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Journal of Bacteriology, November 2007, p. 8120-8129, Vol. 189, No. 22
0021-9193/07/$08.00+0     doi:10.1128/JB.01247-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Phosphate-Controlled Regulator for the Biosynthesis of the Dalbavancin Precursor A40926{triangledown} ,{dagger}

Rosa Alduina,1* Luca Lo Piccolo,1 Davide D'Alia,1,{ddagger} Clelia Ferraro,1 Nina Gunnarsson,2,§ Stefano Donadio,3 and Anna Maria Puglia1

University of Palermo, Dipartimento di Biologia Cellulare e dello Sviluppo, Viale delle Scienze, Parco d'Orleans II, 90128 Palermo, Italy,1 Biocentrum-DTU, Center for Microbial Biotechnology, Building 223, Soltofts plads, 2800 Lyngby, Denmark,2 KtedoGen, Malnate, Italy3

Received 2 August 2007/ Accepted 5 September 2007

The actinomycete Nonomuraea sp. strain ATCC 39727 produces the glycopeptide A40926, the precursor of the novel antibiotic dalbavancin. Previous studies have shown that phosphate limitation results in enhanced A40926 production. The A40926 biosynthetic gene (dbv) cluster, which consists of 37 genes, encodes two putative regulators, Dbv3 and Dbv4, as well as the response regulator (Dbv6) and the sensor-kinase (Dbv22) of a putative two-component system. Reverse transcription-PCR (RT-PCR) and real-time RT-PCR analysis revealed that the dbv14-dbv8 and the dbv30-dbv35 operons, as well as dbv4, were negatively influenced by phosphate. Dbv4 shows a putative helix-turn-helix DNA-binding motif and shares sequence similarity with StrR, the transcriptional activator of streptomycin biosynthesis in Streptomyces griseus. Dbv4 was expressed in Escherichia coli as an N-terminal His6-tagged protein. The purified protein bound the dbv14 and dbv30 upstream regions but not the region preceding dbv4. Bbr, a Dbv4 ortholog from the gene cluster for the synthesis of the glycopeptide balhimycin, also bound to the dbv14 and dbv30 upstream regions, while Dbv4 bound appropriate regions from the balhimycin cluster. Our results provide new insights into the regulation of glycopeptide antibiotics, indicating that the phosphate-controlled regulator Dbv4 governs two key steps in A40926 biosynthesis: the biosynthesis of the nonproteinogenic amino acid 3,5-dihydroxyphenylglycine and critical tailoring reactions on the heptapeptide backbone.

* Corresponding author. Mailing address: Dipartimento di Biologia Cellulare e dello Sviluppo, Università degli Studi di Palermo, Viale delle Scienze, Parco d'Orleans II, 90128 Palermo, Italy. Phone: 39 091 6577306. Fax: 39 091 6577347. E-mail: valduina{at}unipa.it

{triangledown} Published ahead of print on 14 September 2007.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

{ddagger} Present address: Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Kerklaan 30, 9751 NN Haren, The Netherlands.

§ Present address: Fluxome Sciences A/S, Diplomvej 378, 2800 Lyngby, Denmark.

Journal of Bacteriology, November 2007, p. 8120-8129, Vol. 189, No. 22
0021-9193/07/$08.00+0     doi:10.1128/JB.01247-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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