title: Complete characterization of the seventeen step moenomycin biosynthetic pathway.
abstract: The moenomycins are phosphoglycolipid antibiotics produced by Streptomyces ghanaensis and related organisms. The phosphoglycolipids are the only known active site inhibitors of the peptidoglycan glycosyltransferases, an important family of enzymes involved in the biosynthesis of the bacterial cell wall. Although these natural products have exceptionally potent antibiotic activity, pharmacokinetic limitations have precluded their clinical use. We previously identified the moenomycin biosynthetic gene cluster in order to facilitate biosynthetic approaches to new derivatives. Here, we report a comprehensive set of genetic and enzymatic experiments that establish functions for the 17 moenomycin biosynthetic genes involved in the synthesis of moenomycin and variants. These studies reveal the order of assembly of the full molecular scaffold and define a subset of seven genes involved in the synthesis of bioactive analogues. This work will enable both in vitro and fermentation-based reconstitution of phosphoglycolipid scaffolds so that chemoenzymatic approaches to novel analogues can be explored.
authors.affiliation: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bohdan
authors.initials: B
authors.lastname: Ostash
authors.forename: Emma H
authors.initials: EH
authors.lastname: Doud
authors.forename: Cecilie
authors.initials: C
authors.lastname: Lin
authors.forename: Iryna
authors.initials: I
authors.lastname: Ostash
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Perlstein
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Fuse
authors.forename: Manuel
authors.initials: M
authors.lastname: Wolpert
authors.forename: Daniel
authors.initials: D
authors.lastname: Kahne
authors.forename: Suzanne
authors.initials: S
authors.lastname: Walker
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry*; D001455:Bambermycins / Q000096:biosynthesis* / Q000737:chemistry*; D024881:Drug Resistance, Bacterial; D017353:Gene Deletion; D005798:Genes, Bacterial; D006017:Glycolipids / Q000096:biosynthesis / Q000737:chemistry; D005810:Multigene Family; D046928:Peptidoglycan Glycosyltransferase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D010743:Phospholipids / Q000096:biosynthesis / Q000737:chemistry; D013302:Streptomyces / Q000378:metabolism; D048170:Streptomyces lividans / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D006017:Glycolipids; D010743:Phospholipids; D001455:Bambermycins; C437243:moenomycin A; D046928:Peptidoglycan Glycosyltransferase