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Cryptic Phosphorylation-Mediated Divergent Biosynthesis of High-Carbon Sugar Nucleoside Antifungals.

ABSTRACT: Establishing a general biosynthetic scheme for natural products is critical for a broader understanding of natural product biosynthesis and the structural prediction of metabolites based on genome sequence information. High-carbon sugar nucleoside antimicrobials are an underexplored class of natural products with unique structures and important biological activities. Recent studies on C6 sugar nucleoside antifungal natural products, such as nikkomycins and polyoxins, revealed a novel biosynthetic mechanism involving cryptic phosphorylation. However, the generality of this biosynthetic mechanism remained unexplored. We here report in vitro characterization of the biosynthesis of a C7 sugar nucleoside antifungal, malayamycin A. Our results demonstrate that the malayamycin biosynthetic enzymes specifically accept 2'-phosphorylated biosynthetic intermediates, suggesting that cryptic phosphorylation-mediated biosynthesis is conserved beyond C6 sugar nucleosides. Furthermore, the results suggest a generalizable divergent biosynthetic mechanism for high-carbon sugar nucleoside antifungals. In this model, C6 and C7 sugar nucleoside biosyntheses proceed via a common C8 sugar nucleoside precursor, and the sugar size is determined using the functions of α-ketoglutarate (α-KG)-dependent dioxygenases (NikI/PolD for C6 sugar nucleosides and MalI for C7 sugar nucleosides). These results provide an important guidance for the future genome-mining discovery of high-carbon sugar nucleoside antimicrobials.

SUBMITTER: Draelos MM

PROVIDER: S-EPMC9247520 | biostudies-literature |

REPOSITORIES: biostudies-literature

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