Catalytic promiscuity of glycopeptide N-methyltransferases enables bio-orthogonal labelling of biosynthetic intermediates.
We show that two α-N-methyltransferases involved in the biosynthesis of glycopeptide antibiotics (GPAs) already recognise partly crosslinked precursor peptides of teicoplanin aglycone indicating that in vivo N-methylation can occur as an early tailoring step during GPA biosynthesis. This relaxed substrate specificity is accompanied by a remarkable promiscuity regarding the co-substrate enabling modulation of biological activity and the introduction of reactive handles which could be further modified using bio-orthogonal chemistry.
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany. Clara.Brieke@mpimf-heidelberg.mpg.de.
Clara
C
Brieke
Department of Biochemistry and Biomedical Sciences, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Grace
G
Yim
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany. Clara.Brieke@mpimf-heidelberg.mpg.de.
Madeleine
M
Peschke
Department of Biochemistry and Biomedical Sciences, M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Gerard D
GD
Wright
Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany. Clara.Brieke@mpimf-heidelberg.mpg.de and EMBL Australia, Monash University, Clayton, Victoria 3800, Australia and The Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology and ARC Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
Max J
http://orcid.org/0000-0002-9739-6157
MJ
Cryle
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry; D055162:Biocatalysis; D006020:Glycopeptides / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D008968:Molecular Conformation; D013194:Staining and Labeling
D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D008780:Methyltransferases