycerol kinase (Glyk), which participates in the metabolism of endogenously derived and dietary glycerol. Glyk is a member of a small group of kinases termed ambiquitous enzymes that are found in the cytosol or as membrane-bound enzymes associated with the voltage-dependent anion channel of the mitochondrial outer membrane. Deficiency of the human enzyme activity leads to childhood metabolic crisis or asymptomatic adults incidentally identified by hyperlipidemia screening (pseudohypertriglyceridemia).

Apart from the above mentioned role of CDP-diacylglycerol synthase 1 in the modulation of the PA pool the catalysed reaction delivers substrate for the phosphoinositide signal transduction pathway (Lykidis et al. 1997).

Enzymes/gene lists

Associated biological processes


Analysis methods

Chemical synthesis


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