title: Kinetically controlled drug resistance: how Penicillium brevicompactum survives mycophenolic acid.
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 10(3)-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.
authors: Graduate Program in Biochemistry, Brandeis University, Waltham, Massachusetts 02453, USA.
authors: Xin E
authors: XE
authors: Sun
authors: Bjarne Gram
authors: BG
authors: Hansen
authors: Lizbeth
authors: L
authors: Hedstrom
mesh_terms: D000818:Animals; D006224:Cricetinae; D025141:Drug Resistance, Fungal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D009173:Mycophenolic Acid / Q000494:pharmacology*; D010407:Penicillium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D011487:Protein Conformation; D012265:Ribonucleotides / Q000378:metabolism; D019820:Xanthine
chemical_list: D004791:Enzyme Inhibitors; D012265:Ribonucleotides; D019820:Xanthine; C011141:xanthosine monophosphate; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid