Cucurbitacins are triterpenoids that confer a bitter taste in cucurbits such as cucumber, melon, watermelon, squash, and pumpkin. These compounds discourage most pests on the plant and have also been shown to have antitumor properties. With genomics and biochemistry, we identified nine cucumber genes in the pathway for biosynthesis of cucurbitacin C and elucidated four catalytic steps. We discovered transcription factors Bl ( Bitter leaf ) and Bt ( Bitter fruit ) that regulate this pathway in leaves and fruits, respectively. Traces in genomic signatures indicated that selection imposed on Bt during domestication led to derivation of nonbitter cucurbits from their bitter ancestors.

Ten PPAPs with unusual skeletons were isolated from H. perforatum. 6 represents the first multitargeted natural product that could activate PP2A and simultaneously inhibit BACE1, which highlights 6 as a promising lead compound in AD drug development.