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J. Biol. Chem., Vol. 281, Issue 1, 206-212, January 6, 2006

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Regulation of the Interaction of Inosine Monophosphate Dehydrogenase with Mycophenolic Acid by GTP^*

YanShan Ji1, JingJin Gu, Alexander M. Makhov¶, Jack D. Griffith¶, and Beverly S. Mitchell2

From the Departments of Pharmacology, Medicine, and ^¶Microbiology/Immunology and The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295

Inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, is a major therapeutic target. A prototypic uncompetitive inhibitor of IMPDH, mycophenolic acid (MPA), is the active form of mycophenolate mofeteil (CellCept®), a widely used immunosuppressive drug. We have found that MPA interacts with intracellular IMPDH in vivo to alter its mobility on SDS-polyacrylamide gels. MPA also induces a striking conformational change in IMPDH protein in intact cells, resulting in the formation of annular aggregates of protein with concomitant inhibition of IMPDH activity. These aggregates are not associated with any known intracellular organelles and are reversible by incubating cells with guanosine, which repletes intracellular GTP, or with GTPS. GTP also restores IMPDH activity. Treatment of highly purified IMPDH with MPA also results in the formation of large aggregates of protein, a process that is both prevented and reversed by the addition of GTP. Finally, GTP binds to IMPDH at physiologic concentrations, induces the formation of linear arrays of tetrameric protein, and prevents the aggregation of protein induced by MPA. We conclude that intracellular GTP acts as an antagonist to MPA by directly binding to IMPDH and reversing the conformational changes in the protein.

Received for publication, June 28, 2005 , and in revised form, September 7, 2005.

^* This work was supported in part by National Institutes of Health Grant RO-1 CA64192. Electron microscopy studies were supported by National Institutes of Health Grants CA16086 and GM31819 (to J. D. G.). 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.

¹ Supported as a Rothrock Thomas fellow.

² To whom correspondence should be addressed. Tel.: 650-725-9621; Fax: 919-966-8212; E-mail: mitchell{at}med.unc.edu.

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