An independent biosynthetic route to frame a xanthanolide‐type sesquiterpene lactone in Asteraceae

SUMMARY Xanthanolides, also described as seco‐guaianolides, are unique sesquiterpene lactones (STLs) with diverse bioactivities. Most of xanthanolides are 12,8‐olides based on the position of their lactone ring. The biosynthetic pathway leading to xanthanolides has hitherto been elusive, especially how nature creates the xanthane skeleton is a long‐standing question. This study reports the elucidation of a complete biosynthetic pathway to the important 12,8‐xanthanolide 8‐ epi ‐xanthatin. The xanthane‐type backbone is directly derived from the central precursor germacrene‐type sesquiterpene, germacrene A acid, via oxidative rearrangement, catalyzed by an unusual cytochrome P450. Subsequently, a 12,8‐lactone ring is formed within this xanthane‐type backbone resulting in xanthanolides. The biosynthetic pathway for xanthanolides contrasts with the previously unified biosynthetic route for diverse 12,6‐guaianolides, in which a 12,6‐lactone ring formation precedes the transformation of a germacrene‐type skeleton into a guaiane‐type structure. The discovery of the full biosynthetic pathway of 8‐ epi ‐xanthantin opens new opportunities for producing xanthanolides in microbial organisms using synthetic biology strategies.