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{{SI}}
{{Infobox protein
{{CMG}}
| Name = [[Inositol monophosphatase 1]]
| image =
| width =
| caption =
| Symbol = [[Inositol monophosphatase 1|IMPA1]]
| AltSymbols = IMP; IMPA
| IUPHAR_id =
| EntrezGene = 3612
| HGNCid = 6050
| OMIM = 602064
| PDB =
| RefSeq = NP_001138350
| UniProt = P29218
| ECnumber = 3.1.3.25
| Chromosome = 8
| Arm = q
| Band = 21.1
| LocusSupplementaryData = -q21.3
}}
{{Infobox protein
| Name = [[Inositol monophosphatase 2]]
| image =Protein_IMPA2_PDB_2czh.png
| width =
| caption = X-ray crystal structure of inositol monophosphatase 2<ref name="pmid17340635">{{cite journal |vauthors=Arai R, Ito K, Ohnishi T, Ohba H, Akasaka R, Bessho Y, Hanawa-Suetsugu K, Yoshikawa T, Shirouzu M, Yokoyama S | title = Crystal structure of human myo-inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures | journal = Proteins | volume = 67 | issue = 3 | pages = 732–42 |date=May 2007  | pmid = 17340635 | doi = 10.1002/prot.21299 }}</ref>
| Symbol =  [[Inositol monophosphatase 2|IMPA2]]
| AltSymbols =
| IUPHAR_id =
| EntrezGene = 3613
| HGNCid = 6051
| OMIM = 605922
| PDB =
| RefSeq = NP_055029
| UniProt = O14732
| ECnumber = 3.1.3.25
| Chromosome = 18
| Arm = p
| Band = 11.2
| LocusSupplementaryData =
}}
{{Infobox protein
| Name = [[Inositol monophosphatase 3]]
| image =
| width =
| caption =
| Symbol = [[Inositol monophosphatase 3|IMPAD1]]
| AltSymbols = IMPA3
| IUPHAR_id =
| EntrezGene = 54928
| HGNCid = 26019
| OMIM = 614010
| PDB =
| RefSeq = NP_060283
| UniProt = Q9NX62
| ECnumber = 3.1.3.25
| Chromosome = 8
| Arm = q
| Band = 12.1
| LocusSupplementaryData =
}}
{{enzyme
| Name = inositol-1(or 4)-monophosphatase
| EC_number = 3.1.3.25
| CAS_number = 37184-63-7
| IUBMB_EC_number = 3/1/3/25
| GO_code = 0008934
| image =
| width =
| caption =
}}
'''Inositol monophosphatase''', commonly referred to as IMPase, is an [[enzyme]] of the [[phosphodiesterase]] family of enzymes.<ref name="Can_2014">{{cite journal |vauthors=Can A, Schulze TG, Gould TD | title = Molecular Actions and Clinical Pharmacogenetics of Lithium Therapy | journal = Pharmacol. Biochem. Behav. | volume = 123| issue = | pages = 3–16|date=February 2014  | pmid = 24534415 | doi = 10.1016/j.pbb.2014.02.004 | pmc = 4220538}}</ref> 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.<ref name = "hilgemann">{{citation needed|date=February 2014}}<!-- 10.1126/stke.2001.111.re19  does not seem relevant --></ref> Inhibition of inositol monophosphatase may be key in the action of [[Lithium (medication)|lithium]] in treating [[bipolar disorder]], specifically [[manic depression]].<ref name="Harwood_2005">{{cite journal | author = Harwood AJ | title = Lithium and bipolar mood disorder: the inositol-depletion hypothesis revisited | journal = Mol. Psychiatry | volume = 10 | issue = 1 | pages = 117–26 |date=January 2005  | pmid = 15558078 | doi = 10.1038/sj.mp.4001618 | url = }}</ref>


==Overview==
== Structure ==
'''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]]).


The enzyme itself is a [[dimer]] comprising 277 [[amino acid]] residues per subunit which [[phosphorylation|dephosphorylates]] inositol phosphate to [[inositol]] as part of the phosphatidylinositol signalling pathway. Each dimer exists as a five-layered sandwich of three pairs of [[alpha helix|α-helices]] and two [[beta sheet|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.
The enzyme is a [[protein dimer|dimer]] comprising 277 [[amino acid]] residues per subunit. Each dimer exists in 5 layers of alternating [[alpha helix|α-helices]] and [[beta sheet|β-sheets]], totaling to 9 [[alpha helix|α-helices]] and [[beta sheet|β-sheets]] per subunit.<ref name="Lu_2012"/> IMPase has three [[hydrophilic]] hollow active sites, each of which bind water and magnesium molecules.<ref name="Gill_2005"/> These binding sites appear to be conserved in other phosphodiesterases such as [[fructose 1,6-bisphosphatase]] (FBPase) and inositol polyphosphate 1-phosphatase.<ref name="pmid1332026">{{cite journal |vauthors=Bone R, Springer JP, Atack JR | title = Structure of inositol monophosphatase, the putative target of lithium therapy | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 21 | pages = 10031–5 |date=November 1992  | pmid = 1332026 | pmc = 50271 | doi = 10.1073/pnas.89.21.10031}}</ref>


Two kinetically distinct metal-binding environments have been found by metal titration experiments which show that two [[magnesium]] [[ion]]s are involved in the [[catalyst|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.
== Catalytic mechanism ==


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]].
It was previously reported that the hydrolysis of inositol monophosphate was catalyzed by IMPase through a 2-magnesium ion mechanism.<ref name="Lu_2012">{{cite journal |vauthors=Lu S, Huang W, Li X, Huang Z, Liu X, Chen Y, Shi T, Zhang J | title = Insights into the role of magnesium triad in myo-inositol monophosphatase: metal mechanism, substrate binding, and lithium therapy | journal = J Chem Inf Model | volume = 52 | issue = 9 | pages = 2398–409 |date=September 2012  | pmid = 22889135 | doi = 10.1021/ci300172r }}</ref>  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.<ref name="Gill_2005">{{cite journal |vauthors=Gill R, Mohammed F, Badyal R, Coates L, Erskine P, Thompson D, Cooper J, Gore M, Wood S | title = High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy | journal = Acta Crystallogr. D | volume = 61 | issue = Pt 5 | pages = 545–55 |date=May 2005  | pmid = 15858264 | doi = 10.1107/S0907444905004038 }}</ref> 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.<ref name="Lu_2012"/>  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.<ref>{{cite web|last=Singh|first=Parmvir|title=Myo-inositol Monophosphatase, the Target of Lithium Therapy|url=http://maptest.rutgers.edu/drupal/?q=node/354}}</ref>


== References ==
== 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.<ref>{{cite journal|last=Chung|author2=Chang|title=A divergent synthesis of regio-isomers of myo-inositol monophosphate|journal=Korean Journal of Med. Chem.|year=1996|volume=6|pages=162–165}}</ref> Inositol monophosphatase is able to regulate inositol homeostasis because it lies at the convergence of two pathways that generate [[inositol]]:<ref name="Berridge_1989">{{cite journal |vauthors=Berridge MJ, Downes CP, Hanley MR | title = Neural and developmental actions of lithium: a unifying hypothesis | journal = Cell | volume = 59 | issue = 3 | pages = 411–9 |date=November 1989  | pmid = 2553271 | doi =  10.1016/0092-8674(89)90026-3}}</ref>
 
*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 [[PIP2 (disambiguation)|phosphatidylinositol biphosphate]] (PIP<sub>2</sub>), resulting in a membrane associated product, [[diacylglycerol]] (DAG), and a water-soluble product,  [[inositol triphosphate]] (IP3).<ref name="hilgemann"/> 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,<ref name="hilgemann"/><ref name="Berridge_1989"/><ref name="Schloesser_2008">{{cite journal |vauthors=Schloesser RJ, Huang J, Klein PS, Manji HK | title = Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder | journal = Neuropsychopharmacology | volume = 33 | issue = 1 | pages = 110–33 |date=January 2008  | pmid = 17912251 | doi = 10.1038/sj.npp.1301575  }}</ref> 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.<ref>{{cite journal|last=Berridge|title=Inositol trisphosphate and calcium signalling mechanisms|journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research|volume=1793|pages=933–940|doi=10.1016/j.bbamcr.2008.10.005|year=2009}}</ref> Overall, DAG and IP3 signaling has implications for neuronal plasticity, impacting hippocampal long term potentiation, stress-induced cognitive impairment, and neuronal growth cone spreading.<ref name="Schloesser_2008"/> Furthermore, not only is PIP<sub>2</sub> 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.<ref name="hilgemann" />
 
In this pathway, IMPase is the common, final step in recycling IP3 to produce PIP<sub>2</sub>. 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.<ref name="Schloesser_2008"/>
 
===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.<ref name="pmid4287852">{{cite journal |vauthors=Chen IW, Charalampous CF | title = 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 | journal = J. Biol. Chem. | volume = 241 | issue = 10 | pages = 2194–9 |date=May 1966  | pmid = 4287852 | doi =  }}</ref>
 
== Clinical significance ==
 
Inositol monophosphatase has historically been believed to be a direct target of lithium, the primary treatment for bipolar disorder.<ref name="Harwood_2005"/> 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.<ref name="Harwood_2005"/><ref name="Brown_Tracy_2013">{{cite journal |vauthors=Brown KM, Tracy DK | title = Lithium: the pharmacodynamic actions of the amazing ion | journal = Ther Adv Psychopharmacol | volume = 3 | issue = 3 | pages = 163–76 |date=June 2013  | pmid = 24167688 | pmc = 3805456 | doi = 10.1177/2045125312471963 }}</ref> 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.<ref name="pmid8925839">{{cite journal |vauthors=Saudek V, Vincendon P, Do QT, Atkinson RA, Sklenar V, Pelton PD, Piriou F, Ganzhorn AJ | title = <sup>7</sup>Li nuclear-magnetic-resonance study of lithium binding to myo-inositolmonophosphatase | journal = Eur. J. Biochem. | volume = 240 | issue = 1 | pages = 288–91 |date=August 1996  | pmid = 8925839 | doi = 10.1111/j.1432-1033.1996.0288h.x }}</ref> Rodents administered lithium showed a decrease in inositol levels, in line with the hypothesis.<ref name="pmid5288124">{{cite journal |vauthors=Allison JH, Stewart MA | title = Reduced brain inositol in lithium-treated rats | journal = Nature New Biology | volume = 233 | issue = 43 | pages = 267–8 |date=October 1971  | pmid = 5288124 | doi = 10.1038/newbio233267a0 }}</ref>  [[Valproate]], another mood-stabilizing drug given to bipolar disorder patients, has also been shown to mimic the effects of lithium on myo-inositol.<ref name="pmid11032992">{{cite journal |vauthors=O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH | title = Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain | journal = Brain Res. | volume = 880 | issue = 1–2 | pages = 84–91 |date=October 2000  | pmid = 11032992 | doi = 10.1016/s0006-8993(00)02797-9}}</ref>


Bradley JJ, The Pitfalls of Attempted Suicide: Hazards of Lithium Carbonate Therapy. The Medical Protection Society, London, 1988.
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.<ref name="pmid10588403">{{cite journal |vauthors=Moore GJ, Bebchuk JM, Parrish JK, Faulk MW, Arfken CL, Strahl-Bevacqua J, Manji HK | title = Temporal dissociation between lithium-induced changes in frontal lobe myo-inositol and clinical response in manic-depressive illness | journal = Am J Psychiatry | volume = 156 | issue = 12 | pages = 1902–8 |date=December 1999  | pmid = 10588403 | doi = 10.1176/ajp.156.12.1902}}</ref><ref name="pmid19108667">{{cite journal |vauthors=Patel NC, Cecil KM, Strakowski SM, Adler CM, DelBello MP | title = Neurochemical alterations in adolescent bipolar depression: a proton magnetic resonance spectroscopy pilot study of the prefrontal cortex | journal = J Child Adolesc Psychopharmacol | volume = 18 | issue = 6 | pages = 623–7 |date=December 2008  | pmid = 19108667 | pmc = 2935834 | doi = 10.1089/cap.2007.151 }}</ref><ref name="pmid20374155">{{cite journal |vauthors=Silverstone PH, McGrath BM | title = Lithium and valproate and their possible effects on themyo-inositol second messenger system in healthy volunteers and bipolar patients | journal = Int Rev Psychiatry | volume = 21 | issue = 4 | pages = 414–23 | year = 2009 | pmid = 20374155 | doi = 10.1080/09540260902962214 }}</ref> 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<ref name="pmid2844776">{{cite journal |vauthors=Inhorn RC, Majerus PW | title = Properties of inositol polyphosphate 1-phosphatase | journal = J. Biol. Chem. | volume = 263 | issue = 28 | pages = 14559–65 |date=October 1988 | pmid = 2844776 | doi = }}</ref> More research is required to fully explain the role that lithium and IMPase play in bipolar disorder patients.<ref name="Harwood_2005"/><ref name="Brown_Tracy_2013"/>


Fauroux CMJ, Freeman S, J. Enzyme Inhibition, 1999, 14, 97.
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.
<ref name= "Can_2014"/> A novel inhibitor of IMPase that is less toxic could be a more desirable treatment for bipolar disorder.<ref>{{cite journal|last=Atack|first=J.|title=Inositol Monophosphatase Inhibitors— Lithium Mimetics?|journal=Medicinal Research Reviews|year=1997|volume=17|issue=2|pages=215–224|doi=10.1002/(sici)1098-1128(199703)17:2<215::aid-med3>3.0.co;2-2}}</ref> Such an inhibitor would need to cross the [[blood–brain barrier]] in order to reach the IMPase in neurons.<ref name="pmid23299882">{{cite journal |vauthors=Singh N, Halliday AC, Thomas JM, Kuznetsova OV, Baldwin R, Woon EC, Aley PK, Antoniadou I, Sharp T, Vasudevan SR, Churchill GC | title = A safe lithium mimetic for bipolar disorder | journal = Nat Commun | volume = 4 | issue = | pages = 1332 | year = 2013 | pmid = 23299882 | pmc = 3605789 | doi = 10.1038/ncomms2320 }}</ref>


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.
== References ==
{{Reflist|35em}}


Wilkie J, Cole AG, Gani D, J. Chem. Soc., Perkin Trans. 1, 1995, 2709.
== Further reading ==
{{refbegin|35em}}
* {{cite journal |vauthors=Parthasarathy L, Vadnal RE, Parthasarathy R, Devi CS |title=Biochemical and molecular properties of lithium-sensitive myo-inositol monophosphatase |journal=Life Sci. |volume=54 |issue=16 |pages=1127–42 |year=1994 |pmid=8152337 |doi= 10.1016/0024-3205(94)00835-3|url=}}
* {{cite book | author = Bradley JJ | title =The Pitfalls of Attempted Suicide: Hazards of Lithium Carbonate Therapy | publisher = The Medical Protection Society | location = London | year = 1988 }}
* {{cite journal |vauthors=Fauroux CM, Freeman S | title = Inhibitors of inositol monophosphatase | journal = J. Enzym. Inhib. | volume = 14 | issue = 2 | pages = 97–108 | year = 1999 | pmid = 10445037 | doi = }}
* {{cite journal |vauthors=Pollack SJ, Atack JR, Knowles MR, McAllister G, Ragan CI, Baker R, Fletcher SR, Iversen LL, Broughton HB | title = Mechanism of inositol monophosphatase, the putative target of lithium therapy | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 91 | issue = 13 | pages = 5766–70 |date=June 1994 | pmid = 8016062 | pmc = 44077 | doi =  10.1073/pnas.91.13.5766}}
* {{cite journal |vauthors=Wilkie J, Cole AG, Gani D | title = 3-Dimensional interactions between inositol monophosphatase and its substrates, inhibitors and metal ion cofactors | journal = Journal of the Chemical Society, Perkin Transactions 1 |date=January 1995 | issue = 21 | pages = 2709–2727 | doi = 10.1039/P19950002709 }}
* {{cite journal |vauthors=Cole AG, Gani D | title = Active conformation of the inositol monophosphatase substrate, adenosine 2?-phosphate: role of the ribofuranosyl O-atoms in chelating a second Mg<sup>2+</sup> ion | journal=Journal of the Chemical Society, Perkin Transactions 1 |date=January 1995 | issue = 21 | pages = 2685–2694 | doi = 10.1039/P19950002685 }}
{{refend}}


Cole AG, Gani D, J. Chem. Soc., Perkin Trans. 1, 1995, 2685.
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Latest revision as of 08:59, 9 January 2019

Inositol monophosphatase 1
Identifiers
SymbolIMPA1
Alt. symbolsIMP; IMPA
Entrez3612
HUGO6050
OMIM602064
RefSeqNP_001138350
UniProtP29218
Other data
EC number3.1.3.25
LocusChr. 8 q21.1-q21.3
Inositol monophosphatase 2
File:Protein IMPA2 PDB 2czh.png
X-ray crystal structure of inositol monophosphatase 2[1]
Identifiers
SymbolIMPA2
Entrez3613
HUGO6051
OMIM605922
RefSeqNP_055029
UniProtO14732
Other data
EC number3.1.3.25
LocusChr. 18 p11.2
Inositol monophosphatase 3
Identifiers
SymbolIMPAD1
Alt. symbolsIMPA3
Entrez54928
HUGO26019
OMIM614010
RefSeqNP_060283
UniProtQ9NX62
Other data
EC number3.1.3.25
LocusChr. 8 q12.1
inositol-1(or 4)-monophosphatase
Identifiers
EC number3.1.3.25
CAS number37184-63-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO

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

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]

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, 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.
  2. ↑ 2.0 2.1 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. PMC 4220538. PMID 24534415.
  3. ↑ 3.0 3.1 3.2 3.3 [citation needed]
  4. ↑ 4.0 4.1 4.2 4.3 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.
  5. ↑ 5.0 5.1 5.2 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.
  6. ↑ 6.0 6.1 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. 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". Proc. Natl. Acad. Sci. U.S.A. 89 (21): 10031–5. doi:10.1073/pnas.89.21.10031. PMC 50271. PMID 1332026.
  8. ↑ Singh, Parmvir. "Myo-inositol Monophosphatase, the Target of Lithium Therapy".
  9. ↑ Chung; Chang (1996). "A divergent synthesis of regio-isomers of myo-inositol monophosphate". Korean Journal of Med. Chem. 6: 162–165.
  10. ↑ 10.0 10.1 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. ↑ 11.0 11.1 11.2 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 (2009). "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.
  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". J. Biol. Chem. 241 (10): 2194–9. PMID 4287852.
  14. ↑ 14.0 14.1 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.
  15. ↑ 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.
  16. ↑ Allison JH, Stewart MA (October 1971). "Reduced brain inositol in lithium-treated rats". Nature New Biology. 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 Res. 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". Am J Psychiatry. 156 (12): 1902–8. doi:10.1176/ajp.156.12.1902. 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". J Child Adolesc Psychopharmacol. 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". Int Rev Psychiatry. 21 (4): 414–23. doi:10.1080/09540260902962214. PMID 20374155.
  21. ↑ Inhorn RC, Majerus PW (October 1988). "Properties of inositol polyphosphate 1-phosphatase". J. Biol. Chem. 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.
  23. ↑ 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.

Further reading

  • 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.
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