Inositol monophosphatase inhibitors—Lithium mimetics?

  title={Inositol monophosphatase inhibitors—Lithium mimetics?},
  author={John R. Atack},
  journal={Medicinal Research Reviews},
  • 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… 

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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.

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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

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Properties of inositol polyphosphate 1-phosphatase.