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Antimicrobial Agents and Chemotherapy, February 2003, p. 447-457, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.447-457.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Glutamate Mutase Is Involved in the Biosynthesis of the Lipopeptide Antibiotic Friulimicin in Actinoplanes friuliensis

E. Heinzelmann,1 S. Berger,1 O. Puk,1 B. Reichenstein,1 W. Wohlleben,1 and D. Schwartz2*

Hans-Knöll-Institut für Naturstoff-Forschung, 07745 Jena,2 Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, 72076 Tübingen, Germany1

Received 22 July 2002/ Returned for modification 28 August 2002/ Accepted 31 October 2002

Actinoplanes friuliensis produces the lipopeptide antibiotic friulimicin. This antibiotic is active against gram-positive bacteria such as multiresistant Enterococcus and Staphylococcus strains. It consists of 10 amino acids that form a ring structure and 1 exocyclic amino acid to which an acyl residue is attached. By a reverse genetic approach, biosynthetic genes were identified that are required for the nonribosomal synthesis of the antibiotic. In close proximity two genes (glmA and glmB) were found which are involved in the production of methylaspartate, one of the amino acids of the peptide core. Methylaspartate is synthesized by a glutamate mutase mechanism, which was up to now only described for glutamate fermentation in Clostridium sp. or members of the family Enterobacteriaceae. The active enzyme consists of two subunits, and the corresponding genes overlap each other. To demonstrate enzyme activity in a heterologous host, it was necessary to genetically fuse glmA and glmB. The resulting gene was overexpressed in Streptomyces lividans, and the fusion protein was purified in an active form. For gene disruption mutagenesis, a host-vector system was established which enables genetic manipulation of Actinoplanes spp. for the first time. Thus, targeted inactivation of biosynthetic genes was possible, and their involvement in friulimicin biosynthesis was demonstrated.

* Corresponding author. Mailing address: Hans-Knöll-Institute for Natural Products Research, Beutenbergstrasse 11, 07745 Jena, Germany. Phone: 493641656946. Fax: 493641656945. E-mail: schwartz{at}pmail.hki-jena.de.

Antimicrobial Agents and Chemotherapy, February 2003, p. 447-457, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.447-457.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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