The Inositols

The myo, the dextro, and the levo isomers of inositol are readily obtainable from natural sources, whilst the other diastereomers are usually synthesized from these compounds by a series of reactions which amount to epimerizations at one or more centers. These syntheses will be discussed under the individual inositols the present Section deals only with syntheses of inositols from non-cyclitol materials. 

The products of the hydrogenation were fully investigated by Angyal 

Tetrahydroxybenzoquinone can also be hydrogenated at high pressure and temperature with a Raney nickel catalyst,18 to give products ranging from cyclohexanediols to inositols. The yield of myo-inositol is small (2-6 %) somewhat larger proportions of cfs-inositol and czs-quercitol are produced. 

The preparation of inositols by the hydrogenation of tetrahydroxyqui-none amounts to a total synthesis, since the latter can be prepared from the reaction of carbon monoxide with potassium.23 This synthesis has been utilized for the preparation of myo-inositol uniformly labeled24 25 with carbon-14. 

The final step in the synthesis—replacement of the amino group in XI by a hydroxyl group—was carried out by Posternak28 by treatment with nitrous acid. Inversion occurred, giving a 10-15% yield of myo-inositol the other products of the reaction could not be identified. A much better yield (71 %) was achieved by the nitrous acid deamination of the penta-acetate ester of XI, rather than by deamination of the free inosamine.30,31 This method has been utilized30,31 for the preparation of myo-inositol- -C14 from nitromethane-C 14. 

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FIGURE 9.20 The glycosyl phosphatidylinositol (GPI) moiety is an elaborate lipidanchoring group. Note the core of three mannose residues and a glucosamine. Additional modifications may include fatty acids at the inositol and glycerol —OH groups. 

A solution of 1.0 g (33 mmol) of the mixture of heptofuranoside diastereomers (14) in 5 ntL of THE is stirred in an ice-water bath. 3.4 mL of 1 M soln ofTBAF (3.4 mmol) in THF are added, and Ihe reaction is monitored by TLC (CHCI,/CH, OH, 9 1). After ca. 15 min, the reaction mixture is carefully neutralized with dil sulfuric acid, then diluted with water and extracted with CHC13. The extract is dried over Na,S04 and concentrated to give an off-white solid which is a single stereoisomer (by NMR spectroscopy). Column chromatography gives the inositol as a white solid yield 0.61 g (70%) mp 186-187 C (benzene/CH,OH) [a]D + 118 (c = 03, CH, OH). 

Bosanac I et al (2002) Structure of the inositol 1,4,5-trisphosphate receptor binding core in complex with its ligand. Nature 420 696-701... 

Phosphatidylinositol 4,5-bisphosphate is a derivative of phosphatidylinositol in which the inositol ring is phosphorylated at positions 4 and 5. 

Phosphatidylinositol is a phospholipid containing the inositol sugar head group. 

Cellular phosphoinositide concentrations are under tight control by phospholipid kinases and phosphatases. Phospholipid kinases preferentially phosphorylate distinct positions of the inositol ring and hence are subdivided into phosphoinositide 3-kinases (PI3Ks), phosphoinositide 4-kinases (Pl4Ks), and phosphoinositide 5-kinases (PI5Ks) that phosphorylate Pis on position 3, 4 and 5, respectively. In a canonical pathway, Ptdlns... 

Pleckstrin homology domain (PH-domain) was first identified at the amino and carboxyl termini of a haematopoietic protein called pleckstrin. PH-domain, a protein region of approximately 120 amino acids, by binding to phosphatidylinositol lipids of the biological membranes induces the translocation of the PH-domain containing protein to membrane compartment. Various PH-domains possess specificities for phosphoinositides phosphorylated at different sites within the inositol ring. 

Leung WH, Holland S The inositol 5 -phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production. J Immunol 2007 179 95-102. 

The inositol is present in ph osphatidylinositol as the stereoisomer, myoinositol (Figure 14—8). Phosphatidylinositol 4,5-hisphosphate is an important constituent of cell membrane phosphohpids upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers. 

P2j Z = 2 Dx = 1.428 R = 0.033 for 932 intensities. This is a hydrolysis product92 of fortimicin B. The inositol derivative has an almost ideal, chair conformation with Q = 56 pm, and the methylamino and methoxyl groups are axial this is similar to the conformation observed for the parent molecyle. The small differences that are noted are related to the intramolecular hydrogen-bond present in the crystal structure of fortimicin B. 

C-6-C-7 = —124°. There is an intramolecular, inter-residue 0-H N hydrogen-bond. The water molecules are hydrogen-bonded in a chain that includes one of the inositol hydroxyl groups. 

Mobilization of Ca2+ from intracellular pools can be achieved with 2,5-di(tert-butyl)-l,4-benzohydroquinone (tBuBHQ), an agent that elevates intracellular levels of Ca2+ by mobilizing the inositol 1,4,5-triphosphate-sensitive Ca2+ pool without increasing inositol phosphate itself [220], Llopis et al. [204] showed... 

GEN Kass, SK Duddy, GA Moore, S Orrenius. (1992). 2,5-Di(ferf-butyl)-l,4-benzohydroquinone rapidly elevates cytosolic Ca2+ concentration by mobilizing the inositol 1,4,5-trisphosphate-sensitive Ca2+ pool. J Biol Chem 264 15192-15198. 

PI, 2% LysoPI). The inositol content was four times higher in soy than in egg lecithin. 

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. 

Eberhard, D. A., Cooper, C. L., Low, M. G. and Holz R. W. Evidence that the inositol phospholipids are necessary for exocytosis loss of inositol phospholipids and inhibition of secretion in permeabilized cells caused by a bacterial phospholipase C and removal of ATR Biochem. J. 268 15-25, 1990. 

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... 

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... 

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