A Two-Enzyme Cascade Directing Polycyclic Assembly in Tetrodecamycin Biosynthesis

Tetrodecamycins represent a distinctive class of tetronate natural products characterized by a unique polycyclic architecture, in which a dialkyldecalin core is bridged to the γ-lactone tetronate moiety via a rare ether linkage. Through in vivo gene deletions, intermediate structural characterizations, and in vitro enzymatic assays, we elucidated the dihydrotetrodecamycin biosynthetic pathway. Notably, the cytochrome P450 enzyme, TedH, catalyzes both ether bridge formation and regio/stereoselective C-13 hydroxylation to construct the intricate polycyclic ring system.