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J. Biol. Chem., Vol. 277, Issue 11, 9484-9491, March 15, 2002

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The Crystal Structure and Mechanism of 1-L-myo-Inositol- 1-phosphate Synthase^*

Adam J. Stein and James H. Geiger^§

From the  Department of Chemistry, Michigan State University, East Lansing, Michigan 48824

1-L-myo-Inositol-1-phosphate synthase catalyzes the conversion of D-glucose 6-phosphate to 1-L-myo-inositol-1-phosphate (MIP), the first and rate-limiting step in the biosynthesis of all inositol-containing compounds. It involves an oxidation, intramolecular aldol cyclization, and reduction. We have determined the first crystal structure of MIP synthase. We present structures of both the NAD-bound enzyme and the enzyme bound to an inhibitor, 2-deoxy-glucitol-6-phosphate. While 58 amino acids are disordered in the unbound form of the enzyme in the vicinity of the active site, the inhibitor nucleates the folding of this domain in a striking example of induced fit, serving to completely encapsulate it within the enzyme. Three helices and a long -strand are formed in this process. We postulate a mechanism for the conversion based on the structure of the inhibitor-bound complex.

The atomic coordinates and the structure factors (code 1JKF and 1JKI) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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