Inositol-phosphate phosphatase explained

inositol-1(or 4)-monophosphatase
Ec Number:3.1.3.25
Cas Number:37184-63-7
Go Code:0008934
Width:270
Inositol monophosphatase 1
Symbol:IMPA1
Altsymbols:IMP; IMPA
Entrezgene:3612
Hgncid:6050
Omim:602064
Refseq:NP_001138350
Uniprot:P29218
Ecnumber:3.1.3.25
Chromosome:8
Arm:q
Band:21.1
Locussupplementarydata:-q21.3
Inositol monophosphatase 2
Symbol:IMPA2
Entrezgene:3613
Hgncid:6051
Omim:605922
Refseq:NP_055029
Uniprot:O14732
Ecnumber:3.1.3.25
Chromosome:18
Arm:p
Band:11.2
Inositol monophosphatase 3
Symbol:IMPAD1
Altsymbols:IMPA3
Entrezgene:54928
Hgncid:26019
Omim:614010
Refseq:NP_060283
Uniprot:Q9NX62
Ecnumber:3.1.3.25
Chromosome:8
Arm:q
Band:12.1

The enzyme Inositol phosphate-phosphatase (EC 3.1.3.25) is of the phosphodiesterase family of enzymes.[1] It is involved in the phosphophatidylinositol 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.[2]

The catalyzed reaction:

myo-inositol phosphate + H2O

\rightleftharpoons

myo-inositol + phosphate

Nomenclature

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

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. 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.[3]

Catalytic mechanism

It was previously reported that the hydrolysis of inositol monophosphate was catalyzed by IMPase through a 2-magnesium ion mechanism.[4] 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.[5] 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.[4] 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.[6]

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.[7] Inositol monophosphatase is able to regulate inositol homeostasis because it lies at the convergence of two pathways that generate inositol:[8]

Inositol monophosphatase 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, which hydrolyzes phosphatidylinositol biphosphate (PIP2), resulting in a membrane associated product, diacylglycerol, and a water-soluble product, inositol triphosphate. Diacylglycerol acts as a second messenger, activating several protein kinases and produces extended downstream signaling. Inositol triphosphate is also a second messenger which activates receptors on the endoplasmic reticulum to release calcium ion stores into the cytoplasm,[8] [9] 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.[10] Overall, diacylglycerol and inositol triphosphate signaling has implications for neuronal plasticity, impacting hippocampal long term potentiation, stress-induced cognitive impairment, and neuronal growth cone spreading.[9] 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.[9]

Inositol monophosphatase 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.[11]

Clinical significance

Inositol monophosphatase has historically been believed to be a direct target of lithium, the primary treatment for bipolar disorder.[2] 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.[2] [12] 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 inositol monophosphatase at the site of one of the magnesium ions.[13] Rodents administered lithium showed a decrease in inositol levels, in line with the hypothesis.[14] Valproate, another mood-stabilizing drug given to bipolar disorder patients, has also been shown to mimic the effects of lithium on myo-inositol.[15]

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.[16] [17] [18] 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[19] More research is required to fully explain the role that lithium and IMPase play in bipolar disorder patients.[2] [12]

Despite the fact that lithium is effective in treating bipolar disorder, it is an extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose.[1] A novel inhibitor of inositol monophosphatase that is less toxic could be a more desirable treatment for bipolar disorder.[20] Such an inhibitor would need to cross the blood–brain barrier in order to reach the inositol monophosphatase in neurons.[21]

Further reading

Notes and References

  1. Can A, Schulze TG, Gould TD . Molecular actions and clinical pharmacogenetics of lithium therapy . Pharmacology, Biochemistry, and Behavior . 123 . 3–16 . August 2014 . 24534415 . 4220538 . 10.1016/j.pbb.2014.02.004 .
  2. Harwood AJ . Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited . Molecular Psychiatry . 10 . 1 . 117–26 . January 2005 . 15558078 . 10.1038/sj.mp.4001618 . 20026448 . free .
  3. Bone R, Springer JP, Atack JR . 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 . November 1992 . 1332026 . 50271 . 10.1073/pnas.89.21.10031 . 1992PNAS...8910031B . free .
  4. Lu S, Huang W, Li X, Huang Z, Liu X, Chen Y, Shi T, Zhang J . 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 . September 2012 . 22889135 . 10.1021/ci300172r .
  5. Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, Cooper J, Gore M, Wood S . High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy . Acta Crystallographica. Section D, Biological Crystallography . 61 . Pt 5 . 545–55 . May 2005 . 15858264 . 10.1107/S0907444905004038 . free . 2005AcCrD..61..545G .
  6. Web site: Singh. Parmvir. Myo-inositol Monophosphatase, the Target of Lithium Therapy. 2020-01-23. https://web.archive.org/web/20130604175323/http://maptest.rutgers.edu/drupal/?q=node%2F354. 2013-06-04. dead.
  7. Chung. Chang. A divergent synthesis of regio-isomers of myo-inositol monophosphate. Korean Journal of Med. Chem.. 1996. 6. 162–165.
  8. Berridge MJ, Downes CP, Hanley MR . Neural and developmental actions of lithium: a unifying hypothesis . Cell . 59 . 3 . 411–9 . November 1989 . 2553271 . 10.1016/0092-8674(89)90026-3 . 41816045 .
  9. Schloesser RJ, Huang J, Klein PS, Manji HK . Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder . Neuropsychopharmacology . 33 . 1 . 110–33 . January 2008 . 17912251 . 10.1038/sj.npp.1301575 . 2024963 . free .
  10. Berridge MJ . Inositol trisphosphate and calcium signalling mechanisms . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1793 . 6 . 933–40 . June 2009 . 19010359 . 10.1016/j.bbamcr.2008.10.005 . free .
  11. Chen IW, Charalampous CF . 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 . May 1966 . 10.1016/S0021-9258(18)96606-8 . 4287852 . free .
  12. Brown KM, Tracy DK . Lithium: the pharmacodynamic actions of the amazing ion . Therapeutic Advances in Psychopharmacology . 3 . 3 . 163–76 . June 2013 . 24167688 . 3805456 . 10.1177/2045125312471963 .
  13. Saudek V, Vincendon P, Do QT, Atkinson RA, Sklenar V, Pelton PD, Piriou F, Ganzhorn AJ . 7Li nuclear-magnetic-resonance study of lithium binding to myo-inositolmonophosphatase . European Journal of Biochemistry . 240 . 1 . 288–91 . August 1996 . 8925839 . 10.1111/j.1432-1033.1996.0288h.x .
  14. Allison JH, Stewart MA . Reduced brain inositol in lithium-treated rats . Nature . 233 . 43 . 267–8 . October 1971 . 5288124 . 10.1038/newbio233267a0 .
  15. O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH . 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 . October 2000 . 11032992 . 10.1016/s0006-8993(00)02797-9 . 8823582 .
  16. Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK . 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 . December 1999 . 10588403 . 10.1176/ajp.156.12.1902 . 5650139 .
  17. Patel NC, Cecil KM, Strakowski SM, Adler CM, DelBello MP . 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 . December 2008 . 19108667 . 2935834 . 10.1089/cap.2007.151 .
  18. Silverstone PH, McGrath BM . 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 . 2009 . 20374155 . 10.1080/09540260902962214 . 205645556 .
  19. Inhorn RC, Majerus PW . Properties of inositol polyphosphate 1-phosphatase . The Journal of Biological Chemistry . 263 . 28 . 14559–65 . October 1988 . 10.1016/S0021-9258(18)68256-0 . 2844776 . free .
  20. Atack. J.. Inositol Monophosphatase Inhibitors— Lithium Mimetics?. Medicinal Research Reviews. 1997. 17. 2. 215–224. 10.1002/(sici)1098-1128(199703)17:2<215::aid-med3>3.0.co;2-2. 9057165. 27534316 .
  21. Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC . A safe lithium mimetic for bipolar disorder . Nature Communications . 4 . 1332 . 2013 . 23299882 . 3605789 . 10.1038/ncomms2320 . 2013NatCo...4.1332S .

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