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J. Biol. Chem., Vol. 279, Issue 21, 21759-21765, May 21, 2004

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Human 1-D-myo-Inositol-3-phosphate Synthase Is Functional in Yeast^*

Shulin Ju, Galit Shaltiel, Alon Shamir, Galila Agam, and Miriam L. Greenberg¶

From the Department of Biological Sciences, Wayne State University, Detroit, Michigan 48202 and the Stanley Research Center, Zlotowski Center for Neuroscience and Department of Clinical Biochemistry, Ben-Gurion University of the Negev, and Beersheva Mental Health Center, Beersheva, Israel 84170

We have cloned, sequenced, and expressed a human cDNA encoding 1-D-myo-inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted D-glucose 6-phosphate to 1-D-myo-inositol 3-phosphate, the rate-limiting step for de novo inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37 °C and exhibited K_m values of 0.57 mM and 8 µM for glucose 6-phosphate and NAD⁺, respectively. and K⁺ were better activators than other cations tested (Na⁺, Li⁺, Mg²⁺, Mn²⁺), and Zn²⁺ strongly inhibited activity. Expression of the protein in the yeast ino1 mutant lacking MIP synthase (ino1/hINO1) complemented the inositol auxotrophy of the mutant and led to inositol excretion. MIP synthase activity and intracellular inositol were decreased about 35 and 25%, respectively, when ino1/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mM). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in inositol biosynthesis underscores the power of the yeast model in studies of this disorder.

Received for publication, November 4, 2003 , and in revised form, March 4, 2004.

^* This study was supported by National Institutes of Health Grant R01 MH 56220 (to M. L. G.) and United States-Israel Binational Science Foundation Grant 2001035 (to M. L. G. and G. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 313-577-5202; Fax: 313-577-6891; E-mail: mlgreen{at}sun.science.wayne.edu.

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