Inositol-phosphate phosphatase

Inositol phosphate-phosphatase, commonly referred to as IMPase, are enzymes of the phosphodiesterase family of enzymes.[2] They are 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.[3] Inhibition of inositol monophosphatase may be key in the action of lithium in treating bipolar disorder, specifically manic depression.[4]

inositol-1(or 4)-monophosphatase
Inositol monophosphatase 2, dimer, Human
Identifiers
EC number	3.1.3.25
CAS number	37184-63-7
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Inositol monophosphatase 1
Identifiers
Symbol	IMPA1
Alt. symbols	IMP; IMPA
NCBI gene	3612
HGNC	6050
OMIM	602064
RefSeq	NP_001138350
UniProt	P29218
Other data
EC number	3.1.3.25
Locus	Chr. 8 q21.1-q21.3

Inositol monophosphatase 2
X-ray crystal structure of inositol monophosphatase 2[1]
Identifiers
Symbol	IMPA2
NCBI gene	3613
HGNC	6051
OMIM	605922
RefSeq	NP_055029
UniProt	O14732
Other data
EC number	3.1.3.25
Locus	Chr. 18 p11.2

Inositol monophosphatase 3
Identifiers
Symbol	IMPAD1
Alt. symbols	IMPA3
NCBI gene	54928
HGNC	26019
OMIM	614010
RefSeq	NP_060283
UniProt	Q9NX62
Other data
EC number	3.1.3.25
Locus	Chr. 8 q12.1

The catalyzed reaction:

myo-inositol phosphate + H₂O ${\displaystyle \rightleftharpoons }$ myo-inositol + phosphate

Nomenclature

This enzyme belongs to the family of hydrolases, specifically those acting on phosphoric monoester bonds. The systematic name of this enzyme class is myo-inositol-phosphate phosphohydrolase. Other names in common use include:

• myo-inositol-1(or 4)-monophosphatase,
• inositol 1-phosphatase,
• L-myo-inositol-1-phosphate phosphatase,
• myo-inositol 1-phosphatase,
• inositol phosphatase,
• inositol monophosphate phosphatase,
• inositol-1(or 4)-monophosphatase,
• myo-inositol-1(or 4)-phosphate phosphohydrolase,
• myo-inositol monophosphatase, and
• myo-inositol-1-phosphatase.

Structure

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.[5] IMPase has three hydrophilic hollow active sites, each of which bind water and magnesium molecules.[6] These binding sites appear to be conserved in other phosphodiesterases such as fructose 1,6-bisphosphatase (FBPase) and inositol polyphosphate 1-phosphatase.[7]

Catalytic mechanism

It was previously reported that the hydrolysis of inositol monophosphate was catalyzed by IMPase through a 2-magnesium ion mechanism.[5] 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.[6] 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.[5] 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.[8]

Function

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.[9] Inositol monophosphatase is able to regulate inositol homeostasis because it lies at the convergence of two pathways that generate inositol:[10]

• The phosphatidylinositol signaling pathway
• The de novo biosynthesis of inositol from glucose 6-phosphate

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 biphosphate (PIP₂), resulting in a membrane associated product, diacylglycerol (DAG), and a water-soluble product, inositol triphosphate (IP3).[3] 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,[3][10][11] 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.[12] Overall, DAG and IP3 signaling has implications for neuronal plasticity, impacting hippocampal long term potentiation, stress-induced cognitive impairment, and neuronal growth cone spreading.[11] 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.[3]

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.[11]

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.[13]

Clinical significance

Inositol monophosphatase has historically been believed to be a direct target of lithium, the primary treatment for bipolar disorder.[4] 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.[4][14] 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.[15] Rodents administered lithium showed a decrease in inositol levels, in line with the hypothesis.[16] Valproate, another mood-stabilizing drug given to bipolar disorder patients, has also been shown to mimic the effects of lithium on myo-inositol.[17]

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.[18][19][20] 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[21] More research is required to fully explain the role that lithium and IMPase play in bipolar disorder patients.[4][14]

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. [2] A novel inhibitor of IMPase that is less toxic could be a more desirable treatment for bipolar disorder.[22] Such an inhibitor would need to cross the blood–brain barrier in order to reach the IMPase in neurons.[23]

References

1. Arai R, Ito K, Ohnishi T, Ohba H, Akasaka R, Bessho Y, et al. (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.
2. Can A, Schulze TG, Gould TD (August 2014). "Molecular actions and clinical pharmacogenetics of lithium therapy". Pharmacology, Biochemistry, and Behavior. 123: 3–16. doi:10.1016/j.pbb.2014.02.004. PMC 4220538. PMID 24534415.
4. Harwood AJ (January 2005). "Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited". Molecular Psychiatry. 10 (1): 117–26. doi:10.1038/sj.mp.4001618. PMID 15558078.
5. Lu S, Huang W, Li X, Huang Z, Liu X, Chen Y, et al. (September 2012). "Insights into the role of magnesium triad in myo-inositol monophosphatase: metal mechanism, substrate binding, and lithium therapy". Journal of Chemical Information and Modeling. 52 (9): 2398–409. doi:10.1021/ci300172r. PMID 22889135.
6. Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, et al. (May 2005). "High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy". Acta Crystallographica. Section D, Biological Crystallography. 61 (Pt 5): 545–55. doi:10.1107/S0907444905004038. PMID 15858264.
7. Bone R, Springer JP, Atack JR (November 1992). "Structure of inositol monophosphatase, the putative target of lithium therapy". Proceedings of the National Academy of Sciences of the United States of America. 89 (21): 10031–5. Bibcode:1992PNAS...8910031B. doi:10.1073/pnas.89.21.10031. PMC 50271. PMID 1332026.
8. Singh, Parmvir. "Myo-inositol Monophosphatase, the Target of Lithium Therapy". Archived from the original on 2013-06-04. Retrieved 2020-01-23.
9. Chung; Chang (1996). "A divergent synthesis of regio-isomers of myo-inositol monophosphate". Korean Journal of Med. Chem. 6: 162–165.
10. 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.
11. 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.
12. Berridge MJ (June 2009). "Inositol trisphosphate and calcium signalling mechanisms". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1793 (6): 933–40. doi:10.1016/j.bbamcr.2008.10.005. PMID 19010359.
13. 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". The Journal of Biological Chemistry. 241 (10): 2194–9. PMID 4287852.
14. Brown KM, Tracy DK (June 2013). "Lithium: the pharmacodynamic actions of the amazing ion". Therapeutic Advances in Psychopharmacology. 3 (3): 163–76. doi:10.1177/2045125312471963. PMC 3805456. PMID 24167688.
15. Saudek V, Vincendon P, Do QT, Atkinson RA, Sklenar V, Pelton PD, et al. (August 1996). "7Li nuclear-magnetic-resonance study of lithium binding to myo-inositolmonophosphatase". European Journal of Biochemistry. 240 (1): 288–91. doi:10.1111/j.1432-1033.1996.0288h.x. PMID 8925839.
16. Allison JH, Stewart MA (October 1971). "Reduced brain inositol in lithium-treated rats". Nature. 233 (43): 267–8. doi:10.1038/newbio233267a0. PMID 5288124.
17. 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 Research. 880 (1–2): 84–91. doi:10.1016/s0006-8993(00)02797-9. PMID 11032992.
18. 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". The American Journal of Psychiatry. 156 (12): 1902–8. doi:10.1176/ajp.156.12.1902 (inactive 2020-05-21). PMID 10588403.
19. 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". Journal of Child and Adolescent Psychopharmacology. 18 (6): 623–7. doi:10.1089/cap.2007.151. PMC 2935834. PMID 19108667.
20. Silverstone PH, McGrath BM (2009). "Lithium and valproate and their possible effects on themyo-inositol second messenger system in healthy volunteers and bipolar patients". International Review of Psychiatry. 21 (4): 414–23. doi:10.1080/09540260902962214. PMID 20374155.
21. Inhorn RC, Majerus PW (October 1988). "Properties of inositol polyphosphate 1-phosphatase". The Journal of Biological Chemistry. 263 (28): 14559–65. PMID 2844776.
22. 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. PMID 9057165.
23. Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, et al. (2013). "A safe lithium mimetic for bipolar disorder". Nature Communications. 4: 1332. Bibcode:2013NatCo...4.1332S. doi:10.1038/ncomms2320. PMC 3605789. PMID 23299882.

Further reading

• Parthasarathy L, Vadnal RE, Parthasarathy R, Devi CS (1994). "Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase". Life Sciences. 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". Journal of Enzyme Inhibition. 14 (2): 97–108. doi:10.3109/14756369909036548. PMID 10445037.
• Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, et al. (June 1994). "Mechanism of inositol monophosphatase, the putative target of lithium therapy". Proceedings of the National Academy of Sciences of the United States of America. 91 (13): 5766–70. Bibcode:1994PNAS...91.5766P. 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.
• Eisenberg F (April 1967). "D-myoinositol 1-phosphate as product of cyclization of glucose 6-phosphate and substrate for a specific phosphatase in rat testis". The Journal of Biological Chemistry. 242 (7): 1375–82. PMID 4290245.
• Gee NS, Ragan CI, Watling KJ, Aspley S, Jackson RG, Reid GG, et al. (February 1988). "The purification and properties of myo-inositol monophosphatase from bovine brain". The Biochemical Journal. 249 (3): 883–9. doi:10.1042/bj2490883. PMC 1148789. PMID 2833231.
• Hallcher LM, Sherman WR (November 1980). "The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain". The Journal of Biological Chemistry. 255 (22): 10896–901. PMID 6253491.
• Yoshikawa T, Turner G, Esterling LE, Sanders AR, Detera-Wadleigh SD (September 1997). "A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder". Molecular Psychiatry. 2 (5): 393–7. doi:10.1038/sj.mp.4000325. PMID 9322233.
• Cockcroft, S. (Ed.), Biology of Phosphoinositides, Biology of Phosphoinositides, Oxford, 2000, p. 320-338.
• Ackermann KE, Gish BG, Honchar MP, Sherman WR (March 1987). "Evidence that inositol 1-phosphate in brain of lithium-treated rats results mainly from phosphatidylinositol metabolism". The Biochemical Journal. 242 (2): 517–24. doi:10.1042/bj2420517. PMC 1147736. PMID 3036092.