Crystal structure of human myo‐inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures

  title={Crystal structure of human myo‐inositol monophosphatase 2, the product of the putative susceptibility gene for bipolar disorder, schizophrenia, and febrile seizures},
  author={Ryoichi Arai and Kaori Ito and Tetsuo Ohnishi and Hisako Ohba and Ryogo Akasaka and Yoshitaka Bessho and Kyoko Hanawa-Suetsugu and Takeo Yoshikawa and Mikako Shirouzu and Shigeyuki Yokoyama},
  journal={Proteins: Structure},
The human IMPA2 gene, which encodes myo‐inositol monophosphatase 2 (IMPA2), is mapped onto 18p11.2, a susceptibility region for bipolar disorder. This chromosomal region has also been proposed to include a susceptibility locus for schizophrenia and febrile seizures. Here we report the crystal structures of human IMPA2 and its complex with calcium and phosphate ions. Human IMPA2 comprises an α–β protein with a five‐layered sandwich of α‐helices and β‐sheets (α–β–α–β–α). The crystal structure and… 

In silico study on the substrate binding manner in human myo-inositol monophosphatase 2

3D models of three- and two-Mg2+-ion bound myo-inositol monophosphatase 2 are constructed, and substrate-binding manners are studied using the docking program AutoDock3.

Dimerization of inositol monophosphatase Mycobacterium tuberculosis SuhB is not constitutive, but induced by binding of the activator Mg2+

The correlation of Mg2+-driven enzymatic activity with dimerization suggests that catalytic activity is linked to the dimer form, and suggests that the dynamic nature of the monomer-dimer equilibrium may also explain the extended concentration range over which Mg 2+ maintains SuhB activity.

Human myo‐inositol monophosphatase 2 rescues the nematode thermotaxis mutant ttx‐7 more efficiently than IMPA1: functional and evolutionary considerations of the two mammalian myo‐inositol monophosphatase genes

Impa2 knockout mice generated in the laboratory, exhibited neither behavioral abnormalities nor a significant reduction in myo‐inositol content in the brain and other examined tissues, raising a question about the phylogenetic origin of IMPases and the biological roles of mammalian IMPase 2 in mammals.

The biological and pharmacological allosteric modulation of inositol monophosphatase

The purpose of this project was to develop novel pharmacological tools against Inositol Monophosphatase and gain new insights into the Calbindin-IMPase interaction and to find novel inhibiters and binding chemical fragments that could later be developed into potent specific inhibitors of IMPase that would allow for the specific evaluation of IMP enzyme inhibition in vivo.

A structural basis for lithium and substrate binding of an inositide phosphatase

It is found that lithium preferentially occupies a key site involved in metal-activation only when substrate or product is added and a sequence motif for metal binding within this family of regulatory phosphatases is defined.

Mechanistic studies of two phosphatase enzymes involved in inostiol metabolism

The thermoprotection mechanism of compatible solutes was explored using inositol monophosphatase (IMPase) from Archaeoglobus fulgidus as the model protein and results indicate the specific binding of osmolytes to the protein exists, but they do not account for the thermoprotsection.

Defective Craniofacial Development and Brain Function in a Mouse Model for Depletion of Intracellular Inositol Synthesis*

Critical roles for intracellular myo-inositol synthesis in craniofacial development and the maintenance of proper brain function are revealed and this mouse model for cellular inositol depletion could be beneficial for understanding the molecular mechanisms underlying the clinical effect of lithium and myo -inositols-mediated skeletal development.

ONIOM (DFT:MM) study of the catalytic mechanism of myo-inositol monophosphatase: essential role of water in enzyme catalysis in the two-metal mechanism.

The proposed two-metal mechanism, the phosphoryl oxygen of the substrate acts as an acid-base catalyst, activating a water molecule in the first step, and the resultant hydroxide ion attacks the substrate in an inline fashion should advance the understanding of the IMPase mechanism.

Barley (Hordeum vulgare L.) inositol monophosphatase: gene structure and enzyme characteristics

Data indicate that the barley IMP-1 gene is regulated at least in part in response to Ins metabolic needs, and that the enzyme it encodes displays catalytic properties well suited for a role in Ins synthesis, in addition to other roles as an l-gal-1-P phosphatase important to ascorbate synthesis, or as an IMP enzyme important to Ins(1,4,5)P3 signal recycling.



A human myo-inositol monophosphatase gene (IMPA2) localized in a putative susceptibility region for bipolar disorder on chromosome 18p11.2: genomic structure and polymorphism screening in manic-depressive patients

The data show that even in a small sample of bipolar patients, several variants of the IMPA2 gene can be identified, and this gene is an intriguing candidate gene for future association studies of manic-depressive illness.

Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2)

The human myo-inositol monophosphatase 2 (IMPA2) cDNA was cloned and its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder, and the genomic structure and potential promoter were characterized and isolated.

A novel human myo-inositol monophosphatase gene, IMP.18p, maps to a susceptibility region for bipolar disorder

The physical position and possible function suggest that IMP.18p is an important candidate gene for bipolar disorder.

Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples

It is suggested that IMPA2 or a gene nearby may contribute to the overall genetic risk for schizophrenia among Japanese and increase the relevance of 18p11.2 to schizophrenia susceptibility because GNAL, which has been shown previously to be implicated in schizophrenia in an independent study, is in close physical proximity.

Structure of inositol monophosphatase, the putative target of lithium therapy.

Comparison of the phosphatase aligned sequences of several diverse genes with theosphatase structure suggests that the products of these genes and the phosph atase form a structural family with a conserved metal binding site.

Spatial Expression Patterns and Biochemical Properties Distinguish a Second myo-Inositol Monophosphatase IMPA2 from IMPA1*

Data suggest that IMPA2 has a separate function in vivo from that of IMPA1, which is predicted to have lithium-inhibitable IMPase activity based on its homology to IMPA0 and which was inhibited at high lithium and restricted magnesium concentrations.

High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy.

The higher resolution structural information on the active site of inositol monophosphatase will facilitate the design of substrate-based inhibitors and aid in the development of better therapeutic agents for bipolar disorder (manic depression).

Mechanism of inositol monophosphatase, the putative target of lithium therapy.

Model, kinetic, and mutagenesis studies on the enzyme reveal the requirement for two metal ions in the catalytic mechanism, and a two-metal mechanism is reported, consistent with the reduced catalytic activity observed with substrate analogues lacking the 6-OH.