Inositol-phosphate phosphatase
inositol-1(or 4)-monophosphatase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Chr. 8 q21.1-q21.3 | |||||||
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Chr. 18 p11.2 | |||||||
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Chr. 8 q12.1 | |||||||
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The enzyme Inositol phosphate-phosphatase (EC 3.1.3.25) is of the
The catalyzed reaction:
- myo-inositol phosphate + H2O 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:
- 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
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
- The phosphatidylinositol signaling pathway
- The de novo biosynthesis of inositol from glucose 6-phosphate
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
In this pathway, IMPase is the common, final step in recycling IP3 to produce PIP2. IMPase does this by dephosphorylating
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.[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 inositol monophosphatase 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 an extremely toxic metal and the toxic dose is only marginally greater than the therapeutic dose. [2] A novel inhibitor of inositol monophosphatase 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 inositol monophosphatase in neurons.[23]
References
- S2CID 46602105.
- ^ PMID 24534415.
- ^ a b c d [citation needed]
- ^ S2CID 20026448.
- ^ PMID 22889135.
- ^ PMID 15858264.
- PMID 1332026.
- ^ Singh P. "Myo-inositol Monophosphatase, the Target of Lithium Therapy". Archived from the original on 2013-06-04. Retrieved 2020-01-23.
- ^ Chung, Chang (1996). "A divergent synthesis of regio-isomers of myo-inositol monophosphate". Korean Journal of Med. Chem. 6: 162–165.
- ^ S2CID 41816045.
- ^ S2CID 2024963.
- PMID 19010359.
- PMID 4287852.
- ^ PMID 24167688.
- PMID 8925839.
- PMID 5288124.
- S2CID 8823582.
- S2CID 5650139.
- PMID 19108667.
- S2CID 205645556.
- PMID 2844776.
- S2CID 27534316.
- 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. 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. 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. 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. .
- 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. .
- 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. 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. S2CID 24336959.
- 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. PMID 3036092.