3bxd

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==Overview==
==Overview==
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Altered metabolism of the inositol sugars myo-inositol (MI) and d-chiro-inositol is implicated in diabetic complications. In animals, catabolism of MI and D-chiro-inositol depends on the enzyme MI oxygenase (MIOX), which catalyzes the first committed step of the glucuronate-xylulose pathway, and is found almost exclusively in the kidneys. The crystal structure of MIOX, in complex with MI, has been determined by multiwavelength anomalous diffraction methods and refined at 2.0-A resolution (R=0.206, Rfree=0.253). The structure reveals a monomeric, single-domain protein with a mostly helical fold that is distantly related to the diverse HD domain superfamily. Five helices form the structural core and provide six ligands (four His and two Asp) for the di-iron center, in which the two iron atoms are bridged by a putative hydroxide ion and one of the Asp ligands, Asp-124. A key loop forms a lid over the MI substrate, which is coordinated in bidentate mode to one iron atom. It is proposed that this mode of iron coordination, and interaction with a key Lys residue, activate MI for bond cleavage. The structure also reveals the basis of substrate specificity and suggests routes for the development of specific MIOX inhibitors.
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Altered inositol metabolism is implicated in a number of diabetic complications. The first committed step in mammalian inositol catabolism is performed by myo-inositol oxygenase (MIOX), which catalyzes a unique four-electron dioxygen-dependent ring cleavage of myo-inositol to d-glucuronate. Here, we present the crystal structure of human MIOX in complex with myo-inosose-1 bound in a terminal mode to the MIOX diiron cluster site. Furthermore, from biochemical and biophysical results from N-terminal deletion mutagenesis we show that the N terminus is important, through coordination of a set of loops covering the active site, in shielding the active site during catalysis. EPR spectroscopy of the unliganded enzyme displays a two-component spectrum that we can relate to an open and a closed active site conformation. Furthermore, based on site-directed mutagenesis in combination with biochemical and biophysical data, we propose a novel role for Lys(127) in governing access to the diiron cluster.
==About this Structure==
==About this Structure==
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==Reference==
==Reference==
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Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism., Brown PM, Caradoc-Davies TT, Dickson JM, Cooper GJ, Loomes KM, Baker EN, Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15032-7. Epub 2006 Sep 29. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17012379 17012379]
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Structural and Biophysical Characterization of Human myo-Inositol Oxygenase., Thorsell AG, Persson C, Voevodskaya N, Busam RD, Hammarstrom M, Graslund S, Graslund A, Hallberg BM, J Biol Chem. 2008 May 30;283(22):15209-16. Epub 2008 Mar 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18364358 18364358]
[[Category: Inositol oxygenase]]
[[Category: Inositol oxygenase]]
[[Category: Mus musculus]]
[[Category: Mus musculus]]
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[[Category: Oxidoreductase]]
[[Category: Oxidoreductase]]
[[Category: Protein-substrate complex]]
[[Category: Protein-substrate complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 21:11:14 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jun 11 10:57:45 2008''

Revision as of 07:57, 11 June 2008

Image:3bxd.jpg

Template:STRUCTURE 3bxd

Crystal structure of Mouse Myo-inositol oxygenase (re-refined)


Overview

Altered inositol metabolism is implicated in a number of diabetic complications. The first committed step in mammalian inositol catabolism is performed by myo-inositol oxygenase (MIOX), which catalyzes a unique four-electron dioxygen-dependent ring cleavage of myo-inositol to d-glucuronate. Here, we present the crystal structure of human MIOX in complex with myo-inosose-1 bound in a terminal mode to the MIOX diiron cluster site. Furthermore, from biochemical and biophysical results from N-terminal deletion mutagenesis we show that the N terminus is important, through coordination of a set of loops covering the active site, in shielding the active site during catalysis. EPR spectroscopy of the unliganded enzyme displays a two-component spectrum that we can relate to an open and a closed active site conformation. Furthermore, based on site-directed mutagenesis in combination with biochemical and biophysical data, we propose a novel role for Lys(127) in governing access to the diiron cluster.

About this Structure

3BXD is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.

Reference

Structural and Biophysical Characterization of Human myo-Inositol Oxygenase., Thorsell AG, Persson C, Voevodskaya N, Busam RD, Hammarstrom M, Graslund S, Graslund A, Hallberg BM, J Biol Chem. 2008 May 30;283(22):15209-16. Epub 2008 Mar 24. PMID:18364358 Page seeded by OCA on Wed Jun 11 10:57:45 2008

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