Abstract
Abstract6‐Thioguanine (6TG) is a DNA‐targeting therapeutic used in the treatment of various cancers. While 6TG was rationally designed as a proof of concept for antimetabolite therapy, it is also a rare thioamide‐bearing bacterial natural product and critical virulence factor of Erwinia amylovorans, plant pathogens that cause fire blight. Through gene expression, biochemical assays, and mutational analyses, we identified a specialized bipartite enzyme system, consisting of an ATP‐dependent sulfur transferase (YcfA) and a sulfur‐mobilizing enzyme (YcfC), that is responsible for the peculiar oxygen‐by‐sulfur substitution found in the biosynthesis of 6TG. Mechanistic and phylogenetic studies revealed that YcfA‐mediated 6TG biosynthesis evolved from ancient tRNA modifications that support translational fidelity. The successful in vitro reconstitution of 6TG thioamidation showed that YcfA employs a specialized sulfur shuttle that markedly differs from universal RNA‐related systems. This study sheds light on underexplored enzymatic C−S bond formation in natural product biosynthesis.
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