ArticleMicrobial cell factories2016
Production of the forskolin precursor 11β-hydroxy-manoyl oxide in yeast using surrogate enzymatic activities.
Article in Microbial cell factories, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 21 citations in OpenAlex.
- Diterpenoids in medicinal plants: structure, distribution, biological activities, biosynthesis, and bioengineering prospects.Frontiers in plant science · 2026Review
- Unraveling the regulatory dynamics of bidirectional promoters for modulating gene co-expression and metabolic flux in Saccharomyces cerevisiae.Nucleic acids research · 2025Article
- Three cytochrome P450 enzymes consecutively catalyze the biosynthesis of furanoclerodane precursors in Salvia species.Plant communications · 2025Article
- Biotechnological interventions for the production of forskolin, an active compound from the medicinal plant,Physiology and molecular biology of plants : an international journal of functional plant biology · 2024Review
- Terpene produced by coexpression of the TPS and P450 genes from Lavandula angustifolia protects plants from herbivore attacks during budding stages.BMC plant biology · 2023Article
- Progress in heterologous biosynthesis of forskolin.Journal of industrial microbiology & biotechnology · 2021Review
- Orthogonal monoterpenoid biosynthesis in yeast constructed on an isomeric substrate.Nature communications · 2019Article
- Stress and defense responses in plant secondary metabolites production.Biological research · 2019Review
- Engineering of CYP76AH15 can improve activity and specificity towards forskolin biosynthesis in yeast.Microbial cell factories · 2018Article
- Overcoming the plasticity of plant specialized metabolism for selective diterpene production in yeast.Scientific reports · 2017Article
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9 authors at 4 institutions in 1 country.
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Abstract
backgroundSeveral plant diterpenes have important biological properties. Among them, forskolin is a complex labdane-type diterpene whose biological activity stems from its ability to activate adenylyl cyclase and to elevate intracellular cAMP levels. As such, it is used in the control of blood pressure, in the protection from congestive heart failure, and in weight-loss supplements. Chemical synthesis of forskolin is challenging, and production of forskolin in engineered microbes could provide a sustainable source. To this end, we set out to establish a platform for the production of forskolin and related epoxy-labdanes in yeast.
resultsSince the forskolin biosynthetic pathway has only been partially elucidated, and enzymes involved in terpene biosynthesis frequently exhibit relaxed substrate specificity, we explored the possibility of reconstructing missing steps of this pathway employing surrogate enzymes. Using CYP76AH24, a Salvia pomifera cytochrome P450 responsible for the oxidation of C-12 and C-11 of the abietane skeleton en route to carnosic acid, we were able to produce the forskolin precursor 11β-hydroxy-manoyl oxide in yeast. To improve 11β-hydroxy-manoyl oxide production, we undertook a chassis engineering effort involving the combination of three heterozygous yeast gene deletions (mct1/MCT1, whi2/WHI2, gdh1/GDH1) and obtained a 9.5-fold increase in 11β-hydroxy-manoyl oxide titers, reaching 21.2 mg L(-1).
conclusionsIn this study, we identify a surrogate enzyme for the specific and efficient hydroxylation of manoyl oxide at position C-11β and establish a platform that will facilitate the synthesis of a broad range of tricyclic (8,13)-epoxy-labdanes in yeast. This platform forms a basis for the heterologous production of forskolin and will facilitate the elucidation of subsequent steps of forskolin biosynthesis. In addition, this study highlights the usefulness of using surrogate enzymes for the production of intermediates of complex biosynthetic pathways. The combination of heterozygous deletions and the improved yeast strain reported here will provide a useful tool for the production of numerous other isoprenoids.
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