J Am Chem Soc. 2026 May 13. doi: 10.1021/jacs.6c05246. Online ahead of print.

ABSTRACT

Sinefungin is a nucleoside natural product isolated from several strains of Streptomyces. The chemical structure of sinefungin is characterized by an unusual C-C bond linkage between ornithine and adenosyl fragments. Previous studies suggested that pyridoxal 5′-phosphate (PLP)-dependent enzyme catalysis is involved in the key C-C bond-forming step. Here, we show that instead of PLP catalysis, sinefungin biosynthesis involves a B₁₂-dependent radical S-adenosyl-l-methionine (SAM) enzyme, SnfB, that catalyzes the C-adenosylation of arginine. The amidino group in the resulting SnfB product is then hydrolyzed by SnfC to produce sinefungin via a cryptic phosphorylation step catalyzed by SnfH. This study highlights the catalytic versatility of the B₁₂-dependent radical SAM enzyme family and unveils an unconventional assembly pathway for amino acid-nucleoside conjugates in nature.

PMID:42127262 | DOI:10.1021/jacs.6c05246