CefR modulates transporters of beta-lactam intermediates preventing the loss of penicillins to the broth and increases cephalosporin production in Acremonium chrysogenum |
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Authors: | Teijeira F Ullán R V Fernández-Aguado M Martín J F |
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Institution: | aInstitute of Biotechnology (INBIOTEC), Av. Real s/n, 24006 León, Spain;bArea of Microbiology, Department of Molecular Biology, University of León, Campus de Vegazana s/n, 24071 León, Spain |
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Abstract: | The Acremonium chrysogenum cephalosporin biosynthetic genes are divided in two different clusters. The central step of the biosynthetic pathway (epimerization of isopenicillin N to penicillin N) occurs in peroxisomes. We found in the “early” cephalosporin cluster a new ORF encoding a regulatory protein (CefR), containing a nuclear targeting signal and a “Fungal_trans” domain. Targeted inactivation of cefR delays expression of the cefEF gene, increases penicillin N secretion and decreases cephalosporin production. Overexpression of the cefR gene decreased (up to 60%) penicillin N secretion, saving precursors and resulting in increased cephalosporin C production. Northern blot analysis revealed that the CefR protein acts as a repressor of the exporter cefT and exerts a small stimulatory effect over the expression level of cefEF that explains the increased cephalosporin yields observed in transformants overexpressing cefR. In summary, we describe for the first time a modulator of beta-lactam intermediate transporters in A. chrysogenum. |
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Keywords: | Acremonium chrysogenum Cephalosporin biosynthesis regulation Regulatory protein Gene expression regulation Cephalosporin transporters |
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