title: Microbial Synthesis of the Forskolin Precursor Manoyl Oxide in an Enantiomerically Pure Form.
abstract: Forskolin is a promising medicinal compound belonging to a plethora of specialized plant metabolites that constitute a rich source of bioactive high-value compounds. A major obstacle for exploitation of plant metabolites is that they often are produced in small amounts and in plants difficult to cultivate. This may result in insufficient and unreliable supply leading to fluctuating and high sales prices. Hence, substantial efforts and resources have been invested in developing sustainable and reliable supply routes based on microbial cell factories. Here, we report microbial synthesis of (13R)-manoyl oxide, a proposed intermediate in the biosynthesis of forskolin and other medically important labdane-type terpenoids. Process optimization enabled synthesis of enantiomerically pure (13R)-manoyl oxide as the sole metabolite, providing a pure compound in just two steps with a yield of 10 mg/liter. The work presented here demonstrates the value of a standardized bioengineering pipeline and the large potential of microbial cell factories as sources for sustainable synthesis of complex biochemicals.
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Morten T
authors.initials: MT
authors.lastname: Nielsen
authors.affiliation: Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Johan Andersen
authors.initials: JA
authors.lastname: Ranberg
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Christensen
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Hanne Bjerre
authors.initials: HB
authors.lastname: Christensen
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Harrison
authors.affiliation: Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Carl Erik
authors.initials: CE
authors.lastname: Olsen
authors.affiliation: Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Björn
authors.initials: B
authors.lastname: Hamberger
authors.affiliation: Plant Biochemistry Laboratory, Department of Plant and Environmental Sciences, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Birger Lindberg
authors.initials: BL
authors.lastname: Møller
authors.affiliation: Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Hørsholm, Denmark morno@biosustain.dtu.dk.
authors.forename: Morten H H
authors.initials: MH
authors.lastname: Nørholm
mesh_terms: D001709:Biotechnology / Q000379:methods*; D005576:Colforsin / Q000378:metabolism; D004224:Diterpenes / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D060847:Metabolic Engineering; D010944:Plants / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D004224:Diterpenes; C475535:manoyl oxide; D005576:Colforsin