Divergent Biosynthesis of C-Nucleoside Minimycin and Indigoidine in Bacteria

Summary Minimycin (MIN) is a C-nucleoside antibiotic structurally related to pseudouridine, and indigoidine is a naturally occurring blue pigment produced by diverse bacteria. Although MIN and indigoidine have been known for decades, the logic underlying the divergent biosynthesis of these interesting molecules has been obscure. Here, we report the identification of a minimal 5-gene cluster (min) essential for MIN biosynthesis. We demonstrated that a non-ribosomal peptide synthetase (MinA) governs “the switch” for the divergent biosynthesis of MIN and the cryptic indigoidine. We also demonstrated that MinCN (the N-terminal phosphatase domain of MinC), MinD (uracil phosphoribosyltransferase), and MinT (transporter) function together as the safeguard enzymes, which collaboratively constitute an unusual self-resistance system. Finally, we provided evidence that MinD, utilizing an unprecedented substrate-competition strategy for self-resistance of the producer cell, maintains competition advantage over the active molecule MIN-5′-monophosphate by increasing the UMP pool in vivo. These findings greatly expand our knowledge regarding natural product biosynthesis.
Graphical Abstract
Highlights • A minimal 5-gene cluster (min) is essential for minimycin biosynthesis • Divergent biosynthesis of minimycin and indigoidine is mediated by an NRPS enzyme • A cascade of three safeguard enzymes constitutes the unusual self-resistance system • MinD functions as the key safeguard enzyme by increasing the UMP pool in vivo
Biotechnology; Microbial Biotechnology; Systems Biology