Graduate Program in Biochemistry, Brandeis University, Waltham, Massachusetts 02453, USA.
J Biol Chem. 2011 Nov 25;286(47):40595-600. doi: 10.1074/jbc.M111.305235. Epub 2011 Oct 6.
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.
丝状真菌短密青霉产生免疫抑制药物霉酚酸（MPA），它是一种有效的真核 IMP 脱氢酶（IMPDH）抑制剂。IMPDH 通过共价酶中间物 E-XMP催化 IMP 转化为 XMP；MPA 通过捕获 E-XMP来抑制。短密青霉（Pb）含有两种 MPA 抗性 IMPDH，PbIMPDH-A 和 PbIMPDH-B，它们对 MPA 的抗性比通常观察到的高 17 倍和 10（3）倍。令人惊讶的是，这些抗性酶的活性位点与 MPA 敏感酶的活性位点基本相同，因此抗性的机制基础尚不清楚。在这里，我们表明，与 MPA 敏感的 IMPDH 不同，E-XMP*的形成对 PbIMPDH-A 和 PbIMPDH-B 都是限速步骤。因此，MPA 抗性源于无法积累药物敏感的中间物。
