The gene cluster for the biosynthesis of the glycopeptide antibiotic A40926 by nonomuraea species.
The glycopeptide A40926 is the precursor of dalbavancin, a second-generation glycopeptide currently under clinical development. The dbv gene cluster, devoted to A40926 biosynthesis, was isolated and characterized from the actinomycete Nonomuraea species ATCC39727. From sequence analysis, 37 open reading frames (ORFs) participate in A40926 biosynthesis, regulation, resistance, and export. Of these, 27 ORFs find a match in at least one of the previously characterized glycopeptide gene clusters, while 10 ORFs are, so far, unique to the dbv cluster. Putative genes could be identified responsible for some of the tailoring steps (attachment of glucosamine, sugar oxidation, and mannosylation) expected during A40926 biosynthesis. After constructing a Nonomuraea mutant by deleting dbv ORFs 8 to 10, the novel compound dechloromannosyl-A40926 aglycone was isolated.
Sosio
Margherita
M
Vicuron Pharmaceuticals, via R. Lepetit 34, 21040, Gerenzano, Italy.
Stinchi
Sofia
S
Beltrametti
Fabrizio
F
Lazzarini
Ameriga
A
Donadio
Stefano
S
D000192:Actinomycetales / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D006020:Glycopeptides / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008364:Mannosyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family / Q000502:physiology*; D009154:Mutation; D009842:Oligopeptides / Q000096:biosynthesis; D016366:Open Reading Frames / Q000502:physiology*; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics*; D017334:Teicoplanin / Q000031:analogs & derivatives
C054981:A 40926; D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011498:Protein Precursors; C057568:A 40926 aglycone; D017334:Teicoplanin; C469289:dalbavancin; D008364:Mannosyltransferases; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase