Sunday, August 10, 2008
P97

Use of a halogenase of hormaomycin biosynthesis for formation of new clorobiocin analogs with 5-chloro-pyrrole moieties

Lutz Heide1, Lucia Westrich1, Christine Anderle1, Bertold Gust1, Bernd Kammerer2, and Jörn Piel3. (1) Pharmaceutical Institute, University of Tübingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany, (2) Clinical Pharmacology, University of Tübingen, Otfried-Müller Str. 45, 72076 Tuebingen, (3) Kekulé-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk Str. 1, 53121 Bonn, Germany

The depsipeptide antibiotic hormaomycin, produced by Streptomyces griseoflavus W-384, contains a 5-chloro-pyrrole moiety. In the producer strain we identified the gene hrmQ which shows sequence similarity to FADH2-dependent halogenases. This gene was cloned and heterologously expressed in Streptomyces roseochromogenes var. oscitans DS12.976, the producer of the aminocoumarin antibiotic clorobiocin which genuinely contains a 5-methyl-pyrrole moiety. For the present experiment, we used a mutant of this strain in which the respective pyrrole-5-methyltransferase had been inactivated.

Expression of the halogenase hrmQ in this mutant strain led to the formation of two new clorobiocin derivatives which carried a 5-chloro-pyrrole moiety. These compounds were isolated on a preparative scale, their structures were elucidated by 1H NMR and mass spectrometry, and their antibacterial activity was determined.

The substrate of HrmQ is apparently a pyrrole-2-carboxyl-S-[acyl carrier protein] thioester. This study presents the first experiment using a halogenase acting on an acyl carrier protein-bound substrate in combinatorial biosynthesis.


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