Phosphatidic acid kinase

Wissing, J.B. Riedel, B. Behrbohm, H. Diacylglycerol- and phosphatidic acid-kinase studies in plant cell suspension cultures. Biochem. Soc. Trans., 23, 867-871 (1995)... 

The activity of PLD on phosphatidylcholine generates phosphatidic acid, and this may be further metabolised by the enzyme phosphatidate phospho-hydrolase to form DAG (Fig. 6.19). Furthermore, the activity of DAG kinase can convert the DAG (generated either from phosphatidic acid or from the activity of PLC) back into phosphatidic acid. Both phosphatidic acid and DAG have functions as second messengers thus the activities of PLD, phosphatidate phosphohydrolase and DAG kinase all play important roles in the generation of these intracellular signalling molecules. 

Figure 6.19. Products of phosphatidylcholine metabolism. Phosphatidylcholine is metabolised to phosphatidic acid via the activity of phospholipase D. The phosphatidic acid generated in this way may then be converted into diacylglycerol via phosphatidate phospho-hydrolase (which is inhibited by propranolol), and the enzyme diacylglycerol kinase may regenerate the phosphatidic acid. Phospholipase D may also catalyse the transphosphati-dylation of primary alcohols, such as ethanol and butanol, at the expense of the natural substrate, phosphatidylcholine. Thus, primary alcohols can prevent phosphatidic acid production via this route.

Phospholipid turnover also takes place in an asymmetric manner. The enzymes responsible for phospholipid turnover in response to receptor-mediated phospholipase c activation are active from the cytoplasmic surface of the membrane. Likewise, diacylglycerol kinases converting the product of phospholipase c back into the key intermediate of phospholipid biosynthesis, phosphatidic acid, are also located on the cytoplasmic smface of the membrane (Sanjuan et al., 2001). 

Jones, 1990 Nishizuka 1992 and 1995). The second, more sustained inaease in DAG comes from the hydrolysis of PC by PC-specific PLC (direct-route), or indirectly via the sequmtial activation of phosphohpase D (PLD) and phosphatidic acid phosphohydrolase (PAP) to generate PA and DAG, respectively. The second phase of DAG production proceeds without an elevation in the concentration of intracellular and might be related to the activation of Ca -independent protein kinase C isoforms (Wakelam, 1998). 

The first steps of glycerophospholipid synthesis are shared with the pathway to triacylglycerols (Fig. 21-17) two fatty acyl groups are esterified to C-l and C-2 of L-glycerol 3-phosphate to form phosphatidic acid. Commonly but not invariably, the fatty acid at C-l is saturated and that at C-2 is unsaturated. A second route to phosphatidic acid is the phosphorylation of a diacyl-glycerol by a specific kinase. 

Ghosh, S., Moore, S., Bell, R. M., and Dush, M. (2003). Functional analysis of a phosphatidic acid binding domain in human Raf-1 kinase Mutations in the phosphatidate binding domain lead to tail and trunk abnormalities in developing zebrafish embryos. J. Biol. Chem. 278, 45690-45696. 

Lyso-PtdCho is not simply a lipid metabolite producing neurotrophic and neurotoxic effects. It participates in many signal transduction processes. Lyso-PtdCho activates protein kinases such as protein kinase C, protein kinase A, and c-jun terminal kinase. Lyso-PtdCho stimulates phospholipase D and inhibits CTP-phosphocholine cytidylyltransferase (Gomez-Munoz et al., 1999 Boggs et al., 1995). Lyso-PtdCho acts as an agonist for certain G-protein coupled receptors and can be converted to another bioactive lipid, lyso-phosphatidic acid. 

Albumin is the main plasma protein, with a molecular weight of about 69 kDa, and is important for normal plasma oncotic pressure and the transport of many biologically active substances, including free fatty acids, phospholipids (e.g., lysophosphatidic acid), prostanoids, heavy metals, steroid hormones, and vitamins. Albumin-bound lysophosphatidic acid serves as a survival factor for cultured mouse proximal tubular cells (L4). Lysophosphatidic acid is an exquisitely potent inhibitor of apoptosis, comparable with growth factors, for example, EGF. The influence of lysophosphatidic acid on the survival of tubular cells depends on the activation of phophatidylinositol 3-kinase (PI3K) with subsequent activation of Akt and pp70s6k. pp70s6k is a rapamycin-inhibited kinase, which plays an important role in the cellular proliferation. Lysophosphatidic acid also serves as a proliferation factor of mouse proximal tubular cells. Further albumin-bound factors important for the survival of the proximal tubular cells are phosphatidic acid... 

Fig. 5.2 Early G-protein signaling events at the AT]R. Phospholipases C and D are sequentially activated by heterotrimeric G-protein subunits to produce important second messengers such as IP3 and DAG. See text for details. ATiR, angiotensin II type 1 receptor DAG, diacylglycerol IP3, inositol 1,4,5-trisphosphate PA, phosphatidic acid PC, phosphatidylcholine PIP2, phosphatidylinositol-4,5-bisphosphate PKC, protein kinase C PLC, phospholipase C PLD, phospholipase D.

Lee, S., Park, J. and Lee, Y., 2003, Phosphatidic acid induces actin polymerization by activating protein kinases in soybean cells. Mol. Cell 15 313-319. 

Alternatively, the release of platelet phospholipid AA is mediated by the activation of phospholipase Aj (PIA) coupled to PLC, intracellular Ca rise and protein kinase C (PKC) and tyrosine kinase-mediated protein phosphorylations (23,24) and/or by the activation of PLA that is not coupled to these events in platelets (25-29). Furthermore, the hydrolysis of phosphatidic acid (PA) by a PA-specific PLAj may also contribute to eicosanoid synthesis (30,31). It is evident that the differential sensitivity of platelets to multiple agonists and their signals, have contributed to the complexity in understanding the regulation of PLAj. 

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