Amorpha-4,11-diene Amorphadiene

Fig. 5 Computerized 3D structure of amorpha-4,11-diene. Residues marked with red belong to the conserved metal ion binding amino acid sequence IDxxDD. The 3D model of the amorphadiene synthase (AMDS) courtesy of Wolfgang Brandt, Leibniz Institute of Plant Biochemistry Halle, Germany...

Scheme 5.28 Cascade process in S. cerevisiae toward the artimisinin precursor artemisinic acid. Pathway engineering yields amorpha-4,n-diene via farnesyl pyrophosphate (FPP), and oxidations of amorphadiene are catalyzed by CYP71AV1 (redox partner protein not shown), alcohol dehydrogenase ADHl, and aldehyde dehydrogenase ALDHl. Artemisinin is synthesized in vitro from the produced artemisinic acid by established Synthetic chemistry. ADS, amorphadiene synthase.

To provide sufficient amounts of FPP, the yeast pathway starting from acetyl-CoA is up-regulated and the pathway flux through the downstream reactions from FPP to the end-product ergosterol is restricted by repressing the yeast squalene synthase (Erg9). This leads to a substantial accumulation of FPP, which is efficiently converted to amorpha-9,ll-diene by the recom-binantly overexpressed amorphadiene synthase (ADS) from A. annua. A three-step oxidation reaction transforms amorpha-9,ll-diene into artemisinic acid. All steps of the first functional artemisinic acid pathway in... 

---