Journal
METABOLIC ENGINEERING
Volume 11, Issue 2, Pages 125-137Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymben.2008.12.003
Keywords
Penicillium chrysogenum; Metabolic engineering; Adipoyl-7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid; Carbamoylated cephem antibiotics
Categories
Funding
- Netherlands Organisation for Scientific Research (NWO)
- Netherlands Genomics Initiative
- Netherlands Ministry of Economic Affairs
- B-Basic partner organizations
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Penicillium chrysogenum was successfully engineered to produce a novel carbamoylated cephalosporin that can be used as a synthon for semi-synthetic cephalosporins. To this end, genes for Acremonium chrysogenum expandase/hydroxylase and Streptomyces clavuligerus carbamoyltransferase were expressed in a penicillinG high-producing strain of P. chrysogenum. Growth of the engineered strain in the presence of adipic acid resulted in production of adipoyl-7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (ad7-ACCCA) and of several adipoylated pathway intermediates. A combinatorial chemostat-based transcriptome study, in which the ad7-ACCCA-producing strain and a strain lacking key genes in beta-lactam synthesis were grown in the presence and absence of adipic acid, enabled the dissection of transcriptional responses to adipic acid per se and to ad7-ACCCA production. Transcriptome analysis revealed that adipate catabolism in P. chrysogenum occurs via beta-oxidation and enabled the identification of putative genes for enzymes involved in mitochondrial and peroxisomal beta-oxidation pathways. Several of the genes that showed a specifically altered transcript level in ad7-ACCCA-producing cultures were previously implicated in oxidative stress responses. (C) 2009 Elsevier Inc. All rights reserved.
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