ArticleProceedings of the National Academy of Sciences of the United States of America2016
Oxidation and cyclization of casbene in the biosynthesis of Euphorbia factors from mature seeds of Euphorbia lathyris L.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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50 citing papers in PubMed, 92 citations in OpenAlex.
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- Salicylic acid-mediated biosynthesis of anti-oomycete diterpenoids in Euphorbia lathyris L. suspension cells.Plant cell reports · 2026Article
- Evolution of a Synthetic Strategy for Complex Diterpenes fromJournal of the American Chemical Society · 2026Article
- Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis.Beilstein journal of organic chemistry · 2026Review
- Diterpenoids in medicinal plants: structure, distribution, biological activities, biosynthesis, and bioengineering prospects.Frontiers in plant science · 2026Review
- Identification of BAHD-acyltransferase enzymes involved in ingenane diterpenoid biosynthesis.The New phytologist · 2025Article
- Divergent multifunctional P450s-empowered biosynthesis of bioactive tripterifordin and cryptic atiserenoids in Aconitum implies convergent evolution.Nature communications · 2025Article
- Metabolic engineering of narrow-leafed lupin for the production of enantiomerically pure (-)-sparteine.Plant biotechnology journal · 2025Article
- Discovery of ElABCG39: a key player in ingenol transmembrane efflux identified through genome-wide analysis of ABC transporters in Euphorbia lathyris L.Plant cell reports · 2024Article
- Engineering Terpene Production Pathways inMicroorganisms · 2024Article
- EngineeringmLife · 2023Article
- Finding activity through rigidity: syntheses of natural products containing tricyclic bridgehead carbon centers.Natural product reports · 2023Review
- The causal mutation leading to sweetness in modern white lupin cultivars.Science advances · 2023Article
- An Engineered Heat-Inducible Expression System for the Production of Casbene inInternational journal of molecular sciences · 2023Article
- Plant terpene specialized metabolism: complex networks or simple linear pathways?The Plant journal : for cell and molecular biology · 2023Review
- Chromosome-level Genome Assembly of Euphorbia peplus, a Model System for Plant Latex, Reveals that Relative Lack of Ty3 Transposons Contributed to Its Small Genome Size.Genome biology and evolution · 2023Article
- Plant (di)terpenoid evolution: from pigments to hormones and beyond.Natural product reports · 2023Review
- Integrated Analysis of Transcriptome and microRNA Profile Reveals the Toxicity ofMolecules (Basel, Switzerland) · 2022Article
- A gene cluster in Ginkgo biloba encodes unique multifunctional cytochrome P450s that initiate ginkgolide biosynthesis.Nature communications · 2022Article
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The seed oil of Euphorbia lathyris L. contains a series of macrocyclic diterpenoids known as Euphorbia factors. They are the current industrial source of ingenol mebutate, which is approved for the treatment of actinic keratosis, a precancerous skin condition. Here, we report an alcohol dehydrogenase-mediated cyclization step in the biosynthetic pathway of Euphorbia factors, illustrating the origin of the intramolecular carbon-carbon bonds present in lathyrane and ingenane diterpenoids. This unconventional cyclization describes the ring closure of the macrocyclic diterpene casbene. Through transcriptomic analysis of E. lathyris L. mature seeds and in planta functional characterization, we identified three enzymes involved in the cyclization route from casbene to jolkinol C, a lathyrane diterpene. These enzymes include two cytochromes P450 from the CYP71 clan and an alcohol dehydrogenase (ADH). CYP71D445 and CYP726A27 catalyze regio-specific 9-oxidation and 5-oxidation of casbene, respectively. When coupled with these P450-catalyzed monooxygenations, E. lathyris ADH1 catalyzes dehydrogenation of the hydroxyl groups, leading to the subsequent rearrangement and cyclization. The discovery of this nonconventional cyclization may provide the key link to complete elucidation of the biosynthetic pathways of ingenol mebutate and other bioactive macrocyclic diterpenoids.
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