Inhibited inositol monophosphatase and decreased myo-inositol concentration improve wasting in skeletal muscles.
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ABSTRACT:
SUBMITTER: Lee JH
PROVIDER: S-EPMC7724229 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
Publications
Inhibited inositol monophosphatase and decreased myo-inositol concentration improve wasting in skeletal muscles.
Lee Ji-Hyung JH Kim Hyun-Jun HJ Kim Seon-Wook SW Um JungIn J Jung Da-Woon DW Williams Darren R DR
Clinical and translational medicine 20201201 8
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Project description:Molecular recognition is rarely a two-body protein-ligand problem, as it often involves the dynamic interplay of multiple molecules that together control the binding process. Myo-inositol monophosphatase (IMPase), a drug target for bipolar disorder, depends on 3 Mg(2+) ions as cofactor for its catalytic activity. Although the crystallographic pose of the pre-catalytic complex is well characterized, the binding process by which substrate, cofactor and protein cooperate is essentially unknown. Here, we have characterized cofactor and substrate cooperative binding by means of large-scale molecular dynamics. Our study showed the first and second Mg(2+) ions identify the binding pocket with fast kinetics whereas the third ion presents a much higher energy barrier. Substrate binding can occur in cooperation with cofactor, or alone to a binary or ternary cofactor-IMPase complex, although the last scenario occurs several orders of magnitude faster. Our atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.
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Project description:Although neurons are highly polarized, how neuronal polarity is generated remains poorly understood. An evolutionarily conserved inositol-producing enzyme myo-inositol monophosphatase (IMPase) is essential for polarized localization of synaptic molecules in Caenorhabditis elegans and can be inhibited by lithium, a drug for bipolar disorder. The synaptic defect of IMPase mutants causes defects in sensory behaviors including thermotaxis. Here we show that the abnormalities of IMPase mutants can be suppressed by mutations in two enzymes, phospholipase C? or synaptojanin, which presumably reduce the level of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We also found that mutations in phospholipase C? conferred resistance to lithium treatment. Our results suggest that reduction of PIP(2) on plasma membrane is a major cause of abnormal synaptic polarity in IMPase mutants and provide the first in vivo evidence that lithium impairs neuronal PIP(2) synthesis through inhibition of IMPase. We propose that the PIP(2) signaling regulated by IMPase plays a novel and fundamental role in the synaptic polarity.
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Project description:Chickpea (Cicer arietinum L.) is the third most important food legume crop. Seed size is the most economically important trait for chickpea. To understand the genetic regulation of seed size in chickpea, the present study established a three-way association of CT repeat length variation of a simple sequence repeat (SSR) in myo-inositol monophosphatase gene (CaIMP) with seed weight and phytic acid content by large scale validation and genotyping in a set of genetically diverse germplasm accessions and two reciprocal intra-specific mapping populations. Germplasms and mapping individuals with CT repeat-length expansion in the 5' untranslated region of CaIMP exhibited a pronounced increase in CaIMP protein level, enzymatic activity, seed-phytate content and seed weight. A chickpea transient expression system demonstrated this repeat-length variation influenced the translation of CaIMP mRNA, apparently by facilitating translation initiation. Our analyses proposed that the SSR marker derived from 5' UTR of a CaIMP gene is a promising candidate for selection of seed size/weight for agronomic trait improvement of chickpea.
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Project description:BackgroundMyo-inositol (MI), successfully used in polycystic ovary syndrome (PCOS), was administered with α-LA to exploit its action of favouring the passage of other molecules through biological barriers, and also considering its anti-inflammatory effect.MethodsPCOS patients, according to the Rotterdam ESHRE-ASRM criteria, with anovulation and infertility > 1 year, were included in this open and prospective study. The preliminary phase was aimed at determining a set of MI-resistant PCOS patients. This treatment involved 2 g MI, taken twice per day by oral route, for three months. The Homeostasis Model Assessment (HOMA) index and MI plasma levels were measured. In the main phase, previously selected MI-resistant patients received the same daily amount of MI plus 50 mg α-LA twice a day, for a further three months. Ovulation was assessed using ultrasound examination on days 12, 14 and 20 of the cycle. The HOMA index, lipid, hormone and MI plasma levels were detected at baseline and at the end of this phase.ResultsThirty-seven anovulatory PCOS subjects were included in the study. Following MI treatment, 23 of the 37 women (62%) ovulated, while 14 (38%) were resistant and did not ovulate. In the latter group, MI plasma levels did not increase. These MI-resistant patients underwent treatment in the main phase of the study, receiving MI and α-LA. After this combined treatment, 12 (86%) of them ovulated. Their MI plasma levels were found to be significantly higher than at baseline; also, a hormone and lipid profile improvement was recorded.ConclusionThe combination of MI with α-LA allowed us to obtain significant progress in the treatment of PCOS MI-resistant patients. Therefore, this new formulation was able to re-establish ovulation, greatly increasing the chances of desired pregnancy.Trial registrationClinical trial registration number: NCT03422289 ( ClinicalTrials.gov registry).
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Project description:1. An inositol monophosphatase was purified to homogeneity from bovine brain. 2. The enzyme is a dimer of subunit Mr 29,000. 3. The enzyme hydrolyses both enantiomers of myo-inositol 1-phosphate and both enantiomers of myo-inositol 4-phosphate, but has no activity towards inositol bisphosphates, inositol trisphosphates or inositol 1,3,4,5-tetrakisphosphate. 4. Several non-inositol-containing monophosphates are also substrates. 5. The enzyme requires Mg2+ for activity, and Zn2+ supports activity to a small extent. 6. Other bivalent cations (including Zn2+) are inhibitors, competitive with Mg2+. 7. Phosphate, but not inositol, is an inhibitor competitive with substrate. 8. Li+ inhibits hydrolysis of inositol 1-phosphate and inositol 4-phosphate uncompetitively with different apparent Ki values (1.0 mM and 0.26 mM respectively).
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Project description:myo-Inositol monophosphatase is inhibited by the arginine-specific reagent phenylglyoxal. The rate of inactivation is decreased in the presence of Pi, a competitive inhibitor of the enzyme. The effect of Pi is dependent on the presence of Mg2+, but is unaffected by Li+, an uncompetitive inhibitor. In the absence of Mg2+, the substrate, Ins(1)P, binds to the enzyme but is not converted into products, and affords only a small degree of protection against inactivation by phenylglyoxal. Li+ had no further effect under these conditions, but in the presence of Mg2+ caused a marked potentiation of the protective effect of substrate alone. In the absence of substrate, Li+ had no effect on activation by phenylglyoxal. Incorporation of 14C-labelled phenylglyoxal showed that inactivation was associated with modification of a single arginine residue per monomer in the dimeric enzyme. These findings support a mechanism in which Li+ inhibits monophosphatase by trapping a phosphorylated enzyme intermediate and preventing its hydrolysis.
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Project description:Synthesis of myo-inositol is crucial in multicellular eukaryotes for production of phosphatidylinositol and inositol phosphate signaling molecules. The myo-inositol monophosphatase (IMP) enzyme is required for the synthesis of myo-inositol, breakdown of inositol (1,4,5)-trisphosphate, a second messenger involved in Ca(2+) signaling, and synthesis of L-galactose, a precursor of ascorbic acid. Two myo-inositol monophosphatase -like (IMPL) genes in Arabidopsis encode chloroplast proteins with homology to the prokaryotic IMPs and one of these, IMPL2, can complement a bacterial histidinol 1-phosphate phosphatase mutant defective in histidine synthesis, indicating an important role for IMPL2 in amino acid synthesis. To delineate how this small gene family functions in inositol synthesis and metabolism, we sought to compare recombinant enzyme activities, expression patterns, and impact of genetic loss-of-function mutations for each. Our data show that purified IMPL2 protein is an active histidinol-phosphate phosphatase enzyme in contrast to the IMPL1 enzyme, which has the ability to hydrolyze D-galactose 1-phosphate, and D-myo-inositol 1-phosphate, a breakdown product of D-inositol (1,4,5) trisphosphate. Expression studies indicated that all three genes are expressed in multiple tissues, however, IMPL1 expression is restricted to above-ground tissues only. Identification and characterization of impl1 and impl2 mutants revealed no viable mutants for IMPL1, while two different impl2 mutants were identified and shown to be severely compromised in growth, which can be rescued by histidine. Analyses of metabolite levels in impl2 and complemented mutants reveals impl2 mutant growth is impacted by alterations in the histidine biosynthesis pathway, but does not impact myo-inositol synthesis. Together, these data indicate that IMPL2 functions in the histidine biosynthetic pathway, while IMP and IMPL1 catalyze the hydrolysis of inositol- and galactose-phosphates in the plant cell.
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