Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism.
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.
Brown
Peter M
PM
Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, and Department of Chemistry, University of Auckland, Auckland 1142, New Zealand.
Caradoc-Davies
Tom T
TT
Dickson
James M J
JM
Cooper
Garth J S
GJ
Loomes
Kerry M
KM
Baker
Edward N
EN
D000818:Animals; D018360:Crystallography, X-Ray; D007294:Inositol / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050562:Inositol Oxygenase / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D017510:Protein Folding; D013379:Substrate Specificity / Q000235:genetics
D007294:Inositol; D007501:Iron; D050562:Inositol Oxygenase