Inositol monophosphatase inhibitors—Lithium mimetics?

@article{Atack1997InositolMI,
  title={Inositol monophosphatase inhibitors—Lithium mimetics?},
  author={John R. Atack},
  journal={Medicinal Research Reviews},
  year={1997},
  volume={17}
}
  • J. Atack
  • Published 1 March 1997
  • Biology, Chemistry
  • Medicinal Research Reviews
Given the putative role of inositol monophosphatase (IMPase) as the molecular target for the therapeutic effects of lithium, inhibitors of this enzyme have been proposed to be lithium-mimetics. Although cation and natural product inhibitors of IMPase have been described, these have not proved suitable for cell culture studies due to a lack of specificity. On the other hand, substrate (inositol 1-phosphate)-based inhibitors have proved useful for showing that this class of compounds mimic… 

Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme

The atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.

Increased inositol-monophosphatase activity by lithium treatment in bipolar patients

The Calbindin-D28k binding site on inositol monophosphatase may allow inhibition independent of the lithium site of action

Calbindin's effect was significantly reduced by a peptide with the sequence of amino acids 58-63 of IMPase and by six amino-acid peptides including at least part of the Lys-Glu-Lys motif, which may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.

Human chromosomal localization of a gene for inositol monophosphatase by fluorescence in situ hybridization

Fluorescence in situ hybridization analysis using a human cDNA clone, which included the 5′-UTR and the complete coding region, mapped the human IMPase gene to chromosome 8q21.

Regional changes in rat brain inositol monophosphatase 1 (IMPase 1) activity with chronic lithium treatment

Promising Psychotherapeutic Effects of the Natural Sugar: Myo-Inositol.

Recent preliminary clinical studies have suggested the fascinating possibility that myo-inositol has psychoactive effects, and may be effective in the treatment specific mood and anxiety disorders, and increases interest in this newly emerging area of nutritional neuroscience.

Lithium and fluoxetine regulate the rate of phosphoinositide synthesis in neurons: a new view of their mechanisms of action in bipolar disorder

The convergence of both lithium and FLUO in regulating the rate of synthesis of PIns in opposite ways highlights PIns turnover in neurons as a potential new drug target, as well as for understanding mood control in BD.

Direct Ionic Regulation of the Activity of Myo-Inositol Biosynthesis Enzymes in Mozambique Tilapia

It is proposed that the unique and direct ionic regulation of the activities of Ins biosynthesis enzymes represents an efficient biochemical feedback loop for regulation of intracellular physiological ion homeostasis during hyperosmotic stress.

Phosphoinositides: tiny lipids with giant impact on cell regulation.

  • T. Balla
  • Biology
    Physiological reviews
  • 2013
This review is an attempt to give an overview of this enormous research field focusing on major developments in diverse areas of basic science linked to cellular physiology and disease.

References

SHOWING 1-10 OF 25 REFERENCES

Mechanism of inositol monophosphatase, the putative target of lithium therapy.

Model, kinetic, and mutagenesis studies on the enzyme reveal the requirement for two metal ions in the catalytic mechanism, and a two-metal mechanism is reported, consistent with the reduced catalytic activity observed with substrate analogues lacking the 6-OH.

Structure of inositol monophosphatase, the putative target of lithium therapy.

Comparison of the phosphatase aligned sequences of several diverse genes with theosphatase structure suggests that the products of these genes and the phosph atase form a structural family with a conserved metal binding site.

Probing the role of metal ions in the mechanism of inositol monophosphatase by site-directed mutagenesis.

From the recently solved crystal structure of the human enzyme, several amino acid residues in the active site were targeted for mutagenesis studies and resulted in parallel reductions in both lithium and magnesium affinity, suggesting that Li+ and Mg2+ share a common binding site.

A novel inositol mono-phosphatase inhibitor from Memnoniella echinata. Producing organism, fermentation, isolation, physicochemical and in vitro biological properties.

A novel inositol mono-phosphatase inhibitor, L-671,776 (1), was discovered from a culture of the hyphomycete, Memnoniella echinata (ATCC 20928). 1 has a molecular weight of 388 and a molecular

Beryllium competitively inhibits brain myo-inositol monophosphatase, but unlike lithium does not enhance agonist-induced inositol phosphate accumulation.

The disparity in the actions of beryllium and lithium suggest that either (1) selective inhibition of myo-inositol monophosphatase does not completely explain the action of lithium on the phosphatidyl inositol cycle, or (2) that uncompetitive inhibition ofMyo-Inositol Monophosph atase is a necessary requirement to observe functional lithium mimetic activity.

Structural analysis of inositol monophosphatase complexes with substrates.

The structural data suggest that the active site nucleophile is a metal-bound water that is activated by interaction with Glu 70 and Thr 95, suggesting that Li+ from the crystallization solvent partially replaces Gd3+ upon substrate binding.

In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L‐690,330

In peripheral tissues, the effects of L‐690,330 on inositol(1)phosphate levels mimicked those of lithium both qualitatively and quantitatively, however, in the brain, the results were much less than seen with lithium, consistent with the blood‐brain barrier restricting access of the polar L‐680,330 into the CNS, thereby further limiting entry of compound into cells in thebrain.

Properties of inositol polyphosphate 1-phosphatase.