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The impact of bacterial genomics on natural product research – myxobacteria as metabolite factories

Prof. Dr. Rolf Müller
GBF- Gesellschaft für Biotechnologische Forschung / Pharmazeutische Biotechnologie, Universität des Saarlandes
Talk
AG 1, AG 2, AG 3, AG 4, AG 5  
MPI Audience

Date, Time and Location

Wednesday, 28 July 2004
17:00
-- Not specified --
46.1 - MPII
024
Saarbrücken

Abstract

Myxobacteria are prominent producers of natural products with various and unusual biological activities (1, 2). Sorangium cellulosum So ce56 has been chosen as model strain for a functional genome project, because the genus Sorangium is known to produce almost 50% of the secondary metabolites isolated from these microorganisms. The strain shows some advantages compared to other S. cellulosum species and harbours the largest bacterial genome currently known (3). A BAC library has been prepared and the genome project is currently in the finishing phase. Lander-Waterman analysis reveals a genome size of approximately 12.4 Mbp, which is in good agreement with the data derived from pulse-field experiments. An initial analysis of the genome sequence with respect to the production of natural products will be presented; hybridization experiments indicate that 15 up to 25 gene clusters harbouring polyketide synthase or nonribosomal peptide synthetase genes are located in the chromosome. This astonishing variety of secondary metabolite genes contrasts the number of natural products isolated from the strain and thus indicates an immense genetic potential for the production of novel compounds. Similar results have been obtained with Stigmatella aurantiaca strains (4-7) and the knowledge was used to identify novel secondary metabolites by comparing product spectra of mutants generated from each gene cluster to the wild type strain.

Protocols for conjugation and transposon mutagenesis based on the mariner -transposon have been developed for the genome model strain So ce56 and were used to identify the chivosazole biosynthetic gene cluster (8). Physiological and molecular studies show that the production of secondary metabolites is strongly influenced by the growth conditions, e.g. the ammonium concentration, the carbon sources employed or by stress conditions. The identification of a DeoR-like transcriptional regulator positively influencing the production of chivosazole and other secondary metabolites enabled an initial characterization of regulatory networks involved in natural product formation. Prospects of further studies with S. cellulosum and other myxobacteria will be discussed.
1. Gerth, K., Pradella, S., Perlova, O., Beyer, S. & Müller, R. (2003) J Biotechnol doi:10.1016/j.jbiotec.2003.07.015.
2. Reichenbach, H. & Höfle, G. (1999) in Drug discovery from nature , Eds. Grabley, S. & Thieriecke, R. (Springer Verlag, Berlin), pp. 149-179.
3. Pradella, S., Hans, A., Spröer, C., Reichenbach, H., Gerth, K. & Beyer, S. (2002) Arch Microbiol 178, 484-92.
4. Gaitatzis, N., Kunze, B. & Müller, R. (2001) Proc. Natl. Acad. Sci. USA 98, 11136-11141.
5.5. Silakowski, B., Kunze, B. & Müller, R. (2001) Gene 275, 233-240.
6. Gaitatzis, N., Silakowski, B., Kunze, B., Nordsiek, G., Blöcker, H., Höfle, G. & Müller, R. (2002) J Biol Chem 277, 13082-13090.
7. Silakowski, B., Schairer, H. U., Ehret, H., Kunze, B., Weinig, S., Nordsiek, G., Brandt, P., Blöcker, H., Höfle, G., Beyer, S. & Müller, R. (1999) J Biol Chem 274, 37391-37399.
8. Kopp, M., Irschik, H., Gross, F., Perlova, O., Sandmann, A., Gerth, K. & Müller, R. (2003)
J Biotechnol doi:10.1016/j.jbiotec.2003.09.013.

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Ruth Schneppen-Christmann, 07/14/2004 10:18
Ruth Schneppen-Christmann, 07/01/2004 10:01 -- Created document.