Structure and Function of the Glycopeptide N-methyltransferase MtfA, a Tool for the Biosynthesis of Modified Glycopeptide Antibiotics
There is a considerable interest in the modification of existing antibiotics to generate new antimicrobials. Glycopeptide antibiotics (GPAs) are effective against serious Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus. However, resistance to these antibiotics is becoming a serious problem requiring new strategies. We show that the Amycolatopsis orientalis (S)-adenosyl-L-methionine-dependent methyltransferase MtfA, from the vancomycin-class GPA chloroeremomycin biosynthetic pathway, catalyzes in vivo and in vitro methyl transfer to generate methylated GPA derivatives of the teicoplanin class. The crystal structure of MtfA complexed with (S)-adenosyl-L-methionine, (S)-adenosylhomocysteine, or sinefungin inhibitor, coupled with mutagenesis, identified His228 as a likely general base required for methyl transfer to the N terminus of the glycopeptide. Computational docking and molecular dynamics simulations were used to model binding of demethyl-vancomycin aglycone to MtfA. These results demonstrate its utility as a tool for engineering methylated analogs of GPAs.
- Research Organization:
- Argonne National Laboratory (ANL)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1005621
- Journal Information:
- Chem. Biol., Journal Name: Chem. Biol. Journal Issue: (4) ; 04, 2009 Vol. 16; ISSN 1074-5521
- Country of Publication:
- United States
- Language:
- ENGLISH
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