Inositol monophosphatase 1
Inositol monophosphatase 1 is an enzyme that in humans is encoded by the IMPA1 gene.[5][6]
Structure
[edit]Inositol monophosphatase 1 (IMPA1) is a homodimeric enzyme with each subunit consisting of approximately 277 amino acids and a molecular weight of ~30 kDa.[7] The protein adopts a penta-layered αβαβα core structure, characteristic of the metallophosphatase superfamily, which is also observed in related enzymes like fructose 1,6-bisphosphatase.[8][9] Each monomer's active site contains three magnesium ions arranged in an octahedral coordination geometry, bound by conserved residues including Glu70, Asp90, Asp93, and Asp220.[8][9] Structural studies using X-ray crystallography (e.g., PDB entries 1IMA, 1IMB) reveal that the dimeric arrangement facilitates substrate recognition and catalysis.[9] The enzyme features an Inositol_P domain (Pfam: PF00459), which mediates its magnesium-dependent phosphatase activity and interaction with substrates like myo-inositol monophosphate.[7][8][9] These structural features underpin IMPA1's role in inositol recycling and its sensitivity to lithium inhibition, which occurs through competitive displacement of magnesium ions at the active site.[8]
Function
[edit]Inositol monophosphatase 1 (IMPA1) is a magnesium-dependent phosphatase that catalyzes the dephosphorylation of myo-inositol monophosphate to produce free myo-inositol, a crucial precursor for the synthesis of phosphatidylinositol and polyphosphoinositides.[10] These lipids are essential components of cell membranes and play a central role in intracellular signal transduction, particularly in generating the second messengers inositol 1,4,5-trisphosphate and diacylglycerol.[11] IMPA1 exhibits broad substrate specificity, being able to act on various inositol phosphate isomers and other sugar phosphates such as glucose-1-phosphate and fructose-1-phosphate. The enzyme is also notable for being inhibited by lithium at therapeutic concentrations, which underlies its relevance in the treatment of bipolar disorder, as lithium’s inhibition of IMPA1 leads to reduced inositol recycling and may modulate phosphoinositide signaling in the brain.[11] Beyond its metabolic role, IMPA1 has been implicated in processes such as autophagy, apoptosis, and cancer progression, highlighting its broader significance in cellular physiology.[6]
Interacting partners
[edit]IMPA1 has been shown to interact with Bergmann glial S100B[12] and calbindin.[13][14]
Clinical significance
[edit]As a drug target
[edit]Inhibition of IMPA1 can produce pleiotropic effects on cellular function, including alterations in phosphoinositide signalling,[15] autophagy, apoptosis,[16] and other processes.
L-690,330 is a competitive inhibitor of IMPase with high activity in in vitro assays, but it exhibits limited bioavailability in vivo.[17] Owing to its increased specificity relative to lithium, L-690,330 has been widely used to investigate the effects of IMPase inhibition in various cell culture systems. A more cell-permeable prodrug, L-690,488, has also been developed. Treatment of cortical slices with L-690,488 leads to accumulation of inositol, confirming the activity of this inhibitor in tissue.[18]
Bipolar disorder
[edit]It was initially observed that several drugs effective in treating bipolar disorder—such as lithium, carbamazepine, and valproic acid—share a common mechanism of action involving enzymes in the phosphatidylinositol signalling pathway.[19] This led to the proposal of the inositol depletion hypothesis as a potential explanation for the pathophysiology of bipolar disorder. However, extensive research has not confirmed this hypothesis, in part because lithium also affects multiple other enzymes within the same pathway, complicating the interpretation of results from in vitro studies.
Intellectual developmental disorder
[edit]A homozygous 5-base pair duplication in the IMPA1 gene, resulting in a frameshift and premature stop codon, was identified in a Brazilian family with autosomal recessive intellectual developmental disorder (MRT-59).[20] This mutation, which disrupts neuronal progenitor cell function and impairs differentiation, was absent in control populations and may affect intracellular signaling and neurotransmitter release.[21] Genetic analysis suggests that this syndrome arose in Brazil approximately 200 years ago.[22]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000133731 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027531 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ McAllister G, Whiting P, Hammond EA, Knowles MR, Atack JR, Bailey FJ, et al. (Aug 1992). "cDNA cloning of human and rat brain myo-inositol monophosphatase. Expression and characterization of the human recombinant enzyme". The Biochemical Journal. 284 (Pt 3): 749–754. doi:10.1042/bj2840749. PMC 1132602. PMID 1377913.
- ^ a b "Entrez Gene: IMPA1 inositol(myo)-1(or 4)-monophosphatase 1".
- ^ a b "Inositol monophosphatase 1". DrugBank. Canadian Institutes of Health Research. Retrieved 2025-06-04.
- ^ a b c d 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. Bibcode:2005AcCrD..61..545G. doi:10.1107/S0907444905004038. PMID 15858264.
- ^ a b c d Bone R, Frank L, Springer JP, Pollack SJ, Osborne SA, Atack JR, et al. (August 1994). "Structural analysis of inositol monophosphatase complexes with substrates". Biochemistry. 33 (32): 9460–7. doi:10.1021/bi00198a011. PMID 8068620.
- ^ "Inositol monophosphatase 1 (Mus musculus)". UniProt. UniProt Consortium. Retrieved 2025-06-04.
- ^ a b Saha S, Krishnan H, Raghu P (February 2024). "IMPA1 dependent regulation of phosphatidylinositol 4,5-bisphosphate and calcium signalling by lithium". Life Science Alliance. 7 (2): e202302425. doi:10.26508/lsa.202302425. PMC 10700560. PMID 38056909.
- ^ Vig PJ, Shao Q, Subramony SH, Lopez ME, Safaya E (September 2009). "Bergmann glial S100B activates myo-inositol monophosphatase 1 and Co-localizes to purkinje cell vacuoles in SCA1 transgenic mice". Cerebellum. 8 (3). London, England: 231–244. doi:10.1007/s12311-009-0125-5. PMC 3351107. PMID 19593677.
- ^ Schmidt H, Schwaller B, Eilers J (April 2005). "Calbindin D28k targets myo-inositol monophosphatase in spines and dendrites of cerebellar Purkinje neurons". Proceedings of the National Academy of Sciences of the United States of America. 102 (16): 5850–5855. Bibcode:2005PNAS..102.5850S. doi:10.1073/pnas.0407855102. PMC 556286. PMID 15809430.
- ^ Berggard T, Szczepankiewicz O, Thulin E, Linse S (November 2002). "Myo-inositol monophosphatase is an activated target of calbindin D28k". Journal of Biological Chemistry. 277 (44): 41954–41959. doi:10.1074/jbc.M203492200. PMID 12176979.
- ^ King JS, Teo R, Ryves J, Reddy JV, Peters O, Orabi B, et al. (2009). "The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells". Disease Models & Mechanisms. 2 (5–6): 306–312. doi:10.1242/dmm.001271. PMC 2675811. PMID 19383941.
- ^ Sarkar S, Rubinsztein DC (2006). "Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations". Autophagy. 2 (2): 132–134. doi:10.4161/auto.2387. PMID 16874097.
- ^ Atack JR, Cook SM, Watt AP, Fletcher SR, Ragan CI (February 1993). "In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330". Journal of Neurochemistry. 60 (2): 652–658. doi:10.1111/j.1471-4159.1993.tb03197.x. PMID 8380439. S2CID 23498954.
- ^ Atack JR, Prior AM, Fletcher SR, Quirk K, McKernan R, Ragan CI (July 1994). "Effects of L-690,488, a prodrug of the bisphosphonate inositol monophosphatase inhibitor L-690,330, on phosphatidylinositol cycle markers". The Journal of Pharmacology and Experimental Therapeutics. 270 (1): 70–76. doi:10.1016/S0022-3565(25)22382-5. PMID 8035344.
- ^ Williams RS, Cheng L, Mudge AW, Harwood AJ (May 2002). "A common mechanism of action for three mood-stabilizing drugs". Nature. 417 (6886): 292–295. Bibcode:2002Natur.417..292W. doi:10.1038/417292a. PMID 12015604. S2CID 4302048.
- ^ Figueiredo T, Melo US, Pessoa AL, Nobrega PR, Kitajima JP, Rusch H, et al. (August 2016). "A homozygous loss-of-function mutation in inositol monophosphatase 1 (IMPA1) causes severe intellectual disability". Molecular Psychiatry. 21 (8): 1125–1129. doi:10.1038/mp.2015.150. PMID 26416544.
- ^ Figueiredo T, Mendes AP, Moreira DP, Goulart E, Oliveira D, Kobayashi GS, et al. (July 2021). "Inositol monophosphatase 1 (IMPA1) mutation in intellectual disability patients impairs neurogenesis but not gliogenesis". Molecular Psychiatry. 26 (7): 3558–3571. doi:10.1038/s41380-020-00862-9. PMID 32839513.
- ^ de Farias AA, Nunes K, Lemes RB, Moura R, Fernandes GR, Melo US, et al. (8 November 2018). "Origin and age of the causative mutations in KLC2, IMPA1, MED25 and WNT7A unravelled through Brazilian admixed populations". Scientific Reports. 8 (1) 16552. Bibcode:2018NatSR...816552D. doi:10.1038/s41598-018-35022-1. PMC 6224410. PMID 30410084.
Further reading
[edit]- Bone R, Springer JP, Atack JR (Nov 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): 10031–10035. Bibcode:1992PNAS...8910031B. doi:10.1073/pnas.89.21.10031. PMC 50271. PMID 1332026.
- Hallcher LM, Sherman WR (Nov 1980). "The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain". Journal of Biological Chemistry. 255 (22): 10896–10901. doi:10.1016/S0021-9258(19)70391-3. PMID 6253491.
- Frank L, Springer JP, Pollack SJ, Osborne S, Atack JR, Knowles MR, et al. (Aug 1994). "Structural analysis of inositol monophosphatase complexes with substrates". Biochemistry. 33 (32): 9460–9467. doi:10.1021/bi00198a011. PMID 8068620.
- Bone R, Frank L, Springer JP, Atack JR (Aug 1994). "Structural studies of metal binding by inositol monophosphatase: evidence for two-metal ion catalysis". Biochemistry. 33 (32): 9468–9476. doi:10.1021/bi00198a012. PMID 8068621.
- Lepage P, Pelton PD, Strasser F, Vincendon P, Rondeau JM, Ganzhorn AJ (Aug 1996). "The contribution of lysine-36 to catalysis by human myo-inositol monophosphatase". Biochemistry. 35 (33): 10957–10966. doi:10.1021/bi9603837. PMID 8718889.
- Parthasarathy L, Parthasarathy R, Vadnal R (May 1997). "Molecular characterization of coding and untranslated regions of rat cortex lithium-sensitive myo-inositol monophosphatase cDNA". Gene. 191 (1): 81–87. doi:10.1016/S0378-1119(97)00045-0. PMID 9210592.
- Molven A, Løvlie R, Wilcox A, Sikela J, Steen V, Sjøholt G (Oct 1997). "Genomic structure and chromosomal localization of a human myo-inositol monophosphatase gene (IMPA)". Genomics. 45 (1): 113–122. doi:10.1006/geno.1997.4862. PMID 9339367.
- Ebstein RP, Belmaker RH, Osher Y, Agam G, Nemanov L (Mar 1999). "Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels". The International Journal of Neuropsychopharmacology. 2 (1) S1461145799001315: 25–29. doi:10.1017/S1461145799001315. PMID 11281967. S2CID 16964945.
- Kim AY, Jang SH, Lee B, Ahn J, Joo H, Kan T, et al. (Feb 2002). "Production of monoclonal antibodies and immunohistochemical studies of brain myo-inositol monophosphate phosphatase". Molecules and Cells. 13 (1): 21–27. doi:10.1016/S1016-8478(23)14999-5. PMID 11911470.
- Atack JR, Schapiro MB (2002). "Inositol monophosphatase activity in normal, Down syndrome and dementia of the Alzheimer type CSF". Neurobiology of Aging. 23 (3): 389–396. doi:10.1016/S0197-4580(01)00335-9. PMID 11959401. S2CID 24701473.
- Berggard T, Szczepankiewicz O, Thulin E, Linse S (Nov 2002). "Myo-inositol monophosphatase is an activated target of calbindin D28k". Journal of Biological Chemistry. 277 (44): 41954–41959. doi:10.1074/jbc.M203492200. PMID 12176979.
- Ebstein RP, Lie RT, Berle JØ, Mallet J, Deleuze JF, Levinson DF, et al. (Jun 2004). "Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder". Molecular Psychiatry. 9 (6): 621–629. doi:10.1038/sj.mp.4001460. PMID 14699425. S2CID 28747842.
- Wagner L, Feingold EA, Shenmen C, Grouse L, Schuler G, Klein S, et al. (Oct 2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Research. 14 (10B): 2121–2127. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, et al. (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
- Ohba H, Seo KC, Im J, Sato Y, Iwayama Y, Furuichi T, et al. (Jan 2007). "Spatial expression patterns and biochemical properties distinguish a second myo-inositol monophosphatase IMPA2 from IMPA1". Journal of Biological Chemistry. 282 (1): 637–646. doi:10.1074/jbc.M604474200. PMID 17068342.
External links
[edit]- PDBe-KB provides an overview of all the structure information available in the PDB for Human Inositol monophosphatase 1