Journal article
Adaptive evolution of drug targets in producer and non-producer organisms
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.
Language: | English |
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Year: | 2012 |
Pages: | 219-226 |
ISSN: | 14708728 and 02646021 |
Types: | Journal article |
DOI: | 10.1042/BJ20111278 |
ORCIDs: | Genee, Hans Jasper , Nielsen, Jakob Blæsbjerg and Frisvad, Jens Christian |
Drug resistance Gene duplication IMP dehydrogenase (IMPDH) Mycophenolic acid Neofunctionalization Penicillium
Adaptation, Physiological Amino Acid Sequence Binding Sites Biological Evolution Gene Duplication Gene Expression Regulation, Fungal IMP Dehydrogenase IMPDH Models, Molecular Multigene Family Mycophenolic Acid Protein Conformation drug resistance gene duplication mycophenolic acid neofunctionalization