Inositols monophosphates

Inositol monophosphate [15421-51-9] M 260.1, m 195-197 (dec). Crystd from water and EtOH. 

Hirvonen, M. R., Paljarvi, T., and Savolainen, K. M. (1993). Sustained effects of pilocarpine-induced convulsions on brain inositol and inositol monophosphate levels, and brain morphology in young and old male rats. Toxicol. Appl. Pharmacol. 122, 290-299. 

FIGURE 20-7 Pathways of inositol phosphate metabolism. Note that the metabolism of the second messenger I(1,4,5)P3 is shown to the left of the dashed line, while the interconversions of the higher inositol phosphates are shown to the right of the dashed line. Only the quantitatively major established pathways are depicted. Li+ is known to block the dephosphorylation reactions indicated by the (black) bars. Numbers refer to the following enzymes 1, inositol polyphosphate 5-phosphatase (I) 2, inositol polyphosphate 1-phosphatase 3,I(1,4,5)P3 3-kinase 4, inositol polyphosphate 4-phosphatase 5, inositol polyphosphate 3-phosphatase 6, inositol monophosphate phosphatase 7, I(1,3,4)P3 6-kinase/I(3,4,5,6)P4 1-kinase 8, Ipmk 9, DIPP 10, IP6 kinase 11, Ipk 1 12, MIPP 13, PP-IP5 kinase. 

A single enzyme, inositol monophosphatase, leads to loss of the remaining phosphate and the regeneration of free inositol. This enzyme exhibits similar affinities for all five of the equatorial inositol monophosphate hydroxyls. Inositol 2-phosphate, which is not produced in this degra-dative pathway, is a poor substrate, a property that is probably attributable to its axial configuration. The enzyme is inhibited by Li+ in an uncompetitive manner i.e. the degree of inhibition is a function of substrate concentration. The putative link between the ability of Li+ to interfere with phosphoinositide turnover and its therapeutic efficacy in the treatment of bipolar disorders is discussed in Box 20-1 and Chapter 55. It should be noted that unlike most other tissues, brain can synthesize inositol de novo by the action of inositol monophosphate synthase, which cyclizes glucose 6-phosphate to form I(3)P. The enzyme has been localized immunohistochemically to the brain vasculature. 

In biological systems, therefore, the behavior of Li+ is predicted to be similar to that of Na+ and K+ in some cases, and to that of Mg2+ and Ca2+ in others [12]. Indeed, research has demonstrated numerous systems in which one or more of these cations is normally intrinsically involved, including ion transport pathways and enzyme activities, in which Li+ has mimicked the actions of these cations, sometimes producing inhibitory or stimulatory effects. For example, Li+ can replace Na+ in the ATP-dependent system which controls the transport of Na+ through the endoplasmic reticulum Li+ inhibits the activity of some Mg2+-dependent enzymes in vitro, such as pyruvate kinase and inositol monophosphate phosphatase Li+ affects the activity of some Ca2+-dependent enzymes— it increases the levels of activated Ca2+-ATPase in human erythrocyte membranes ex vivo and inhibits tryptophan hydroxylase. 

Inositol Monophosphate Phosphatase and Inositol Polyphosphate 1 -Phosphatase... 

The mechanism of the action of IMPase and its inhibition by Li+ has been studied in depth, and is detailed by Gani et al. [54]. IMPase catalyzes the hydrolysis of all the myo-inositol monophosphates except Ins(2)P. It is completely dependent upon Mg2+ for activity Ca2+ and Mn2+... 

Figure 6. Schematic representation of inositol monophosphate phosphatase (left) and inositol polyphosphate 1-phosphatase (right), showing the helical (green cylinders) and (3-sheet (yellow arrows) regions. The monophosphatase is complexed with lns(1)P (solid spheres) and Gd3+ (orange sphere) in the binding cleft and the polyphosphatase has two Mg2+ (lilac spheres) ions. (The coordinates were obtained from the Brookhaven Protein Data Bank).

Figure 12.19 Phosphatidylinositol bisphosphate cycle and treatment of bipolar disease. The metal ion lithium inhibits inositol monophosphate phosphatases and, therefore, inhibits the flux from IP3 to inositol, so that the concentration of the latter decreases. This can restrict formation of phosphatidylinositol the bisphosphate (PIP ) so that the amount in the membrane decreases and the phospholipase no longer catalyses a zero order reaction. The extent of the decrease in the IP3 concentration will depend on how far the process is removed from zero order. This may explain the well-known variability in the response of patients to lithium which is probably dependent on the patient taking the precise dose of the drug (Chapter 14).

The General myo-lnositol and scyllo-Inosamine Pathway. Two distinct cyclitol pathways, which we earlier called Ca (started by myo-inositolphos-phate synthase) and Cb (started by T-deoxy-i cy/to-inosose synthase), are used in the initiation of AGA pathways. Here we will describe the Ca route and the Cb pathway in the paragraph on NEOs (see Section 2.2.2.1.3). The cyclitol pathway in the biosynthetic pathways for STRs, but also for other AGAs such as SPCs, KAS, and FORs and also the mixed type antibiotic HYG-A (see Section 2.2.4.3.1), starts with the formation of myo-inositol in a two-step pathway (Ca) that is not encoded in the itrAtt-clusters. The first step in streptidine biosynthesis (and any other myo-inositol utilising pathway) is the formation of a myo-inositol monophosphate (D-myo-inositol-3-phosphate or L-myo-inositol-1-phosphate) via L-myo-inositol-1-phosphate synthase, which in actinomycetes... 

Formation of the Initial Cyclitol. The first steps of FOR production are the same as in the biosynthesis of STR in short, the first step in FOR biosynthesis is postulated to be the formation of a myo-inositol monophosphate (D-myo-inositol-3-phosphate or L-myo-inositol-1-phosphate) via the cellular l-myo-inositol-1-phosphate synthase as in the STR pathway (Ca pathway see Section 2.2.1.2). As in the itr-Att-clusters, no gene for this enzyme has been found in the/or-cluster. As a second step in FOR biosynthesis the dephosphorylation of D-myo-inositol-3-phosphate via an inositolmonophosphate phosphatase has to follow. A putative gene product with this activity is that of the ForA protein (cf. Tables 2.17 and 2.18). The cyclitol is postulated to be first converted via two enzymes, a cluster-encoded myo-inositol 3-dehydrogenase (ForG member of the GFO/IDH/MocA oxidoreductase family) and the L-glutamine icy//o-3-inosose 3-aminotransferase (ketocyclitol aminotransferase I ForS), to icy//o-inosamine (3-deoxy-3-amino- cy/to-mositol). 

Lithium inhibits inositol monophosphate and decreases brain levels of inositol. Belmaker s group [see Levine et ah. Chapter 9, in this volume) showed a selective therapeutic effect of inositol in patients with either depression or panic disorder. Because of the possible importance of the second-messenger system of the phosphatidylinositol [PI) cycle in mood regulation, and because of its influence by lithium, it would be of future in-... 

FIPhosphatidylinositol cycle. A = activator CMPPA = cytidine monophosphate phosphatidic acid DAG = diacylglycerol G = G protein Glu-6-P, glucose 6-phosphate IPj = inositol monophosphate IP2 = inositol biphosphate ... 

T. O Donnell, S. Rotzinger, T. T. Nakashima, C. C. Hanstock, M. Ulrich and P. H. Silverstone, Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain. Brain Res., 2000, 880, 84-91. 

Mixed monolayers of PVPC6 poly-(2-methyl-5-vinyl-hexylpyridinium bromide) and L phosphalidyl inositol monophosphate, were studied as model of complex membranes. 

Figure 3. Effect of pH on the chemical shift of several monoester phosphate compounds. Serine phosphate and inositol monophosphate are in a pure water matrix, and adenosine monophosphate is in a concentrated humic-FeEDTA...

On hydrolysis of the phosphatides, myo-inositol monophosphate—and, from a brain phosphatide, a diphosphate—is obtained but, these products have, in most cases, not been adequately characterized, and it is not yet known whether all phospholipids contain the same myo-inositol phosphate. It has been shown169-170 that the phosphate obtained by hydrolysis of liver phosphatide171 or soybean phosphatide172 is a mixture of myo-inositol 1- and 2-phosphates. A myo-inositol phosphate, of unknown constitution, was isolated173 from liver without previous hydrolysis apparently it occurs in the free state. 

A Summation. It is possible at this point in time to isolate, separate, and identify glycerophosphoinositol and inositol monophosphate by sophisticated HPLC on anion exchange resins. This approach, using well-defined synthetic compounds (available from commercial suppliers) for standards, has made a significant impact on identification of inositol phospholipid metabolites in stimulated cell preparations. Certainly these latter techniques, together with the methodologies described earlier, have made life much easier for scientists in this field. 

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