Abstract
Mycophenolic acid (MPA) is an immunosuppressive drug produced by several fungi in Penicillium subgenus Penicillium. This toxic metabolite is an inhibitor of IMP dehydrogenase (IMPDH). The MPA biosynthetic cluster of P. brevicompactum contains a gene encoding a B-type IMPDH, IMPDH-B, which confers MPA-resistance. Surprisingly, all members of subgenus Penicillium contain genes encoding IMPDHs of both the A and B type, regardless of their ability to produce MPA. Duplication of the IMPDH gene occurred prior to and independent of the acquisition of the MPA biosynthetic cluster. Both P. brevicompactum IMPDHs are MPA-resistant while the IMPDHs from a nonproducer are MPA-sensitive. Resistance comes with a catalytic cost: while P. brevicompactum IMPDH-B is >1000-fold more resistant to MPA than a typical eukaryotic IMPDH, its value of k cat / K m 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 Pencillium 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.