ArticleProceedings of the National Academy of Sciences of the United States of America2021
Complete biosynthesis of the bisbenzylisoquinoline alkaloids guattegaumerine and berbamunine in yeast.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 48 citations in OpenAlex.
- Yeast species resource exploration and application in cell factories.Synthetic and systems biotechnology · 2026Review
- Benzylisoquinoline Alkaloid Production in Yeast via Norlaudanosoline Improves Titer, Selectivity, and Yield.ACS synthetic biology · 2026Article
- Biosynthesis of benzylisoquinoline alkaloids and its evolution in plants.Plant communications · 2026Review
- Efficient, complete biosynthesis of isoflavonoid calycosin-7-glucoside by metabolically engineered yeast cell factories.Frontiers in bioengineering and biotechnology · 2026Article
- A Modular Chemoenzymatic Cascade Simplifies Divergent Synthesis of Natural and Unnatural Benzylisoquinoline Alkaloids.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification and Characterization of Two Se6OMTs fromMetabolites · 2025Article
- Article
- Bis-benzylisoquinoline alkaloids inhibit flavivirus entry and replication by compromising endolysosomal trafficking and autophagy.Virologica Sinica · 2024Article
- New insights into the roles of fungi and bacteria in the development of medicinal plant.Journal of advanced research · 2024Review
- Lineage-Specific CYP80 Expansion and Benzylisoquinoline Alkaloid Diversity in Early-Diverging Eudicots.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme.Nature communications · 2024Article
- Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.Nature communications · 2024Article
- Modular assembly of an artificially concise biocatalytic cascade for the manufacture of phenethylisoquinoline alkaloids.Nature communications · 2024Article
- Genome-wide analysis of theFrontiers in plant science · 2024Article
- Recent Advances in the Total Synthesis of the Tetrahydroisoquinoline Alkaloids (2002-2020).Chemical reviews · 2023Review
- Design of Four Small-Molecule-Inducible Systems in the Yeast Chromosome, Applied to Optimize Terpene Biosynthesis.ACS synthetic biology · 2023Article
- De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae.Communications chemistry · 2023Article
- Alkaloid binding to opium poppy major latex proteins triggers structural modification and functional aggregation.Nature communications · 2022Article
- Biosynthesis Investigations of Terpenoid, Alkaloid, and Flavonoid Antimicrobial Agents Derived from Medicinal Plants.Antibiotics (Basel, Switzerland) · 2022Review
- Biosynthesis of tetrahydropapaverine and semisynthesis of papaverine in yeast.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Benzylisoquinoline alkaloids (BIAs) are a diverse class of medicinal plant natural products. Nearly 500 dimeric bisbenzylisoquinoline alkaloids (bisBIAs), produced by the coupling of two BIA monomers, have been characterized and display a range of pharmacological properties, including anti-inflammatory, antitumor, and antiarrhythmic activities. In recent years, microbial platforms have been engineered to produce several classes of BIAs, which are rare or difficult to obtain from natural plant hosts, including protoberberines, morphinans, and phthalideisoquinolines. However, the heterologous biosyntheses of bisBIAs have thus far been largely unexplored. Here, we describe the engineering of yeast strains that produce the Type I bisBIAs guattegaumerine and berbamunine de novo. Through strain engineering, protein engineering, and optimization of growth conditions, a 10,000-fold improvement in the production of guattegaumerine, the major bisBIA pathway product, was observed. By replacing the cytochrome P450 used in the final coupling reaction with a chimeric variant, the product profile was inverted to instead produce solely berbamunine. Our highest titer engineered yeast strains produced 108 and 25 mg/L of guattegaumerine and berbamunine, respectively. Finally, the inclusion of two additional putative BIA biosynthesis enzymes, SiCNMT2 and NnOMT5, into our bisBIA biosynthetic strains enabled the production of two derivatives of bisBIA pathway intermediates de novo: magnocurarine and armepavine. The de novo heterologous biosyntheses of bisBIAs presented here provide the foundation for the production of additional medicinal bisBIAs in yeast.
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