(+)-Costunolide is a naturally occurring sesquiterpene lactone, first isolated in Saussurea costus roots in 1960.

The synthesis begins with the cyclization of compound 1, farnesyl pyrophosphate (FPP), which is mediated by a sesquiterpene cyclase, (+)-germacrene A synthase, to form compound 2, (+)-germacryl cation.

[2] The isoprenyl side chain of (+)-germacrene A is then hydroxylated by (+)-germacrene A hydroxylase, which is a cytochrome P450 enzyme, to form 4.

[1] NAD(P)+ dependent hydrogenase(s) then oxidize 4, germacra-1(10),4,11(13)-trien-12-ol, through the intermediate 5, germacra-1(10),4,11(13)-trien-12-al to form compound 6, germacrene acid.

The cytochrome P450 enzyme, (+)-costunolide synthase, which is a NADPH and O2 dependent enzyme, then oxidizes germacrene acid to give the alcohol intermediate, 7, which then cyclizes to form the lactone 8, (+)-costunolide.