Disease relevance of IMPA1

• The genes located between IMPA1 and CBFA2T1 are the most likely candidates for chicken muscular dystrophy [1].
• Inositol monophosphatase activity in normal, Down syndrome and dementia of the Alzheimer type CSF [2].
• Purification and biochemical characterization of Mycobacterium tuberculosis SuhB, an inositol monophosphatase involved in inositol biosynthesis [3].
• The purified MJ109 gene product showed inositol monophosphatase activity with kinetic parameters (K(m) = 0.091 +/- 0.016 mM; Vmax = 9.3 +/- 0.45 mumol of Pi min-1 mg of protein-1) comparable to those of mammalian and E. coli enzymes [4].
• Characterization of a tetrameric inositol monophosphatase from the hyperthermophilic bacterium Thermotoga maritima [5].

Psychiatry related information on IMPA1

• No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response [6].
• Reduced inositol monophosphatase (IMPase) activity and elevated basal intracellular calcium levels ([Ca(2+)](B)) have been reported in B lymphoblast cell lines (BLCLs) from bipolar I affective disorder (BD-I) patients, which may reflect cellular endophenotypes of this disorder [7].
• In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis [2].
• The purpose of this study was to determine whether taking 10,000 steps in a day is equivalent to meeting the current minimum physical activity guidelines of accumulating at least 30 min of moderate physical activity (IMPA) [8].

High impact information on IMPA1

• The recent cDNA cloning of inositol monophosphatase (Diehl et al., 1990), Ins(1,4,5)P3 3-kinase (Choi et al., 1990), and inositol polyphosphate 1-phosphatase (York and Majerus, 1991) should provide tools to define further the cell biology of the phosphatidylinositol signaling pathway [9].
• This release of intracellular calcium is suppressed by an inhibitor of the enzyme inositol monophosphatase and hence of the phosphatidylinositol signalling pathway; this suppression can be rescued by injection of the compound myo-inositol, which overcomes the decrease in this intermediate caused by the inhibitor [10].
• A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3 [11].
• However, inhibitors of IMPase mimic the effects of Li+ on some aspects of PI cell signalling, thus highlighting the potential of IMPase as a target for the treatment of bipolar disorder [12].
• Attenuation of the phosphatidylinositol (PI) signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as the mechanism for the efficacy of Li+ in the treatment of bipolar disorder [12].

Chemical compound and disease context of IMPA1

• Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity [2].
• Lithium has been the standard treatment for bipolar disorder, and it is known to be an uncompetitive inhibitor of inositol monophosphatase in the phosphoinositide (PI) signaling cascade at clinically relevant concentrations [13].
• The ability of hIMPase to suppress galactose toxicity is sensitive to the presence of Li(+) in the medium [14].

Biological context of IMPA1

• Two genes encoding human IMPases have so far been isolated, namely IMPA1 on chromosome 8q21 [15].
• 2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios [6].
• Using an RT-PCR assay, mRNA levels were estimated for IMPA1 and 2 genes encoding human IMPase 1 and 2, respectively, in BLCLs phenotyped on [Ca(2+)](B), from patients with a DSM-IV diagnosis of BD-I (n = 12 per phenotype) and from age- and sex-matched healthy subjects (n = 12) [7].
• Inositol monophosphatase (EC 3.1.3.25), the putative molecular site of action of lithium therapy for manic-depressive illness, plays a key role in the phosphatidylinositol signaling pathway by catalyzing the hydrolysis of inositol monophosphates [16].
• The presence of a CCTGTG in the 3'-UTR (putative carbohydrate response element) links IMPase mRNA to brain carbohydrate metabolic pathways [17].

Anatomical context of IMPA1

• The fact that lithium treatment upregulates both MIP synthase and IMPA1 mRNA levels in mouse hippocampus may reflect a compensatory response of both genes to inositol depletion [18].
• Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF) [2].
• IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord [2].
• A cell-based screening assay in which the compound needs to cross the cell membrane before reaching the target enzyme offers a new approach for discovering novel structure leads of the inositol monophosphatase inhibitor [19].
• The authors investigated IMPase activities in fresh erythrocytes and leukocytes in 63 bipolar patients (42 euthymic, 8 depressive, 13 manic episodes) and 16 control subjects [20].

Associations of IMPA1 with chemical compounds

• Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11 [6].
• The enzyme myo-inositol monophosphatase (IMPase) in the phospholipase C signaling system is inhibited by lithium at therapeutically relevant concentrations, and is a candidate target of lithium's mood-stabilizing action [15].
• METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate [21].
• OBJECTIVES: Therapeutically relevant concentrations of lithium (Li) exert an uncompetitive inhibition on inositol monophosphatase (IMPase) [22].
• Inositol monophosphatase (EC 3.1.3.25) is a key enzyme in the phosphoinositide cell-signalling system [23].

Regulatory relationships of IMPA1

• Both apo and Ca(2+)-bound calbindin was found to activate IMPase up to 250-fold, depending on the pH and substrate concentration [24].

Other interactions of IMPA1

• Fluorescence spectroscopy showed that isolated calbindin and IMPase interact with an apparent equilibrium dissociation constant, K(D), of 0.9 microm [24].
• We had previously cloned two novel brain-derived transcripts from this region: the gene for a second human myo-inositol monophosphatase (IMPA2) and a gene of unknown function, C18orf1 [25].
• Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF [2].
• Five monoclonal antibodies that recognize porcine brain myo-inositol monophosphate phosphatase (IMPase) have been selected and designated as mAb IMPP 9, IMPP 10, IMPP 11, IMPP 15, and IMPP 17 [26].
• Thus, we have found the FBPase that was 'missing' in thermophiles and shown that it also functions as an IMPase [27].

Analytical, diagnostic and therapeutic context of IMPA1

• METHODS: IMPase activity in human postmortem brain specimens with or without 10 microM human recombinant calbindin was quantified spectrophotometrically in an enzyme-linked immunosorbent assay (ELISA) reader [22].
• To provide a structural basis from which to design better therapeutic agents for manic-depressive illness, the structure of human inositol monophosphatase has been determined to 2.1-A resolution by using x-ray crystallography [16].
• PCR analysis for the coding region and the deduced amino acid sequence demonstrated a DNA fragment of 831 bp and 277 amino acids, respectively, which are strikingly similar to human hippocampal IMPase [17].
• When the total proteins of the porcine brain homogenate separated by SDS-PAGE were probed with monoclonal antibodies, a single reactive protein band of 29 kDa, co-migrating with the purified porcine brain IMPase, was detected [26].
• The recent description of the three-dimensional structure of IMPase in conjunction with site-directed mutagenesis and kinetic studies has led to the elucidation of the enzyme mechanism [12].

References