title: An Efficient Chemoenzymatic Synthesis of Dihydroartemisinic Aldehyde.
abstract: 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 high-value natural products.
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, Great Britain.
authors.forename: Melodi
authors.initials: M
authors.lastname: Demiray
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, Great Britain.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Tang
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, Great Britain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, Great Britain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Faraldos
authors.affiliation: School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, Great Britain.
authors.forename: Rudolf K
authors.initials: RK
authors.lastname: Allemann
keywords: artemisinin; chemoenzymatic synthesis; sesquiterpenoids; substrate engineering; synthetic biology