Kinases are annotated in many nucleoside biosynthetic gene clusters (BGCs) but generally are considered responsible only for self-resistance. Here, we report an unexpected 2’-phosphorylation of nucleoside biosynthetic intermediates in the nikkomycin and polyoxin pathways. This phosphorylation is a unique cryptic modification as it is introduced in the third of the seven steps of the aminohexuronic acid (AHA) nucleoside biosynthesis, retained throughout the pathway’s duration, and is removed in the last step of the pathway (Fig. 1A). This is in sharp contrast to previous proposals, which did not recognize the relevance of 2'-phosphorylation in nikkomycin and polyoxin biosynthesis (Fig. 1B). Bioinformatic analysis of reported nucleoside BGCs suggests the presence of cryptic phosphorylation in other pathways and the importance of functional characterization of kinases in nucleoside biosynthetic pathways. This study also functionally characterized all of the enzymes responsible for AHA biosynthesis and revealed that AHA is constructed via a unique oxidative C-C bond cleavage reaction. The results suggest a divergent biosynthesis mechanism for three classes of antifungal nucleoside natural products (Fig. 2).

Peptidyl nucleoside natural product biosynthesis proceeds through cryptic 2'-phosphorylation

ACS Spring Meeting 2021

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