Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum
Artikel i vetenskaplig tidskrift, 2011

Mycophenolic acid (MPA) is the active ingredient in the increasingly important immunosuppressive pharmaceuticals CellCept (Roche) and Myfortic (Novartis). Despite the long history of MPA, the molecular basis for its biosynthesis has remained enigmatic. Here we report the discovery of a polyketide synthase (PKS), MpaC, which we successfully characterized and identified as responsible for MPA production in Penicillium brevicompactum. mpaC resides in what most likely is a 25-kb gene cluster in the genome of Penicillium brevicompactum. The gene cluster was successfully localized by targeting putative resistance genes, in this case an additional copy of the gene encoding IMP dehydrogenase (IMPDH). We report the cloning, sequencing, and the functional characterization of the MPA biosynthesis gene cluster by deletion of the polyketide synthase gene mpaC of P. brevicompactum and bioinformatic analyses. As expected, the gene deletion completely abolished MPA production as well as production of several other metabolites derived from the MPA biosynthesis pathway of P. brevicompactum. Our work sets the stage for engineering the production of MPA and analogues through metabolic engineering.

polyketide synthase genes

identification

prediction

transformation

aspergillus-nidulans

database

domain

proteins

inhibitors

origin

Författare

T. B. Regueira

Danmarks Tekniske Universitet (DTU)

Novozymes AS

K. R. Kildegaard

Danmarks Tekniske Universitet (DTU)

B. G. Hansen

Danmarks Tekniske Universitet (DTU)

U. H. Mortensen

Danmarks Tekniske Universitet (DTU)

C. Hertweck

Hans-Knoll-Institute (HKI)

Jens B Nielsen

Kemi- och bioteknik, Livsvetenskaper, Systembiologi

Applied and Environmental Microbiology

0099-2240 (ISSN) 1098-5336 (eISSN)

Vol. 77 3035-3043

Ämneskategorier

Industriell bioteknik

Mikrobiologi

Styrkeområden

Livsvetenskaper och teknik

DOI

10.1128/aem.03015-10