TY - JOUR

T1 - Adaptive evolution of drug targets in producer and non-producer organisms

A1 - Hansen,Bjarne Gram

A1 - Sun,Xin E.

A1 - Genee,Hans Jasper

A1 - Kaas,Christian Schrøder

A1 - Nielsen,Jakob Blæsbjerg

A1 - Frisvad,Jens Christian

A1 - Hedstrom,Lizbeth

AU - Hansen,Bjarne Gram

AU - Sun,Xin E.

AU - Genee,Hans Jasper

AU - Kaas,Christian Schrøder

AU - Nielsen,Jakob Blæsbjerg

AU - Frisvad,Jens Christian

AU - Hedstrom,Lizbeth

PB - Portland Press Ltd.

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

KW - Neofunctionalization

KW - Gene duplication

KW - Penicillium

KW - Mycophenolic acid

KW - Drug resistance

KW - IMP dehydrogenase (IMPDH)

U2 - 10.1042/BJ20111278

DO - 10.1042/BJ20111278

JO - Biochemical Journal

JF - Biochemical Journal

SN - 0264-6021

IS - 1

VL - 441

SP - 219

EP - 226

ER -