title: CefR modulates transporters of beta-lactam intermediates preventing the loss of penicillins to the broth and increases cephalosporin production in Acremonium chrysogenum.
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.
authors.affiliation: Institute of Biotechnology, Av. Real s/n, León, Spain. fteir@unileon.es
authors.forename: F
authors.initials: F
authors.lastname: Teijeira
authors.forename: R V
authors.initials: RV
authors.lastname: Ullán
authors.forename: M
authors.initials: M
authors.lastname: Fernández-Aguado
authors.forename: J F
authors.initials: JF
authors.lastname: Martín
mesh_terms: D000164:Acremonium / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002511:Cephalosporins / Q000096:biosynthesis*; D005656:Fungal Proteins / Q000096:biosynthesis* / Q000235:genetics; D055785:Gene Knockdown Techniques; D010406:Penicillins / Q000378:metabolism*; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D002511:Cephalosporins; D005656:Fungal Proteins; D010406:Penicillins; C025163:cephalosporin C; C006414:penicillin N