Tailoring of glycopeptide scaffolds by the acyltransferases from the teicoplanin and A-40,926 biosynthetic operons.
The teicoplanin acyltransferase (Atf) responsible for N-acylation of the glucosamine moiety to create the teicoplanin lipoglycopeptide scaffold has recently been identified. Here we use that enzyme (tAtf) and the cognate acyltransferase from the related A-40,926 biosynthetic cluster (aAtf) to evaluate specificity for glycopeptide scaffolds and for the acyl-CoA donor. In addition to acylation of 2-aminoglucosyl glycopeptide scaffolds with k(cat) values of 400-2000 min(-1), both Atfs transfer acyl groups to regioisomeric 6-aminoglucosyl scaffolds and to glucosyl scaffolds at rates of 0.2-0.5 min(-1) to create variant lipoglycopeptides. Using the teicoplanin glycosyltransferase tGtfA, tAtf, and GtfD, a glycosyltransferase from the vancomycin producer, it is possible to assemble a novel lipoglycopeptide with GlcNAc at beta-OH-Tyr(6) and an N(6)-acyl-glucosaminyl-vancosamine at Phegly(4). This study illustrates the utility of chemo- and regioselective acyltransferases and glycosyltransferases to create novel lipoglycopeptides.
Kruger
Ryan G
RG
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Lu
Wei
W
Oberthür
Markus
M
Tao
Junhua
J
Kahne
Daniel
D
Walsh
Christopher T
CT
D000214:Acyl Coenzyme A / Q000737:chemistry; D000217:Acyltransferases / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D003001:Cloning, Molecular; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008968:Molecular Conformation; D009876:Operon; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D017334:Teicoplanin / Q000138:chemical synthesis / Q000737:chemistry* / Q000031:analogs & derivatives; D013997:Time Factors
C054981:A 40926; D000214:Acyl Coenzyme A; D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D017334:Teicoplanin; D000217:Acyltransferases