Inositol lipids

Vanhaesebroeck B, Leevers SJ, Ahmadi K, et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 2001 70 535-602. 

JR Williamson, SK Joseph, KE Coll, AP Thomas, A Verhoeven, M Prentki. (1986). Hormone-induced inositol lipid breakdown and calcium-mediated cellular responses in liver. In G Poste, ST Crooke, eds. New Insights into Cell and Membrane Transport Processes. New York Plenum Press, pp 217-247. 

Newer uses have appeared in the treatment of viral diseases including AIDS, alteration of the immune response, and cancer. The lithium salt of 7-linolenic acid (LiGLA) has a significant anticancer effect against certain cancers. The neurochemical basis for lithium action is difficult to define. Lithium carbonate induces a wide range of intra- and extracellular changes—most emphasis has been naturally on the similarities with Na/K/Ca/Mg ions. Lithium selectively interferes with the inositol lipid cycle, representing a unified hypothesis of action. The biochemistry, distribution, and cellular localization of lithium has been extensively documented. 

Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers 358... 

The Chilton Conference nomenclature for inositol lipids is used throughout this chapter, e.g. PI, PI4P, PI(4,5)P2 for phosphatidylinositol, phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate respectively. Note that the IUB-recommended nomenclature for these lipids is Ptdlns, PtdIns4P and PtdIns(4,5)P2 (see Ch. 3). 

There exists an unusual uniformity in the fatty acid composition of the inositol lipids. All three of the major phosphoinositides are enriched in the 1-stearoyl, 2-arachidonoyl ( ST/AR ) sn-glycerol species (=80% in brain). The polyphosphoinositides (PI4P and PI(4,5)P2) are present in much lower amounts than PI. PI(4,5)P2 has been shown to be predominantly, although not... 

It should be noted that the process whereby PI(4,5)P2 is cleaved by PLC and subsequently resynthesized is meta-bolically expensive. Thus, for each mole of PI(4,5)P2 hydrolyzed and resynthesized, 3 moles of ATP and 1 mole of CTP are consumed. ATP is consumed at the DAG kinase, PI4-kinase and PIP-kinase steps, whereas CTP is utilized by CDP-DAG synthase. Consequently, it is likely that, under physiological conditions, PI(4,5)P2 breakdown is kept to a minimum. Since PI(4,5)P2 represents only a minor fraction of the total inositol lipid pool, its resynthesis would be a prerequisite for both acute and sustained signaling. Despite the obvious physiological importance, mechanisms that regulate the resynthesis of PI(4,5)P2 have not been well-defined. However, some evidence has... 

The inositol polyphosphate 5-phosphatases belong to a family of enzymes that terminate the signals generated by inositol lipid kinases and PLC. To date, two major types of 5-phosphatase have been identified, both of which share a common 5-phosphatase domain of approximately 300 amino acids, with several highly conserved motifs. Type-I enzymes are 43-65 kDa and preferentially hydrolyze 1(1,4,5)P3 and 1(1,3,4,5)P4, with the attendant formation of I(1,4)P2 and 1(1,3,4)P3, but have little or no activity towards membrane-bound phosphoinositides. The pro-totypic form of a type-15-phosphatase is a 43 kDa protein that is post-translationally modified by farnesylation of the carboxyl terminus CAAX motif this modification juxtaposes the enzyme with the membrane. Type-II enzymes are larger (75-160 kDa) and will hydrolyze both water-soluble inositol phosphates and lipids that... 

TABLE 20-2 Examples of domains within proteins that specifically interact with inositol lipids... 

Rodriguez de Turco, E. B., Tan, W., Topham, M. K., Sakane, F., Marcheselli, V. L., Chen, C., Taketomi, A., Prescott, S. and Bazan N. G. Diacylglycerol kinase epsilon regulates seizures susceptibility and long-term potentiation through inositol lipid signaling. Proc. Natl Acad. Sci. U.S.A. 98 4740-4745, 2001. 

Li+ was first found to interfere with inositol lipid metabolism when significantly decreased levels of myo-inositol were observed in the cerebral cortex of Li+-treated rats [89]. Subsequent work revealed a corresponding increase in the levels of Ins( 1 )P [90] and this behavior was shown to be the result of a Li+-induced inhibition of IMPase, the enzyme which dephosphorylates the monophosphates Ins(l)P, Ins(3)P, and Ins(4)P to produce free inositol [91]. These results stimulated much research in this field involving a wide variety of cell types, tissues, and animals where the Li+ inhibition of IMPase was found to be ubiquitous. However, it was found that, in vivo, this Li+-induced effect is predominantly limited to the brain, being observed in different regions of the brain to different extents, with similar results for both acute and chronic treatment with Li+. It is probable that those cells that are able to accumulate inositol, or which are exposed to and can rapidly import an extracellular supply of inositol, may be relatively insensitive to the effects of Li+. 

Neutrophil membranes contain inositol lipids, which comprise about 5-6% of the total membrane lipids. About 80% of these inositol lipids possess stearic acid (Cl8 0) at Cl and arachidonic acid (C20 4) at C2 positions. Phosphatidylinositol accounts for most of these lipids (90%), with smaller amounts of PIP (6%) and PIP 2 (4%), which are synthesised sequentially by the action of 4- and 5-specific kinases, respectively (see Fig. 6.6). Neutrophil membranes also possess a phosphatidylinositol-specific phospholipase C which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into Ins 1,4,5 P3 and DAG (Fig. 6.7). Both PLC-/3(/ 2) and PLC-y (72) families appear to be present in neutrophils. The coupling of receptor occupancy to PLC activation in neutrophils can be through a heterotrimeric G-protein, the mobile subunit of which has been termed G p. Evidence for this G-protein link comes from the following facts ... 

More recently, the importance of a group of highly polar inositol lipids, present in neutrophils and many other cell types, has been recognised. Activation of neutrophils by fMet-Leu-Phe results in the transient accumulation of phosphatidylinositol 3-phosphate (Ptdlns 3-P), phosphatidylinositol 3,4-bisphosphate (Ptdlns 3,4-P2) and phosphatidylinositol 3,4,5-trisphosphate (Ptdlns 3,4,5-P3). Apparently, the enzyme phosphatidylinositol 3-hydroxy (3-OH) kinase plays a key role in the formation of these novel lipids. This enzyme can catalyse the formation of these lipids from phosphatidylinositol, phosphatidylinositol 4-phosphate (Ptdlns 4-P) and phosphatidylinositol 4,5 bisphosphate (Ptdlns 4,5-P2) in vitro (Fig. 6.10). Alternatively, it is possible that Ptdlns 3,4-P2 and Ptdlns 3-P are derived from the sequential dephosphorylation of Ptdlns 3,4,5-P3. 

Figure 6.10. Phosphatidylinositol 3-hydroxy kinase activity. The enzyme phosphatidylinositol 3-hydroxy (Ptdlns 3-OH) kinase may phosphorylate inositol lipids as shown, to generate a series of novel polar lipids that may function in cell activation. See text for details.

Cockroft, S., and Thomas, G.M.H., 1992, Inositol lipid specific phospholipase C isoenzymes and their differential regulation by receptors. Biochem. J. 288 1-14. 

The structural element of PARK that interacts specifically with the Py-complex is localized in the C-terminal third of the PARK seqimce (Inglese et al., 1994). It possesses the characteristics of an independently folding protein domain and is ranked with the pleckstrin homology domains (PH domains). The PH domains are protein modules (see Chapter 8), foimd in many proteins, that by binding of inositol lipids (see Chapter 6) mediate protein-membrane interactions. 

Fig. 6.9. A) Metabolism of phosphatidyl inositol lipids. The figure shows different membrane-associated phosphatidyl inositol phosphate compounds and their mutual conversion. PI3-kinase (PI3K) is responsible, in particular, for the formation of PtdIns(3,4,5)P3 from PtdIns(3,4)P2. For the reactions marked with a question mark, involvement of PI(3) kinase is not certain.

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