ArticleProceedings of the National Academy of Sciences of the United States of America2017
Biosynthesis of the microtubule-destabilizing diterpene pseudolaric acid B from golden larch involves an unusual diterpene synthase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 26 citations in OpenAlex.
- Insight into TPS-d Subfamily: The Evolutionary and Functional Diversity in Gymnosperms.Biomolecules · 2026Review
- A Review of Plant-Derived Diterpenoid Biosynthesis: From Structural Scaffold Diversity and Lineage-Associated Distribution to Enzyme Mining and Discovery Strategies.Molecules (Basel, Switzerland) · 2026Review
- Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis.Beilstein journal of organic chemistry · 2026Review
- Discovery of UbiA-Type Cyathane Synthases in Bacteria.ACS catalysis · 2025Article
- Exo-Selective Intramolecular (4+3) Cycloadditions to Trans-Fused Perhydroazulenes: An Asymmetric Formal Synthesis of (-)-Pseudolaric Acid B.Angewandte Chemie (International ed. in English) · 2025Article
- Sequence-Structure Analysis Unlocking the Potential Functional Application of the Local 3D Motifs of Plant-Derived Diterpene Synthases.Biomolecules · 2024Article
- Pseudolaric acid B induces apoptosis associated with the mitochondrial and PI3K/AKT/mTOR pathways in triple‑negative breast cancer.Oncology reports · 2023Article
- Diterpene Resin Acids and Olefins in Calabrian Pine (Plants (Basel, Switzerland) · 2021Article
- Functional identification of the terpene synthase family involved in diterpenoid alkaloids biosynthesis inActa pharmaceutica Sinica. B · 2021Article
- Structure of human GABANature · 2020Article
- Promiscuous terpene synthases from Prunella vulgaris highlight the importance of substrate and compartment switching in terpene synthase evolution.The New phytologist · 2019Article
- Terpene Synthases as Metabolic Gatekeepers in the Evolution of Plant Terpenoid Chemical Diversity.Frontiers in plant science · 2019Review
- Protonation-Initiated Cyclization by a Class II Terpene Cyclase Assisted by Tunneling.Chembiochem : a European journal of chemical biology · 2017Article
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12 authors at 2 institutions in 3 countries.
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Abstract
The diversity of small molecules formed via plant diterpene metabolism offers a rich source of known and potentially new biopharmaceuticals. Among these, the microtubule-destabilizing activity of pseudolaric acid B (PAB) holds promise for new anticancer agents. PAB is found, perhaps uniquely, in the coniferous tree golden larch (Pseudolarix amabilis, Pxa). Here we describe the discovery and mechanistic analysis of golden larch terpene synthase 8 (PxaTPS8), an unusual diterpene synthase (diTPS) that catalyzes the first committed step in PAB biosynthesis. Mining of the golden larch root transcriptome revealed a large TPS family, including the monofunctional class I diTPS PxaTPS8, which converts geranylgeranyl diphosphate into a previously unknown 5,7-fused bicyclic diterpene, coined "pseudolaratriene." Combined NMR and quantum chemical analysis verified the structure of pseudolaratriene, and co-occurrence with PxaTPS8 and PAB in P amabilis tissues supports the intermediacy of pseudolaratriene in PAB metabolism. Although PxaTPS8 adopts the typical three-domain structure of diTPSs, sequence phylogeny places the enzyme with two-domain TPSs of mono- and sesqui-terpene biosynthesis. Site-directed mutagenesis of PxaTPS8 revealed several catalytic residues that, together with quantum chemical calculations, suggested a substantial divergence of PxaTPS8 from other TPSs leading to a distinct carbocation-driven reaction mechanism en route to the 5,7-trans-fused bicyclic pseudolaratriene scaffold. PxaTPS8 expression in microbial and plant hosts provided proof of concept for metabolic engineering of pseudolaratriene.
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