title: Insights into the bioactivity of mensacarcin and epoxide formation by MsnO8.
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.
authors.affiliation: Institut für Pharmazeutische Biologie und Biotechnologie, Albert-Ludwigs Universität, Stefan-Meier-Strasse 19, 79104 Freiburg (Germany).
authors.forename: Sarah
authors.initials: S
authors.lastname: Maier
authors.forename: Tobias
authors.initials: T
authors.lastname: Pflüger
authors.forename: Sandra
authors.initials: S
authors.lastname: Loesgen
authors.forename: Katharina
authors.initials: K
authors.lastname: Asmus
authors.forename: Elke
authors.initials: E
authors.lastname: Brötz
authors.forename: Thomas
authors.initials: T
authors.lastname: Paululat
authors.forename: Axel
authors.initials: A
authors.lastname: Zeeck
authors.forename: Susana
authors.initials: S
authors.lastname: Andrade
authors.forename: Andreas
authors.initials: A
authors.lastname: Bechthold
mesh_terms: D000595:Amino Acid Sequence; D000873:Anthracenes / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism*; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010105:Oxygenases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D013302:Streptomyces / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D004852:Epoxy Compounds; C510239:mensacarcin; D048630:Polyketide Synthases; D010105:Oxygenases
keywords: antitumor agents; biosynthesis; epoxidation; mensacarcin; monooxygenases; polyketides