A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis.

Li, Yang, Sun, Wang, Lu, Zhu, Shen (2025) A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis. J Am Chem Soc (IF: 15.6)

Abstract

Primary amide-specific N-methyltransferases are extremely scarce in microbial secondary metabolism. Here, Asc-Orf2, an N-methyltransferase involved in the biosynthesis of ansacarbamitocins, was identified to catalyze the methylation of the 3-O-carbamoyl moiety. Structural analysis identified an unprecedented NPPH catalytic motif, offering a mechanistic basis to overcome the chemical inertness of primary amides. The 3-O-(N-methyl)-carbamoyl maytansinoid derivatives, modified via Asc-Orf2-catalyzed methylation, exhibited markedly enhanced antitumor activity, highlighting the magic methylation effect in bioactivity modulation. Furthermore, structure-targeted engineering expanded the catalytic scope of Asc-Orf2, enabling the directed synthesis of an N-allylated carbamoyl maytansinoid derivative optimized for antibody-drug conjugate payload.

Links

http://www.ncbi.nlm.nih.gov/pubmed/40601550
http://dx.doi.org/10.1021/jacs.5c05398

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