Phosphatidylinositols phosphatidyl inositol

During the surge in interest in the phosphatidylinositol derivatives, Takai et al. (1979) noted that an unsaturated diacylglycerol diminished the Ca2+ and phospholipid concentration required for complete activation of a Ca2+-activated, phospholipid-dependent protein kinase (now known as protein kinase C). In this latter system, phosphatidylserine was most active (as the required phospholipid), with phosphatidylethanolamine and phosphatidyl inositol much less effective and phosphatidylcholine without any activity. Probably the enzyme was activated by an amphipathic molecule bearing a net negative charge, and any available cellular phospholipid mixture with the requisite surface change served this purpose. 

Fig. 2. Major mechanisms involved in [i-AR desensitization and internalization. AP2, adaptor protein 2 p-ARK, P-adrenergic receptor kinase PI3K, phosphatidylinositol-3 kinase PIP3, phosphatidyl-inositol-3,4,5-triphosphate. (See Color Plate 3 following p. 148.)...

Figure 7, Phospholipase C-mediated hydrolysis of phosphatidyl inositol 4,5-bisphos-phate. Phosphoinositide-specific phospholipase C is activated during cellular stimulation and mediates the hydrolysis of phosphatidylinositol 4,5-bisphosphate. The two products of this reaction, DAG and IP3, are both intracellular second messengers. Thus, a single hydrolytic reaction initiates a bifurcating pathway of signal transduction mediated by protein kinase C activation and calcium mobilization, respectively.

Of the different classes of non-protein kinases, the development of inhibitors of lipid kinases has received by far the most attention. A majority of this work centers on inhibitors of phosphatidylinositol kinases, which reflects the important role that phosphatidylinositols play as second messengers. In this section, we review inhibitors of PI3K and related kinases, as well as inhibitors of other phosphatidyl inositol kinases. We also discuss sphingosine kinase inhibitors and we end this section with a brief summary of inhibitors of other lipid kinases. 

Neuronal and hormonal signals may often be transduced via receptor-mediated activation of phophoinositidase C (inositol lipid-directed phospholipase C), which converts phosphatidyl-inositol 4,5-bisphosphate (PIP2) to 1,2-diacyl-glycerol (1,2 DG) and D-inositol 1,4,5-triphosphate [(1,4,5)IP3] in the cell membrane. These metabolic products are second messengers 1,2 DG stimulates protein kinase C and (1,4,5)IP3 releases intracellular calcium from the endoplasmic reticulum. Subsequently, (1,4,5)IP3 is ultimately converted to myoinositol. That in turn is converted to phosphatidylinositol, which is used to replenish PIP2 stores and thus complete the cycle. ... 

Figure 1, Phosphoinositide Pathway. Enzymes a. phosphatidyl-inositol synthetase (PI synthetase) h. phosphatidylinositol kinase (PI kinase) c. phosphatidylinositol-4-phosphate kinase (pip kinase) d. phospholipase C (R = palmitoyl or other long-chain fatty acid chain).

Figure 50. PTEN. The tumor suppressor gene and gene product protein PTEN (phosphatase tensin homolog deleted on chromosome ten, human 10q23.3) (Table VIII), is the natural inhibitor of oncogenes PI3K/Akt (phosphatidyl inositol kinase 3 protein kinase 3 phosphatidylinositol 3 phosphate Jacob Furth s AK mouse strain thymic lymphoma retroviral oncogene phosphoinosite-dependent kinase). The PTEN protein inactivates PIP3 by dephosphorylation PDKl (phosphoinositol-dependent kinase) is not recruited to the plasma membrane to activate Akt by phosphorylation. Sarah M. Planchon et al. The nuclear affairs of PTEN. J Cell Sci 2008 121 249-253. doi 10.1242/jcs.022459...

Inositol phosphates phosphate esters of the cyclic alcohol myo-inositol. They are found in the plasma membrane as components of phospholipids known as phosphatidyl inositols. Inositol 1,4,5-truphosphate (InsP]) is released from phosphatidylinositol-43-hplasma membrane by a variety of membrane receptors for hormones or neu-rotransmitters when the receptors are occupied. InsPj appears to be the active species responsible for the release of Ca which follows stimulation of the cell it is thus a second messenger (see Hormones, Caldum) for such agents as acetylcholine, vasopressin, substance P and epidermal growth factor (see Peptide hormones). 

The preparation of phosphatidyl inositol derivatives with a thiophospho linkage has been reported,together with a synthesis of phosphatidylinositol 3-phosphate by diisopropyl carbodiimide-promoted migration of the 4-phosphate. ... 

Some lipid transfer proteins isolated from castor bean (Tanaka and Yamada, 1982) (acidic ones) transfer preferentially phosphatidylcholine or phosphatidylinositol. However, the main characteristics shared by the more abundant lipid transfer proteins from plants is their non-specific character for phospholipids. As indicated by Table 2, proteins Isolated from castor bean, maize or spinach are able to transfer phosphatidylcholine, phosphatidylethanolamine, phosphatidyl-inositol from liposomes to mitochondria. In addition, spinach protein also transfers phosphatidylglycerol and castor bean protein, phosphatidic acid. The possibility for these proteins to transfer... 

Figure 6.9. Pathways of inositol phosphate metabolism. Ins 1,4,5-P3, generated via the hydrolysis of phosphatidyl 4,5-bisphosphate by phospholipase C, can be metabolised by a kinase (to generate Ins 1,3,4,5-P4) or via a phosphatase (to yield Ins 1,4-P2). These products can be metabolised further to produce inositol, which itself may be sequentially phosphory-lated to regenerate phosphatidylinositol 4,5-bisphosphate.

Substitution of the CMP residue by inositol then provides phosphatidylinositol (Ptdlns enzyme CDPdiacylglycerolinositol-3-phosphatidyl transferase 2.7.8.11). 

PHOSPHATIDYLINOSITOL SYNTHASE 1-Phosphatidyl-1 D-myo-inositol 4,5-bisphos-phate synthesis,... 

In animal cells there are three major myo-inositol-containing phospholipids (Fig. 1) phosphatidylinositol [l-(3-sn-phosphatidyl)-D-myo-inositol) (Ptdlns)], which usually accounts for over 90% of the total inositol lipid, phosphatidylinositol-4-phosphate (Ptdlns 4-P) and phosphatidylinositol 4,5-bisphosphate (Ptdlns 4,5-P2). The polyphosphorylated inositides generally constitute 1-10% of total inositol lipids, which are themselves 6-10% of total phospholipids. The polyphosphoinositides are considered to be located on the cytoplasmic side of the plasma membrane, which places them in an ideal position to play a role in signal transduction. Ptdlns, on the other hand, is found in all cellular membranes. In some cells there is evidence for separate hormone sensitive and hormone insensitive pools of the inositol lipids [3],... 

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