School of Biological Sciences, University of Auckland
○Peter M. Brown Tom T. Caradoc-Davies James M. Dickson Kerry L. Loomes Garth J.S. Cooper Edward N. Baker

Diabetes mellitus (DM) and its complications are associated with altered metabolism of inositol sugars myo-inositol (MI) and D-chiro inositol (DCI). In animals, catabolism of MI and DCI depends on a highly conserved enzyme myo-inositol oxygenase (MIOX), which catalyzes the first committed step of the glucuronate-xylulose pathway. This enzymatic mechanism involves a 4-electron oxidation that appears to be unique in biological systems (1). As MIOX activity increases during hyperglycaemic conditions (2), MIOX inhibition may be a therapeutic strategy to alleviate DM and its complications.
Here, we present the first crystal structure of MIOX at 2.0-Å resolution, in complex with MI. This protein is monomeric with a mostly-helical fold that is distantly related to the HD domain superfamily yet differs from other di-iron oxygenases such as ribonucleotide reductase. Five helices form the structural core and provide 4 His and 2 Asp ligands to result in a novel di-iron center. The MI substrate is coordinated in a bidentate mode to one iron atom. The structure reveals the basis of substrate specificity, insight into the enzyme mechanism and suggests routes for the development of specific MIOX inhibitors.

1. Moskala, R., Reddy, C. C., Minard, R. D. & Hamilton, G. A. (1981) Biochem. Biophys. Res. Commun. 99, 107-113.

2. Nayak, B., Xie, P., Akagi, S., Yang, Q., Sun, L., Wada, J., Thakur, A., Danesh, F. R., Chugh, S. S. & Kanwar, Y. S. (2005) Proc. Natl. Acad. Sci. USA 102, 17952-17957.