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Macrocycles represent a common structural framework in many naturally occurring peptides. Several strategies exist for macrocyclization, and the enzymes that incorporate them are of great interest, as they enhance our repertoire for creating complex molecules. We recently discovered a new peptide cyclization reaction involving a crosslink between the side chains of lysine and tryptophan that is installed by a radical SAM enzyme. Herein, we characterize relatives of this metalloenzyme from the pathogens Streptococcus agalactiae and Streptococcus suis. Our results show that the corresponding enzymes, which we call AgaB and SuiB, contain multiple [4Fe-4S] clusters and catalyze Lys-Trp crosslink formation in their respective substrates. Subsequent high-resolution-MS and 2D-NMR analyses located the site of macrocyclization. Moreover, we report that AgaB can accept modified substrates containing natural or unnatural amino acids. Aside from providing insights into the mechanism of this unusual modification, the substrate promiscuity of AgaB may be exploited to create diverse macrocyclic peptides.
ACS Chem Biol 2017 04 21
PMID:Lysine-Tryptophan-Crosslinked Peptides Produced by Radical SAM Enzymes in Pathogenic Streptococci. 2819 19

S-Adenosyl-l-methionine (SAM)-dependent methyltransferases are intensely studied because they play important roles in the methylation of biomolecules in all domains of life. In this study, we describe that the methyltransferase VioH from Cysotobacter violaceus catalyzes a so far unknown cyclization of SAM to azetidine-2-carboxylic acid (AZE), which is proposed to be the precursor of the unusual 4-methylazetidinecarboxylic acid (MAZ) moiety of vioprolides. In vitro biochemical investigations reveal that SAM is converted to AZE in the presence of VioH while MAZ is generated by coexpression of VioH and the radical SAM enzyme VioG in Myxococcus xanthus or by combination of VioH and the cell lysate of M. xanthus expressing VioG. Thus, our findings unveil a novel function of SAM-dependent methyltransferases and shed light on the biosynthetic mechanism of MAZ formation.
ACS Chem Biol 2019 01 18
PMID:Class I Methyltransferase VioH Catalyzes Unusual S-Adenosyl-l-methionine Cyclization Leading to 4-Methylazetidinecarboxylic Acid Formation during Vioprolide Biosynthesis. 3054 Jan 88