Engineering of Penicillium chrysogenum for fermentative production of a novel carbamoylated cephem antibiotic precursor
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...
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Veröffentlicht in: | Metabolic engineering 2009-03, Vol.11 (2), p.125-137 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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 β-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 β-oxidation and enabled the identification of putative genes for enzymes involved in mitochondrial and peroxisomal β-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. |
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ISSN: | 1096-7176 1096-7184 |
DOI: | 10.1016/j.ymben.2008.12.003 |