Journal article
Kinetically Controlled Drug Resistance: How Penicillium Brevicompactum Survives Mycophenolic Acid : HOW PENICILLIUM BREVICOMPACTUM SURVIVES MYCOPHENOLIC ACID*
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.
Language: | English |
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Publisher: | American Society for Biochemistry and Molecular Biology |
Year: | 2011 |
Pages: | 40595-40600 |
ISSN: | 1083351x , 00219258 and 10678816 |
Types: | Journal article |
DOI: | 10.1074/jbc.M111.305235 |
Animals Cricetinae Dehydrogenase Drug Resistance Drug Resistance, Fungal Enzyme Inhibitors Enzyme Mechanisms Fungi IMP Dehydrogenase IMP Dehydrogenase (IMPDH) Kinetics Models, Molecular Mycophenolic Acid Nucleoside/Nucleotide Biosynthesis Penicillium Protein Conformation Ribonucleotides Xanthine xanthosine monophosphate