Phosphatidylinositol-4,5-diphosphate

Inositol triphosphate (IP3)-gated channels are also associated with membrane-bound receptors for hormones and neurotransmitters. In this case, binding of a given substance to its receptor causes activation of another membrane-bound protein, phospholipase C. This enzyme promotes hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2) to IP3. The IP3 then diffuses to the sarcoplasmic reticulum and opens its calcium channels to release Ca++ ions from this intracellular storage site. 

Fig. 1. A compact visual summary of the signaling of cytoplasmic/nuclear and cell surface receptors. ER, endoplasmic reticulum M, mitochondrion PIP2, phosphatidylinositol-4,5-diphosphate IP3, inositol triphosphate PK, protein kinase, second messenger.

CDP-diacylglycerol is also part of the phosphatidylinositol (PI) synthesis pathway, shown in Figure 6.7. The PI formed can be phosphorylated on the inositol group to produce phosphatidylinositol-4,5-diphosphate. This lipid is a minor... 

FIGURE 9.98 Events taking place in the plasma membrane on stimulation of a cell. Phosphatidylinositol (PI) and more highly phosphorylated versions of this lipid account for 2 to 8% of the lipids of the plasma membrane of eukaryotic cells. The inositol 1,4,5-triphosphate (IP3) moiety of phosphatidylinositol- 4,5-diphosphate may be hydrolyzed from this lipid immediately after the cell is stimulated. For example, the stimulation of platelets by thrombin or the islets of the pancreas by glucose is followed by the release of IP3 into the cytoplasm. In some cells, arachidonic acid is hydrolyzed from l-acyl-2-arachidonyl-glycerol, which can support a burst of prostaglandin synthesis. 

The muscarinic receptors are considered to be part of the superfamily of G protein-coupled receptors. They consist of seven transmembrane helices and are linked to their G protein through interaction with the second and third intracellular loops (25). There are five subtypes of receptor, designated M1-5, and the odd-numbered receptors (Mi, M3, and Ms) are coupled to the Gq/Gn class. This class of receptors activate intracellular phospholipase C to hydrolyze phosphatidylinositol 4,5-diphosphate to diacylglycerol and inositol triphosphate as intracellular messengers. The even-numbered receptors (M2 and M4) are coupled to the Gi/Go class, which mediates the inhibition of adenylate cyclase (Fig. 44.14). 

Production of PI compounds like phosphatidylinositol-4,5-diphosphate (PI(4,5)P2) leads to the recruitment of PH domain containing proteins such as actin-binding proteins (ABP) and thereby regulating their activity (2, generally leading to the... 

Stimulation of the native 5-HT2A receptor results in the activation of phospholipase C. This enzyme catal3rzes the hydrolysis of phosphatidylinositol 4,5-diphosphate producing diacylglycerol and inositol 1,4,5 triphosphate IP3. 

Phosphatidylinositol 4,5-diphosphate (R, R > saturated and unsaturated long-chain fatty adds)... 

Prod, in vivo by hydrol. of phosphatidylinositol 4,5-diphosphate. Present in mammalian brain tissue. Important cellular second messenger. Controls Ca release from intracellular stores. Cryst. (MeOH aq.) (as tri-Na salt), [a] -11.1 (c, 0.9 in H2O) (tri-Na salt). Mp >270° (as tri-Na salt). Chiral, D-form. 

Characterizations of oligomerization and dynamics of equine infectious anemia virus matrix protein and its interaction with membrane signaling molecule phosphatidylinositol 4,5-diphosphate. ... 

Step 2 Phospholipase C hydrolyzes phosphatidylinositol diphosphate and releases diacyl glycerol (DG) and inositol-3-phosphate (IP3). 

NUCLEOSIDE DIPHOSPHATE KINASE 5-OXOPROLINASE PHENYLALANINE RACEMASE 1-PHOSPHATIDYLINOSITOL 4-KINASE PHOSPHATIDYLINOSITOL-4-PHOSPHATE 5-KINASE... 

Figure 21-3 Major pathways of synthesis of fatty acids and glycerolipids in the green plant Arabidopsis. The major site of fatty acid synthesis is chloroplasts. Most is exported to the cytosol as oleic acid (18 1). After conversion to its coenzyme A derivative it is converted to phosphatidic acid (PA), diacylglycerol (DAG), and the phospholipids phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidylglycerol (PG), and phosphatidylethanolamine (PE). Desaturation also occurs, and some linoleic and linolenic acids are returned to the chloroplasts. See text also. From Sommerville and Browse.106 See also Figs. 21-4 and 21-5. Other abbreviations monogalactosyldiacylglycerol (MGD), digalactosyldiacylglycerol (DGD), sulfolipid (SL), glycerol 3-phosphate (G3P), lysophosphatidic acid (LPA), acyl carrier protein (ACP), cytidine diphosphate-DAG (CDP-DAG).

Fig. 2. Targeted lipidomics of 2-AG metabolism. Postulated pathways for 2-AG metabolism. Abbreviations PLC, phospholipase C DAG, diacylglycerol DGL, diacylglycerol lipase MGL, monoacylglycerol lipase PLA, phospholipase A AT, acyltransferase TAGL, triacylglycerol lipase PIP2, phosphatidylinositol bisphosphate ABHD-6/12 hydrolase lyso-PL, lysophospholipid lyso-PA, lysophosphatidic acid PA, phosphatidic add P, phosphatase COX, cydooxygen-ase LOX, lipoxygenase CYP450, cytochrome P450 CDP, cytidine diphosphate.

The type II pneumocytes synthesize phosphatidylcholine in a fashion quite different from that in other cells. Most other cells synthesize phosphatidylserine from cytidine diphosphate diacylglycerol and serine. The phosphatidylserine is then decarboxylated to yield phosphatidyl ethanoiamine. The final step is the successive donation of three methyl groups via S-adenosylmethionine to form phosphatidylcholine. The pulmonary biosynthetic pathway is shown in Figure 54-2. The enzyme choline phosphotransferase forms PC directly from cytidine diphosphocholine and diacylglycerol. Phosphatidylinositol formation peaks at about 35 weeks. As PI decreases in concentration, PG begins to increase. 

Phospholipases are very versatile enzymes which allow the transformation of inexpensive natural products into highly valuable compounds like specific structurally defined phospholipids, organic monophosphates or diphosphates and DAG with the natural absolute configuration. Of particular synthetic utility is PLD from bacterial sources which is able to effect the phosphoryl transfer in a water-containing biphasic system. PLD shows a wide substrate specificity for both the polar head and the alcohol acceptors as well as for the lipophilic part of the molecule. The enzyme behaves like a generic phosphodiesterase with broad substrate specificity and high transphosphatidylation ability. The molecular basis of this behavior should become clear by inspection of the three-dimensional structure and comparison with other phosphoric acid ester hydrolytic enzymes. The crystal structure of this enzyme has not been elucidated. The potential of the many different PLD from plants which show peculiar substrate specificity should allow one to expand the synthetic utility to the hydrolysis-synthesis of natural and unnatural phosphatidylinositols. 

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