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J. Biol. Chem., Vol. 277, Issue 15, 13082-13090, April 12, 2002

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The Biosynthesis of the Aromatic Myxobacterial Electron Transport Inhibitor Stigmatellin Is Directed by a Novel Type of Modular Polyketide Synthase^*

Nikolaos Gaitatzis^§, Barbara Silakowski^§, Brigitte Kunze, Gabriele Nordsiek, Helmut Blöcker, Gerhard Höfle, and Rolf Müller^§¶

From the  GBF-German Research Centre for Biotechnology, Mascheroder Weg 1, 38124 Braunschweig, Germany and the ^§ Institut für Pharmazeutische Biologie, TU Braunschweig, Mendelssohnstrasse 1, 38106 Braunschweig, Germany

Deductions from the molecular analysis of the 65,000-bp stigmatellin biosynthetic gene cluster are reported. The biosynthetic genes (stiA-J) encode an unusual bacterial modular type I polyketide synthase (PKS) responsible for the formation of this aromatic electron transport inhibitor produced by the myxobacterium Stigmatella aurantiaca. Involvement of the PKS gene cluster in stigmatellin biosynthesis is shown using site-directed mutagenesis. One module of the PKS is assumed to be used iteratively during the biosynthetic process, which seems to involve an unusual transacylation of the biosynthetic intermediate from an acyl carrier protein domain back to the preceding ketosynthase domain. Finally, the polyketide chain which is presumably catalyzed by a novel C-terminal domain in StiJ that does not resemble thioesterases, is cyclized and aromatized. The presented results of feeding experiments are in good agreement with the proposed biosynthetic scheme. In contrast to all other PKS type I systems reported to date, each module of StiA-J is encoded on a separate gene. The gene cluster contains a "stand alone" O-methyltransferase and two unusual O-methyltransferase domains embedded in the PKS. In addition, inactivation of a cytochrome P450 monooxygenase-encoding gene involved in post-PKS hydroxylation of the aromatic ring leads to the formation of two novel stigmatellin derivatives.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ421825.

This article is dedicated to Prof. Dr. T. Hartmann on the occasion of his 65th birthday.

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