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Structural and biophysical characterization of human myo-inositol oxygenase.


ABSTRACT: 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.

SUBMITTER: Thorsell AG 

PROVIDER: S-EPMC3258897 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Structural and biophysical characterization of human myo-inositol oxygenase.

Thorsell Ann-Gerd AG   Persson Camilla C   Voevodskaya Nina N   Busam Robert D RD   Hammarström Martin M   Gräslund Susanne S   Gräslund Astrid A   Hallberg B Martin BM  

The Journal of biological chemistry 20080324 22


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-termin  ...[more]

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