The immunosuppressive agent mizoribine monophosphate forms a transition state analogue complex with inosine monophosphate dehydrogenase

Lu Gan, Mohammad R. Seyedsayamdost, Satoshi Shuto, Akira Matsuda, Gregory A. Petsko, Lizbeth Hedstrom

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Mizoribine monophosphate (MZP) is the active metabolite of the immunosuppressive agent mizoribine and a potent inhibitor of IMP dehydrogenase (IMPDH). This enzyme catalyzes the oxidation of IMP to XMP with the concomitant reduction of NAD via a covalent intermediate at Cys319 (E-XMP*). Surprisingly, mutational analysis indicates that MZP is a transition state analogue although its structure does not resemble that of the expected transition state. Here we report the X-ray crystal structure of the E·MZP complex at 2.0 Å resolution that reveals a transition state-like structure and solves the mechanistic puzzle of the IMPDH reaction. The protein assumes a new conformation where a flap folds into the NAD site and MZP, Cys319, and a water molecule are arranged in a geometry resembling the transition state. The water appears to be activated by interactions with a conserved Arg418-Tyr419 dyad. Mutagenesis experiments confirm that this new closed conformation is required for the hydrolysis of E-XMP*, but not for the reduction of NAD. The closed conformation provides a structural explanation for the differences in drug selectivity and catalytic efficiency of IMPDH isozymes.

Original languageEnglish (US)
Pages (from-to)857-863
Number of pages7
JournalBiochemistry
Volume42
Issue number4
DOIs
StatePublished - Feb 4 2003

All Science Journal Classification (ASJC) codes

  • Biochemistry

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