Determination of the Lithium Binding Site in Inositol Monophosphatase, the Putative Target for Lithium Therapy, by Magic-Angle-Spinning Solid-State NMR
| Autor: | Anat Haimovich, Uzi Eliav, Amir Goldbourt |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Binding Sites Magnetic Resonance Spectroscopy biology Stereochemistry Active site Inositol monophosphatase chemistry.chemical_element General Chemistry Nuclear magnetic resonance spectroscopy Lithium Biochemistry Phosphoric Monoester Hydrolases Catalysis chemistry.chemical_compound Colloid and Surface Chemistry chemistry Solid-state nuclear magnetic resonance Escherichia coli biology.protein Magic angle spinning Humans Inositol Binding site |
| Zdroj: | Journal of the American Chemical Society. 134:5647-5651 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | Inositol monophosphatase (IMPase) catalyzes the hydrolysis of inositol monophosphate to inorganic phosphate and inositol. For this catalytic process to occur, Mg(2+) cations must exist in the active site. According to the inositol depletion hypothesis, IMPase activity is assumed to be higher than normal in patients suffering from bipolar disorder. Treatment with Li(+), an inhibitor of IMPase, reduces its activity, but the mechanism by which lithium exerts its therapeutic effects is still at a stage of conjecture. The Escherichia coli SuhB gene product possesses IMPase activity, which is also strongly inhibited by Li(+). It has significant sequence similarity to human IMPase and has most of its key active-site residues. Here we show that by using (7)Li magic-angle-spinning solid-state NMR spectroscopy, including {(13)C}(7)Li dipolar recoupling experiments, the bound form of lithium in the active site of wild-type E. coli SuhB can be unambiguously detected, and on the basis of our data and other biochemical data, lithium binds to site II, coupled to aspartate residues 84, 87, and 212. |
| Databáze: | OpenAIRE |
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