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

@article{Arai2007CrystalSO,
  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},
  year={2007},
  volume={67}
}
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… 

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References

SHOWING 1-10 OF 38 REFERENCES

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.