|Inositol monophosphatase 1|
|Alt. symbols||IMP; IMPA|
|Locus||Chr. 8 q21.1-q21.3|
|Inositol monophosphatase 2|
X-ray crystal structure of inositol monophosphatase 2
|Locus||Chr. 18 p11.2|
|Inositol monophosphatase 3|
|Locus||Chr. 8 q12.1|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Inositol monophosphatase, commonly referred to as IMPase, is an enzyme of the phosphodiesterase family of enzymes. It is involved in the phosphophatidylinositol [PI] signaling pathway, which affects a wide array of cell functions, including but not limited to, cell growth, apoptosis, secretion, and information processing. Inhibition of inositol monophosphatase may be key in the action of lithium in treating bipolar disorder, specifically manic depression.
The enzyme is a dimer comprising 277 amino acid residues per subunit. Each dimer exists in 5 layers of alternating α-helices and β-sheets, totaling to 9 α-helices and β-sheets per subunit. IMPase has three hydrophilic hollow active sites, each of which bind water and magnesium molecules. These binding sites appear to be conserved in other phosphodiesterases such as fructose 1,6-bisphosphatase (FBPase) and inositol polyphosphate 1-phosphatase.
It was previously reported that the hydrolysis of inositol monophosphate was catalyzed by IMPase through a 2-magnesium ion mechanism. However a recent 1.4 A resolution crystal structure shows 3 magnesium ions coordinating in each active binding site of the 2 dimers, supporting a 3-magnesium ion mechanism. The mechanism for hydrolysis is now thought to proceed as such: the enzyme is activated by a magnesium ion binding to binding site I, containing three water molecules, and stabilized by the negative charges on the carboxylates of Glu70 and Asp90, and the carbonyl of Ile92. Another magnesium ion then cooperatively binds to binding site 2, which has of carboxylates of Asp90, Asp93, Asp220, and three water molecules, one of which is shared by binding site 1. Then, a third magnesium weakly and non-cooperatively to the third binding site, which has 5 water molecules and residue Glu70. After all three magnesium ions have bound, the inositol monophosphatase can bind, the negatively charge phosphate group stabilized by the three positively charged magnesium ions. Finally an activated water molecule acts a nucleophile and hydrolyzes the substrate, giving inositol and inorganic phosphate.
Inositol monophosphatase plays an important role in maintaining intracellular levels of myo-inositol, a molecule that forms the structural basis of several secondary messengers in eukaryotic cells. IMPase dephosphorylates the isomers of inositol monophosphate to produce inositol, mostly in the form of the stereoisomer, myo-inositol. Inositol monophosphatase is able to regulate inositol homeostasis because it lies at the convergence of two pathways that generate inositol:
- The phosphatidylinositol signaling pathway
IMPase in the phosphatidylinositol signaling pathway
In this pathway, G-coupled protein receptors and tyrosine kinase receptors are activated, resulting in the activation of phospholipase C (PLC). PLC hydrolyzes phosphatidylinositol bisphosphate (PIP2), resulting in a membrane associated product, diacylglycerol (DAG), and a water-soluble product, inositol triphosphate (IP3). DAG acts as a second messenger, activating several protein kinases and produces extended downstream signaling. IP3 is also a second messenger which activates receptors on the endoplasmic reticulum to release calcium ion stores into the cytoplasm, creating a complex signaling system that can be involved in modulating fertilization, proliferation, contraction, cell metabolism, vesicle and fluid secretion, and information processing in neuronal cells. Overall, DAG and IP3 signaling has implications for neuronal plasticity, impacting hippocampal long term potentiation, stress-induced cognitive impairment, and neuronal growth cone spreading. Furthermore, not only is PIP2 a precursor to several signaling molecules, it can be phosphorylated at the 3’ position to become PIP3, which is involved in cell proliferation, apoptosis and cell movement.
In this pathway, IMPase is the common, final step in recycling IP3 to produce PIP2. IMPase does this by dephosphorylating inositol monophosphate to produce inorganic phosphate and myo-inositol, the precursor to PIP2. Because of IMPase's crucial role in this signaling pathway, it is a potential drug target for inhibition and modulation.
IMPase in the de novo synthesis of myo-inositol
There are at least 2 known steps in the de novo synthesis of myo-inositol from glucose 6-phosphate. In the first step, glucose 6-phosphate is converted to D-inositol 1 monophosphate by the enzyme glucose 6 phosphate cyclase. Inositol monophosphatase catalyzes the final step in which D-inositol 1 monophosphate is dephosphorylated to form myo-inositol.
Inositol monophosphatase has historically been believed to be a direct target of lithium, the primary treatment for bipolar disorder. It is thought that lithium acts according to the inositol depletion hypothesis: lithium produces its therapeutic effect by inhibiting IMPase and therefore decreasing levels of myo-inositol. Scientific support for this hypothesis exists but is limited; the complete role of lithium and inositol monophosphatase in treating bipolar disorder or reducing myo-inositol levels is not well understood.
In support of the inositol depletion hypothesis, researchers have shown that lithium binds uncompetitively to purified bovine IMPase at the site of one of the magnesium ions. Rodents administered lithium showed a decrease in inositol levels, in line with the hypothesis. Valproate, another mood-stabilizing drug given to bipolar disorder patients, has also been shown to mimic the effects of lithium on myo-inositol.
However, some clinical studies have found that bipolar disorder patients that had been administered lithium showed lower myo-inositol levels, while others found no effect on myo-inositol levels. Furthermore, lithium also binds to inositol polyphosphate 1-phosphatase (IPP), an enzyme also present in the phosphoinositide pathway, and could lower inositol levels through this mechanism More research is required to fully explain the role that lithium and IMPase play in bipolar disorder patients.
Despite the fact that lithium is effective in treating bipolar disorder, it is extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose.  A novel inhibitor of IMPase that is less toxic could be a more desirable treatment for bipolar disorder. Such an inhibitor would need to cross the blood–brain barrier in order to reach the IMPase in neurons.
- Arai R, Ito K, Ohnishi T, Ohba H, Akasaka R, Bessho Y, Hanawa-Suetsugu K, Yoshikawa T, Shirouzu M, Yokoyama S (May 2007). "Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures". Proteins 67 (3): 732–42. doi:10.1002/prot.21299. PMID 17340635.
- Can A, Schulze TG, Gould TD (February 2014). "Molecular Actions and Clinical Pharmacogenetics of Lithium Therapy". Pharmacol. Biochem. Behav. 123: 3–16. doi:10.1016/j.pbb.2014.02.004. PMID 24534415.
- 
- Harwood AJ (January 2005). "Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited". Mol. Psychiatry 10 (1): 117–26. doi:10.1038/sj.mp.4001618. PMID 15558078.
- Lu S, Huang W, Li X, Huang Z, Liu X, Chen Y, Shi T, Zhang J (September 2012). "Insights into the role of magnesium triad in myo-inositol monophosphatase: metal mechanism, substrate binding, and lithium therapy". J Chem Inf Model 52 (9): 2398–409. doi:10.1021/ci300172r. PMID 22889135.
- Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, Cooper J, Gore M, Wood S (May 2005). "High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy". Acta Crystallogr. D Biol. Crystallogr. 61 (Pt 5): 545–55. doi:10.1107/S0907444905004038. PMID 15858264.
- Bone R, Springer JP, Atack JR (November 1992). "Structure of inositol monophosphatase, the putative target of lithium therapy". Proc. Natl. Acad. Sci. U.S.A. 89 (21): 10031–5. doi:10.1073/pnas.89.21.10031. PMC 50271. PMID 1332026.
- Singh, Parmvir. "Myo-inositol Monophosphatase, the Target of Lithium Therapy".
- Chung; Chang (1996). "A divergent synthesis of regio-isomers of myo-inositol monophosphate". Korean Journal of Med. Chem. 6: 162–165.
- Berridge MJ, Downes CP, Hanley MR (November 1989). "Neural and developmental actions of lithium: a unifying hypothesis". Cell 59 (3): 411–9. doi:10.1016/0092-8674(89)90026-3. PMID 2553271.
- Schloesser RJ, Huang J, Klein PS, Manji HK (January 2008). "Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder". Neuropsychopharmacology 33 (1): 110–33. doi:10.1038/sj.npp.1301575. PMID 17912251.
- Berridge. "Inositol trisphosphate and calcium signalling mechanisms". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1793: 933–940. doi:10.1016/j.bbamcr.2008.10.005.
- Chen IW, Charalampous CF (May 1966). "Biochemical studies on inositol. IX. D-Inositol 1-phosphate as intermediate in the biosynthesis of inositol from glucose 6-phosphate, and characteristics of two reactions in this biosynthesis". J. Biol. Chem. 241 (10): 2194–9. PMID 4287852.
- Brown KM, Tracy DK (June 2013). "Lithium: the pharmacodynamic actions of the amazing ion". Ther Adv Psychopharmacol 3 (3): 163–76. doi:10.1177/2045125312471963. PMC 3805456. PMID 24167688.
- Saudek V, Vincendon P, Do QT, Atkinson RA, Sklenar V, Pelton PD, Piriou F, Ganzhorn AJ (August 1996). "7Li nuclear-magnetic-resonance study of lithium binding to myo-inositolmonophosphatase". Eur. J. Biochem. 240 (1): 288–91. doi:10.1111/j.1432-1033.1996.0288h.x. PMID 8925839.
- Allison JH, Stewart MA (October 1971). "Reduced brain inositol in lithium-treated rats". Nature New Biol. 233 (43): 267–8. doi:10.1038/newbio233267a0. PMID 5288124.
- O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH (October 2000). "Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain". Brain Res. 880 (1-2): 84–91. doi:10.1016/s0006-8993(00)02797-9. PMID 11032992.
- Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK (December 1999). "Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness". Am J Psychiatry 156 (12): 1902–8. PMID 10588403.
- Patel NC, Cecil KM, Strakowski SM, Adler CM, DelBello MP (December 2008). "Neurochemical alterations in adolescent bipolar depression: a proton magnetic resonance spectroscopy pilot study of the prefrontal cortex". J Child Adolesc Psychopharmacol 18 (6): 623–7. doi:10.1089/cap.2007.151. PMC 2935834. PMID 19108667.
- Silverstone PH, McGrath BM (2009). "Lithium and valproate and their possible effects on themyo-inositol second messenger system in healthy volunteers and bipolar patients". Int Rev Psychiatry 21 (4): 414–23. doi:10.1080/09540260902962214. PMID 20374155.
- Inhorn RC, Majerus PW (October 1988). "Properties of inositol polyphosphate 1-phosphatase". J. Biol. Chem. 263 (28): 14559–65. PMID 2844776.
- Atack, J. (1997). "Inositol Monophosphatase Inhibitors— Lithium Mimetics?". Medicinal Research Reviews 17 (2): 215–224. doi:10.1002/(sici)1098-1128(199703)17:2<215::aid-med3>3.0.co;2-2.
- Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC (2013). "A safe lithium mimetic for bipolar disorder". Nat Commun 4: 1332. doi:10.1038/ncomms2320. PMC 3605789. PMID 23299882.
- Parthasarathy L, Vadnal RE, Parthasarathy R, Devi CS (1994). "Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase". Life Sci. 54 (16): 1127–42. doi:10.1016/0024-3205(94)00835-3. PMID 8152337.
- Bradley JJ (1988). The Pitfalls of Attempted Suicide: Hazards of Lithium Carbonate Therapy. London: The Medical Protection Society.
- Fauroux CM, Freeman S (1999). "Inhibitors of inositol monophosphatase". J. Enzym. Inhib. 14 (2): 97–108. PMID 10445037.
- Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, Fletcher SR, Iversen LL, Broughton HB (June 1994). "Mechanism of inositol monophosphatase, the putative target of lithium therapy". Proc. Natl. Acad. Sci. U.S.A. 91 (13): 5766–70. doi:10.1073/pnas.91.13.5766. PMC 44077. PMID 8016062.
- Wilkie J, Cole AG, Gani D (January 1995). "3-Dimensional interactions between inositol monophosphatase and its substrates, inhibitors and metal ion cofactors". Journal of the Chemical Society, Perkin Transactions 1 (21): 2709–2727. doi:10.1039/P19950002709.
- Cole AG, Gani D (January 1995). "Active conformation of the inositol monophosphatase substrate, adenosine 2?-phosphate: role of the ribofuranosyl O-atoms in chelating a second Mg2+ ion". Journal of the Chemical Society, Perkin Transactions 1 (21): 2685–2694. doi:10.1039/P19950002685.