Insights into the Bioactivity of Mensacarcin and Epoxide Formation by MsnO8 |
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| Authors: | Sarah Maier Tobias Pflüger Prof Dr Sandra Loesgen Dr Katharina Asmus Dr Elke Brötz Dr Thomas Paululat Prof Dr Axel Zeeck Prof Dr Susana Andrade Prof Dr Andreas Bechthold |
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| Affiliation: | 1. Institut für Pharmazeutische Biologie und Biotechnologie, Albert‐Ludwigs Universit?t, Stefan‐Meier‐Strasse 19, 79104 Freiburg (Germany);2. Institut für Biochemie, Albert‐Ludwigs‐Universit?t and BIOSS Centre for Biological Signalling, Albertstrasse 23, 79104 Freiburg (Germany);3. Institut für Organische und Biomolekulare Chemie, Georg‐August‐Universit?t, Tammanstrasse 2, 37077 G?ttingen (Germany);4. Current address: Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis OR 97331 (USA);5. Organic Chemistry II, Universit?t Siegen, Adolf‐Reichwein‐Strasse 2, 57068 Siegen (Germany);6. Current address: Helmholtz Insitut für Pharmazeutische Forschung Saarland, Postfach 151150, 66041 Saarbrücken (Germany) |
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| Abstract: | Mensacarcin, a potential antitumour drug, is produced by Streptomyces bottropensis. The structure consists of a three‐membered ring system with many oxygen atoms. Of vital importance in this context is an epoxy moiety in the side chain of mensacarcin. Our studies with different mensacarcin derivatives have demonstrated that this epoxy group is primarily responsible for the cytotoxic effect of mensacarcin. In order to obtain further information about this epoxy moiety, inactivation experiments in the gene cluster were carried out to identify the epoxy‐forming enzyme. Therefore the cosmid cos2, which covers almost the complete type II polyketide synthase (PKS) gene cluster, was heterologously expressed in Streptomyces albus. This led to production of didesmethylmensacarcin, due to the fact that methyltransferase genes are missing in the cosmid. Further gene inactivation experiments on this cosmid showed that MsnO8, a luciferase‐like monooxygenase, introduces the epoxy group at the end of the biosynthesis of mensacarcin. In addition, the protein MsnO8 was purified, and its crystal structure was determined to a resolution of 1.80 Å. |
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| Keywords: | antitumor agents biosynthesis epoxidation mensacarcin monooxygenases polyketides |
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