Inositol monophosphatase

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. 

The action of Li+ on inositol monophosphatase has greatly facilitated the use of [3H] inositol in the study of stimulated phosphoinositide turnover [19]. Berridge and colleagues demonstrated that in the presence of both Li+ and a phosphoinositide-linked ligand, the amount of labeled intracellular inositol phosphates that accumulates... 

Inositol monophosphatase catalyzes the hydrolysis of inositol-1-phosphate, inositol-4-phosphate, and various nucleoside 2 -phosphates. The enzyme has attracted considerable interest in recent years because it is believed to be an important target for lithium therapy in treatment of manic-depression. Inositol monophosphatase inhibited in the presence... 

Figure 5. Proposed reaction mechanism of inositol monophosphatase.

There are three mechanistic possibilities for catalysis by two-metal ion sites (Fig. 10). The first of these is the classic two-metal ion catalysis in which one metal plays the dominant role in activating the substrate toward nucleophilic attack, while the other metal ion furnishes the bound hydroxide as the nucleophile (Fig. 10 a). Upon substrate binding, the previously bridged hydroxide shifts to coordinate predominately with one metal ion. Enzymes believed to function through such a mechanism include a purple acid phosphatase [79], DNA polymerase I [80], inositol monophosphatase [81],fructose-1,6-bisphosphatase [82], Bam HI [83], and ribozymes [63]. 

Fig. 22. A model for the interaction of Li(I) with the enzyme inositol monophosphatase. Lithium(I) occupies the second Mg(II) site in the enzyme. Adapted from (479). 

Enzymes that probably require three metal ions for full activity include the Tetrahymena group I ribozyme, a Mn " -activated bifimctional enzyme with inositol monophosphatase and fructose 1,6-bisphosphatase activities described belowand some endonucleases. " Inorganic pyrophosphatases from E. coli and S. cerevisiae are well characterized both structurally and mechanistically. Both Mg " " and Mn + are activating metal ions and the enzyme from E. coli is most active with just three metal ions in the active site. These enzymes have been described in Section 5.1.8.2.4. 

Figure 41 Schematic of the active site in the bifunctional inositol monophosphatase/fructose 1,6-bisphosphatase from Methanococcus jannaschii MJ109.

Kosbash You mentioned briefly inositol monophosphatase. My impression from the literature, and in particular the recent Nature paper (Williams et al 2002), is that somewhat more than half of the people interested in brain neurochemistry and lithium would vote for the inositol pathway rather than GSK3. In any case, it is up for grabs. 

Atack, J.R., Broughton, H.B., and Pollack, S.J. (1995) Inositol monophosphatase—a putative target for Li-H in the treatment of bipolar disorder. Trends Neurosci, 18 343-349. 

In recent years, research on the molecular mechanisms underlying lithium s therapeutic effects has focused on intracellular second messenger generating systems and, in particular, receptor-coupled hydrolysis of phosphoinositide 4,5-biphosphate (PIP2) (Baraban et al. 1989). Lithium, at therapeutically relevant concentrations in the brain, is a potent inhibitor of the intracellular enzyme, inositol monophosphatase [Kj = 0.8 mM), which plays a major role in... 

Honchar MP, Ackermann KE, Sherman WR Chronically administered lithium alters neither myo-inositol monophosphatase nor phosphoinositide levels in rat brain. J Neurochem 53 590-594, 1989... 

Vaccarino FJ Nucleus accumbens dopamine-CCK interactions in psychostimulant reward and related behaviours. Neurosci Biobehav Rev 18 207-214, 1994 Vadnal R, Parthasarathy R Myo-inositol monophosphatase diverse effects of lithium, carbamazepine, and valproate. Neuropsychopharmacology 12 277-285, 1995 Vale W, Spiess J, Rivier C, et al Characterization of a 41 residue ovine hypothalamic peptide that stimulates secretion of corticotropin of 3-endorphin. Science 213 1394-1397, 1981... 

Inositol monophosphatase The rate-limiting enzyme in inositol recycling inhibited by lithium, resulting in depletion of substrate for IP3 production (Figure 29-4)... 

The two-metal mechanisms have been known for most phosphotransferases e.g., alkaline phosphatase (7), inositol monophosphatase... 

Further reaction of 53 with diphenyl phosphate afforded a phospho-diester-bridged dinuclear magnesium(II) complex 54. The Mg-Mg distance of 4.11 A is comparable to similar distances in the Klenow fragment of E. coli DNA polymerase I (3.9 A) (39), rat DNA polymerase j8 (4 A) (46), and inositol monophosphatase (3.8 A) (35). The flexibility of the bridging carboxylates in 52 is manifested by the ca. 0.75-A range of Mg-Mg distances in these complexes, which can readily adjust the metal coordination environment. 

Mood disorders characterized by elevations of mood above normal as well as depressions below normal are classically treated with lithium, an ion whose mechanism of action is not certain. Candidates for its mechanism of action are sites beyond the receptor in the second messenger system, perhaps either as an inhibitor of an enzyme, called inositol monophosphatase, involved in the phosphatidyl inositol system as a modulator of G proteins, or even as a regulator of gene expression by modulating protein kinase C (Fig. 7—22). 

FIGURE 7—22. The mechanism of action of lithium is not well understood but is hypothesized to involve modifying second messenger systems. One possibility is that lithium alters G proteins and their ability to transduce signals inside the cell once the neurotransmitter receptor is occupied by the neurotransmitter. Another theory is that lithium alters enzymes that interact with the second-messenger system, such as inositol monophosphatase, or others. 

The phosphate derivatives (301)-(303) of 6-0-(2-hydroxyethyl)cyclohexane-l,2,4,6-tetraol have been synthesized as inositol monophosphatase inhibitors, the putative target for lithium therapy.270 Compounds (303) and (302) are the most potent examples of a primary alkyl phosphate and phosphate monanion inhibitor so far reported. 

In addition, there is increasing evidence that lithium exerts its therapeutic action by interfering with the polyphosphoinositide metabolism in the brain and by preventing inositol recycling through the uncompetitive inhibition of inositol monophosphatase. 

In nature, many enzymes that hydrolyze phosphate monoesters are activated by two or more metal ions. They include alkaline phosphatase [79], purple acid phosphatase [80], inositol monophosphatase [81], and D-fructose 1,6-biphosphate 1-phosphatase [82]. The active sites of protein serine and threonine phosphatases also consist of dinuclear... 

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