title: Identification of the function of gene lndM2 encoding a bifunctional oxygenase-reductase involved in the biosynthesis of the antitumor antibiotic landomycin E by Streptomyces globisporus 1912 supports the originally assigned structure for landomycinone.
abstract: The angucycline antibiotic family of the landomycins displays potent antitumor activity. To elucidate early post polyketide synthase (PKS) tailoring steps of the landomycin E biosynthetic pathway in Streptomyces globisporus 1912, the mutant S. globisporus M12 was prepared through gene replacement experiment of lndM2. It encodes an enzyme with putative oxygenase and reductase domains, according to sequencing of the gene and its counterpart lanM2 from S. cyanogenus S136 landomycin A biosynthetic gene cluster. The isolation of the novel shunt products 11-hydroxytetrangomycin and 4-hydroxytetrangomycin along with the well-known angucyclines tetrangomycin and tetrangulol from the culture of S. globisporus M12 provides evidence for the involvement of lndM2 in the early biosynthetic pathway of the landomycins, in particular in the formation of the alicyclic 6-hydroxy function of the landomycin aglycon. We therefore propose LndM2 to be responsible for both hydroxylation of the 6-position and its subsequent reduction. These reactions are necessary before the glycosylation reactions can occur. The results are in agreement with the originally published structure of landomycin but do not support the recently suggested revised structure.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, Kentucky 40536-0082, USA.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhu
authors.forename: Bohdan
authors.initials: B
authors.lastname: Ostash
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Mohammad
authors.initials: M
authors.lastname: Nur-E-Alam
authors.forename: Almuth
authors.initials: A
authors.lastname: Mayers
authors.forename: Andriy
authors.initials: A
authors.lastname: Luzhetskyy
authors.forename: Carmen
authors.initials: C
authors.lastname: Mendez
authors.forename: Jose A
authors.initials: JA
authors.lastname: Salas
authors.forename: Andreas
authors.initials: A
authors.lastname: Bechthold
authors.forename: Victor
authors.initials: V
authors.lastname: Fedorenko
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
mesh_terms: D000617:Aminoglycosides / Q000096:biosynthesis* / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000737:chemistry; D004269:DNA, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D005798:Genes, Bacterial / Q000235:genetics*; D015394:Molecular Structure; D005810:Multigene Family; D009154:Mutation; D009285:Naphthoquinones / Q000737:chemistry*; D009844:Oligosaccharides / Q000737:chemistry*; D010088:Oxidoreductases / Q000235:genetics*; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics*
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D004269:DNA, Bacterial; D009285:Naphthoquinones; D009844:Oligosaccharides; C113593:landomycin E; C490011:landomycinone; D010088:Oxidoreductases