Inositol monophosphatase, inhibition

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... 

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. 

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

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. 

Lithium has been hypothesized to exert its therapeutic effects in the treatment of bipolar disorder by inhibiting inositol monophosphatase (IMPase), thereby causing a depletion of intracellular inositol. This in turn results in a reduction of the synthesis of the phosphoinositol required to sustain this signaling pathway. Several alicyclic and aromatic bisphosphonates, putative analogues of inositol 1-phosphate, were synthesized and tested, and some showed significant in-vitro potency [26]. 

The mechanism of action of mood-stabilizing drugs in the treatment of BAD is not fully understood. The inositol-depletion hypothesis has been suggested to explain the mechanism of action of lithium (Berridge and Irvine, 1989 Berridge et al., 1982). This hypothesis postulates that the therapeutic effects of lithium are due to uncompetitive inhibition of inositol monophosphatase (IMPase), which leads to depletion of myo-inositol in brain cells, and... 

Specifically, inhibits inositol monophosphatase, possibly affecting neurotransmission via phosphatidyl inositol second messenger system... 

The lithium cation (Li" ) has been shown to inhibit GSK-3P with a potency around 2 mM IC50 (3.3 mM K ) and, although weak, this concentration is achievable clinically, thus offering the potential as a useful therapeutic. Other than GSK-3, Ii+ has been shown to also inhibit polyphosphate 1-phosphatase, inositol monophosphatase, casein kinase-II (CKII), MAP kinase-activated protein kinase-2 (MAPKAP-K2) and p38-regulated/activated kinase (PRAK) as well as activating, in cells, PI3-kinase/PKB and c-jun N-terminal kinase (JNK) [63-66]. Naturally this polypharmacology complicates the interpretation between target and function of Li+. 

Ganzhorn. A.J.. Hoflack. J.. Pelton. P.D., Strasser, E, Chanal, M.-C., and Piettre, S.R., Inhibition of zuyp-inositol monophosphatase isoforms by aromatic phosphonates, Bioorg. Med. Chem., 6, 1865, 1998. 

Baker, R., and Broughton, H.B., Mechanism and inhibition of inositol monophosphatase. Phosphorus, Sulfur Silicon Relat. Elem., 109-110, 337, 1996. 

Inositol monophosphatase hydrolyzes phosphate groups of all inositol monophosphates with the exception of inositol 2-phosphate it requires Mg + for activity and is inhibited by Li+. Its apparent molecular mass is 55 kDa. 

Ganzhom AJ, Hoflack J, Pelton PD et al (1998) Inhibition of myo-inositol monophosphatase isoforms by aromatic phosphonates. Bioorg Med Chem 6 1865—1874... 

Lithium also inhibits other enzymes in the interconversion and breakdown of polyphosphoinositides, though not by an uncompetitive mechanism. Either because of the uncompetitive inhibition of the monophosphatase or because of the inhibition of the other enzymes, or, indeed, by a combination of these, lithium reduces the cell concentrations of myo-inositol, which would otherwise be converted into phosphatidylinositol. The reduction in cell inositol content attenuates the brain response to external stimuli. This scheme has been suggested as... 

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