title: Adaptive evolution of drug targets in producer and non-producer organisms.
abstract: 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 Penicillium 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 kcat/Km value 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.
authors.affiliation: Technical University of Denmark, Department of Systems Biology, Center for Microbial Biotechnology, 2800 Kgs Lyngby, Denmark.
authors.forename: Bjarne G
authors.initials: BG
authors.lastname: Hansen
authors.forename: Xin E
authors.initials: XE
authors.lastname: Sun
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Genee
authors.forename: Christian S
authors.initials: CS
authors.lastname: Kaas
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Nielsen
authors.forename: Uffe H
authors.initials: UH
authors.lastname: Mortensen
authors.forename: Jens C
authors.initials: JC
authors.lastname: Frisvad
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Hedstrom
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics*; D000595:Amino Acid Sequence; D001665:Binding Sites; D005075:Biological Evolution; D020440:Gene Duplication; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D005810:Multigene Family; D009173:Mycophenolic Acid / Q000378:metabolism* / Q000494:pharmacology; D010407:Penicillium / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid