Inositol monophosphatase

Inositol monophosphatase, commonly referred to as IMPase, is an enzyme found in all cells and is thought to be key in bipolar disorder (manic depression).

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The enzyme itself is a dimer comprising 277 amino acid residues per subunit which dephosphorylates inositol phosphate to inositol as part of the phosphatidylinositol signalling pathway. Each dimer exists as a five-layered sandwich of three pairs of α-helices and two β-sheets. IMPase’s two active sites are located in large, hydrophilic caverns at the base of the two central helices where several segments of secondary structure intersect.

Two kinetically distinct metal-binding environments have been found by metal titration experiments which show that two magnesium ions are involved in the catalytic mechanism. It is thought that one magnesium ion is responsible for the stabilisation of a negative charge on nucleophilic water and the second is involved in stabilising the negative charge on the phosphate leaving group. IMPase is unusual in its mechanism for the dephosphorylation of inositol-1-phosphate as, unlike most phosphatases, it does not proceed by a phospho-enzyme intermediate. Two mechanisms have been proposed, dependent on the location of the water in the active site. The first suggests that the nucleophile (OH- from water) attacks opposite the leaving group in the substrate, resulting in inversion of stereochemistry at the phosphorus, whilst the second proposes that the nucleophile attacks the phosphorus at the face thus causing the stereochemistry to be retained.

In bipolar disorder sufferers, it has been found that the phosphatidylinositol signalling pathway is hyperactive and by inhibiting IMPase - a key enzyme in the pathway - the cycle can be halted resulting in the symptomatic relief of the disorder. It is known that lithium ions, usually from lithium carbonate drug therapy, are good inhibitors of the active sites of IMPase. Lithium is, however, an extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose. Therefore, a great deal of research is currently being undertaken to develop a novel inhibitor of IMPase without the risk of lithium. However, as the IMPase which needs to be inhibited is only that present in the brain, the new inhibitor must have a good bioavailability and be able to easily cross the blood-brain barrier.

References

Bradley JJ, The Pitfalls of Attempted Suicide: Hazards of Lithium Carbonate Therapy. The Medical Protection Society, London, 1988.

Fauroux CMJ, Freeman S, J. Enzyme Inhibition, 1999, 14, 97.

Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, Fletcher SR, Iversen LL, Broughton HB, Proc. Natl. Acad. Sci. USA., 1994, 91, 5766.

Wilkie J, Cole AG, Gani D, J. Chem. Soc., Perkin Trans. 1, 1995, 2709.

Cole AG, Gani D, J. Chem. Soc., Perkin Trans. 1, 1995, 2685.