The biosynthesis of teicoplanin-type glycopeptide antibiotics: assignment of p450 mono-oxygenases to side chain cyclizations of glycopeptide a47934.
Streptomyces toyocaensis produces A47934, a teicoplanin-like type-IV glycopeptide with antibiotic activity against methicillin-resistant Staphylococcus aureus. A47934 differs from the type-I vancomycin glycopeptides, which possess a tricyclic peptide backbone, by the presence of an additional ring closure between the aromatic amino acids 1 and 3. To elucidate the order of crosslinking reactions, P450 mono-oxygenase-inactivation mutants (DeltastaF, DeltastaG, DeltastaH, and DeltastaJ) of the A47934 producer were generated, and the accumulated intermediates were analyzed. Thus, the formation of each crosslink could unambiguously be assigned to a specific oxygenase. The structure of the released intermediates from the wild-type nonribosomal peptide synthetase assembly line facilitated the determination of the cyclization order. Unexpectedly, the additional ring closure in A47934, catalyzed by StaG, is the second oxygenase reaction.
Hadatsch
Bianka
B
Institut für Mikrobiologie/Biotechnologie, Eberhard-Karls-Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany.
Butz
Diane
D
Schmiederer
Timo
T
Steudle
Julia
J
Wohlleben
Wolfgang
W
Süssmuth
Roderich
R
Stegmann
Evi
E
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D001426:Bacterial Proteins; D003500:Cyclization; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005798:Genes, Bacterial; D006020:Glycopeptides / Q000138:chemical synthesis*; D009154:Mutation; D040901:Proteomics / Q000379:methods; D012310:Ristocetin / Q000031:analogs & derivatives* / Q000737:chemistry; D013211:Staphylococcus aureus; D013302:Streptomyces / Q000378:metabolism; D017334:Teicoplanin
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006020:Glycopeptides; D012310:Ristocetin; D017334:Teicoplanin; C051056:antibiotic A 47934; D003577:Cytochrome P-450 Enzyme System