title: Structures of NAD(+)- and NADH-bound 1-l-myo-inositol 1-phosphate synthase.
abstract: 1-l-myo-Inositol 1-phosphate synthase catalyzes the conversion of d-glucose 6-phosphate to 1-l-myo-inositol 1-phosphate, the first and rate-limiting step in the biosynthesis of all inositol-containing compounds. It involves an oxidation, an intramolecular aldol cyclization and a reduction. Here, the structure of the enzyme in its NAD(+)-bound, NADH-bound and apo forms is presented. These structures confirm that a significant portion of the active site is disordered in the absence of a small molecule, as none of the NAD(+)-bound forms of the enzyme have ordered active sites. On the other hand, the NADH-bound form contains two small molecules in the active site: a phosphate and glycerol. The entire active site is ordered in the presence of these two molecules, completely encapsulating them within the interior cavity. Significant changes in the structure of the active site are also seen, including repositioning of the nicotinamide ring and a motion of a loop region to accommodate the bound phosphate. These changes call into question the mechanism previously proposed for the enzyme. A comparison of the yeast and mycobacterial enzymes shows a surprisingly large change in the relative orientation of the catalytic and Rossmann-fold domains in the two enzymes.
authors.affiliation: Department of Chemistry, Michigan State University, USA.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Jin
authors.forename: James H
authors.initials: JH
authors.lastname: Geiger
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D007296:Myo-Inositol-1-Phosphate Synthase / Q000737:chemistry*; D009243:NAD / Q000737:chemistry*
chemical_list: D009243:NAD; D007296:Myo-Inositol-1-Phosphate Synthase