Genome Mining Reveals a Carboxyl O-Methyltransferase Gatekeeping the Biosynthetic Divergence of Tryptophan Dimers

Bacterial tryptophan dimers comprise a large family of natural products with promising biological activities. Herein, we report the identification of a methyltransferase, SpmM1, which acts as a gatekeeping enzyme to govern the divergent biosynthesis of tryptophan dimers spiroindimicins (SPMs) and indimicins (IDMs) in Streptomyces marincola SCSIO 03032. Bioinformatics, genetic, and biochemical studies revealed that SpmM1-catalyzed carboxyl O -methylation enabled the common precursor of SPMs and IDMs to flux into the spiro-forming pathway to generate SPMs.