Adaptive evolution of drug targets in producer and non-producer organisms

Bjarne Gram Hansen, Xin E. Sun, Hans Jasper Genee, Christian Schrøder Kaas, Jakob Blæsbjerg Nielsen, Jens Christian Frisvad, Lizbeth Hedstrom

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    Abstract

    MPA (mycophenolic acid) is an immunosuppressive drug produced by several fungi in Penicillium subgenus Penicillium. This toxic metabolite is an inhibitor of IMPDH (IMP dehydrogenase). The MPA-biosynthetic cluster of Penicillum brevicompactum contains a gene encoding a B-type IMPDH, IMPDH-B, which confers MPA resistance. Surprisingly, all members of the subgenus Penicillium contain genes encoding IMPDHs of both the A and B types, regardless of their ability to produce MPA. Duplication of the IMPDH gene occurred before and independently of the acquisition of the MPAbiosynthetic cluster. Both P. brevicompactum IMPDHs are MPA-resistant, whereas the IMPDHs from a non-producer are MPA-sensitive. Resistance comes with a catalytic cost: whereas P. brevicompactum IMPDH-B is >1000-fold more resistant to MPA than a typical eukaryotic IMPDH, its value of kcat/Km is 0.5%of ‘normal’. Curiously, IMPDH-B of Penicillium chrysogenum, which does not produce MPA, is also a very poor enzyme. The MPA-binding site is completely conserved among sensitive and resistant IMPDHs. Mutational analysis shows that the C-terminal segment is a major structural determinant of resistance. These observations suggest that the duplication of the IMPDH gene in the subgenus Penicillium was permissive for MPA production and that MPA production created a selective pressure on IMPDH evolution. Perhaps MPA production rescued IMPDH-B from deleterious genetic drift.
    Original languageEnglish
    JournalBiochemical Journal
    Volume441
    Issue number1
    Pages (from-to)219-226
    ISSN0264-6021
    DOIs
    Publication statusPublished - 2012

    Bibliographical note

    The final version of record is available at http://www.biochemj.org/bj/default.htm

    Keywords

    • Neofunctionalization
    • Gene duplication
    • Penicillium
    • Mycophenolic acid
    • Drug resistance
    • IMP dehydrogenase (IMPDH)

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