Kinetically Controlled Drug Resistance: How Penicillium Brevicompactum Survives Mycophenolic Acid

Xin E. Sun, Bjarne Gram Hansen, Lizbeth Hedstrom

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E-XMP*. P. brevicompactum (Pb) contains two MPA-resistant IMPDHs, PbIMPDH-A and PbIMPDH-B, which are 17- and 103-fold more resistant to MPA than typically observed. Surprisingly, the active sites of these resistant enzymes are essentially identical to those of MPA-sensitive enzymes, so the mechanistic basis of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate.
    Original languageEnglish
    JournalJournal of Biological Chemistry
    Volume286
    Issue number47
    Pages (from-to)40595-40600
    ISSN0021-9258
    DOIs
    Publication statusPublished - 2011

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