ArticleMetabolic engineering2015
De novo production of the key branch point benzylisoquinoline alkaloid reticuline in yeast.
Article in Metabolic engineering, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 118 citations in OpenAlex.
- Benzylisoquinoline Alkaloid Production in Yeast via Norlaudanosoline Improves Titer, Selectivity, and Yield.ACS synthetic biology · 2026Article
- Multi-omics insights into co-fermentation byFrontiers in nutrition · 2026Article
- Directed evolution of L-DOPA sensing and production enables efficient incorporation of an expanded genetic code into proteins.bioRxiv : the preprint server for biology · 2025Article
- A concise enzyme cascade enables the manufacture of natural and halogenated protoberberine alkaloids.Nature communications · 2025Article
- Engineering Saccharomyces cerevisiae for medical applications.Microbial cell factories · 2025Review
- Advances in the biosynthesis of naturally occurring benzylisoquinoline alkaloids.Frontiers in plant science · 2025Review
- Engineering the L-tryptophan metabolism for efficient de novo biosynthesis of tryptophol in Saccharomyces cerevisiae.Biotechnology for biofuels and bioproducts · 2024Article
- Guide RNA structure design enables combinatorial CRISPRa programs for biosynthetic profiling.Nature communications · 2024Article
- Building Synthetic Cells─From the Technology Infrastructure to Cellular Entities.ACS synthetic biology · 2024Review
- The CYP80A and CYP80G Are Involved in the Biosynthesis of Benzylisoquinoline Alkaloids in the Sacred Lotus (International journal of molecular sciences · 2024Article
- An Enzymatic Strategy for the Selective Methylation of High-Value-Added Tetrahydroprotoberberine Alkaloids.International journal of molecular sciences · 2023Article
- Concise synthesis of (Chemical science · 2023Article
- De novo biosynthesis of berberine and halogenated benzylisoquinoline alkaloids in Saccharomyces cerevisiae.Communications chemistry · 2023Article
- Enzymatic synthesis of benzylisoquinoline alkaloids using a parallel cascade strategy and tyrosinase variants.Nature communications · 2022Article
- Biosynthesis of tetrahydropapaverine and semisynthesis of papaverine in yeast.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Metabolic engineering of Saccharomyces cerevisiae for hydroxytyrosol overproduction directly from glucose.Microbial biotechnology · 2022Article
- Biotechnological production of specialty aromatic and aromatic-derivative compounds.World journal of microbiology & biotechnology · 2022Review
- Synthetic Biology in Plants, a Boon for Coming Decades.Molecular biotechnology · 2021Review
- Multi-modular engineering of Saccharomyces cerevisiae for high-titre production of tyrosol and salidroside.Microbial biotechnology · 2021Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Microbial biosynthesis for plant-based natural products, such as the benzylisoquinoline alkaloids (BIAs), has the potential to address limitations in plant-based supply of established drugs and make new molecules available for drug discovery. While yeast strains have been engineered to produce a variety of downstream BIAs including the opioids, these strains have relied on feeding an early BIA substrate. We describe the de novo synthesis of the major BIA branch point intermediate reticuline via norcoclaurine in Saccharomyces cerevisiae. Modifications were introduced into yeast central metabolism to increase supply of the BIA precursor tyrosine, allowing us to achieve a 60-fold increase in production of the early benzylisoquinoline scaffold from fed dopamine with no supply of exogenous tyrosine. Yeast strains further engineered to express a mammalian tyrosine hydroxylase, four mammalian tetrahydrobiopterin biosynthesis and recycling enzymes, and a bacterial DOPA decarboxylase produced norcoclaurine de novo. We further increased production of early benzylisoquinoline scaffolds by 160-fold through introducing mutant tyrosine hydroxylase enzymes, an optimized plant norcoclaurine synthase variant, and optimizing culture conditions. Finally, we incorporated five additional plant enzymes--three methyltransferases, a cytochrome P450, and its reductase partner--to achieve de novo production of the key branch point molecule reticuline with a titer of 19.2 μg/L. These strains and reconstructed pathways will serve as a platform for the biosynthesis of diverse natural and novel BIAs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.