An efficient chemoenzymatic synthesis of dihydroartemisinic aldehyde
2017
Artemisinin from the plant Artemisia annua is the
most potent pharmaceutical for the treatment of malaria. In the
plant, the sesquiterpene cyclase amorphadiene synthase, a cytochrome-
dependent CYP450, and an aldehyde reductase convert
farnesyl diphosphate (FDP) into dihydroartemisinic
aldehyde (DHAAl), which is a key intermediate in the
biosynthesis of artemisinin and a semisynthetic precursor for
its chemical synthesis. Here, we report a chemoenzymatic
process that is able to deliver DHAAl using only the
sesquiterpene synthase from a carefully designed hydroxylated
FDP derivative. This process, which reverses the natural order
of cyclization of FDP and oxidation of the sesquiterpene
hydrocarbon, provides a significant improvement in the synthesis
of DHAAl and demonstrates the potential of substrate
engineering in the terpene synthase mediated synthesis of highvalue
natural products.
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