Evidence map›Paper›PMID 39074544›Full record

ArticleMetabolic engineering2024

Verazine biosynthesis from simple sugars in engineered Saccharomyces cerevisiae.

Peter H Winegar, Graham A Hudson, Luisa B Dell, Maria C T Astolfi, James Reed, Rocky D Payet, Hugo C J Ombredane, Anthony T Iavarone, Yan Chen, Jennifer W Gin and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Metabolic engineering, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

11 citing papers in PubMed.

  1. Article
  2. Biomedicines · 2026
    Article
  3. Reconstruction ofEngineering in life sciences · 2026
    Article
  4. Review
  5. Review
  6. Article
  7. Review
  8. Article
  9. Article
  10. Article
  11. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Peter H WinegarJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; California Institute for Quantitative Biosciences (QB3 Institute), University of California, Berkeley, CA, 94720, USA.
Graham A HudsonJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; California Institute for Quantitative Biosciences (QB3 Institute), University of California, Berkeley, CA, 94720, USA.
Luisa B DellJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; Department of Chemical and Biomolecular Engineering and Department of Bioengineering, University of California, Berkeley, CA, 94720, USA.
Maria C T AstolfiJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; Department of Chemical and Biomolecular Engineering and Department of Bioengineering, University of California, Berkeley, CA, 94720, USA.
James ReedJohn Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
Rocky D PayetJohn Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
Hugo C J OmbredaneJohn Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
Anthony T IavaroneCalifornia Institute for Quantitative Biosciences (QB3 Institute), University of California, Berkeley, CA, 94720, USA.
Yan ChenJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
Jennifer W GinJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
Christopher J PetzoldJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
Anne E OsbournJohn Innes Centre, Norwich Research Park, Norwich, NR4 7UH, UK.
Jay D KeaslingJoint BioEnergy Institute, Lawrence Berkeley National Laboratory, Emeryville, CA, 94608, USA; Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA; California Institute for Quantitative Biosciences (QB3 Institute), University of California, Berkeley, CA, 94720, USA; Department of Chemical and Biomolecular Engineering and Department of Bioengineering, University of California, Berkeley, CA, 94720, USA; The Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, Kemitorvet, Building 220, Kongens, Lyngby, 2800, Denmark. Electronic address: keasling@berkeley.edu.

Funding

Synthetic biology tools for scalable production of medicinal plant terpenesR01AT010593 · NCCIH · STANFORD UNIVERSITY · PI KEASLING, JAY D, LANGE, BERND MARKUS · 2019 to 2023
$3.5M
High Definition Ion Mobility SpectrometerS10OD020062 · OD · UNIVERSITY OF CALIFORNIA BERKELEY · PI WILLIAMS, EVAN R · 2015 to 2015
$590k
Biosynthesis of Cyclopamine and New-to-Nature Triterpenoids in YeastF32GM153046 · NIGMS · UNIVERSITY OF CALIFORNIA BERKELEY · PI Peter Henry Winegar · 2024 to 2026
$229k
NCCIH NIH HHS R01 AT010593NIGMS NIH HHS F32 GM153046NIH HHS S10 OD020062Wellcome Trust 227375
6 · The paper itself

Abstract

Steroidal alkaloids are FDA-approved drugs (e.g., Zytiga) and promising drug candidates/leads (e.g., cyclopamine); yet many of the ≥697 known steroidal alkaloid natural products remain underutilized as drugs because it can be challenging to scale their biosynthesis in their producing organisms. Cyclopamine is a steroidal alkaloid produced by corn lily (Veratrum spp.) plants, and it is an inhibitor of the Hedgehog (Hh) signaling pathway. Therefore, cyclopamine is an important drug candidate/lead to treat human diseases that are associated with dysregulated Hh signaling, such as basal cell carcinoma and acute myeloid leukemia. Cyclopamine and its semi-synthetic derivatives have been studied in (pre)clinical trials as Hh inhibitor-based drugs. However, challenges in scaling the production of cyclopamine have slowed efforts to improve its efficacy and safety profile through (bio)synthetic derivatization, often limiting drug development to synthetic analogs of cyclopamine such as the FDA-approved drugs Odomzo, Daurismo, and Erivedge. If a platform for the scalable and sustainable production of cyclopamine were established, then its (bio)synthetic derivatization, clinical development, and, ultimately, widespread distribution could be accelerated. Ongoing efforts to achieve this goal include the biosynthesis of cyclopamine in Veratrum plant cell culture and the semi-/total chemical synthesis of cyclopamine. Herein, this work advances efforts towards a promising future approach: the biosynthesis of cyclopamine in engineered microorganisms. We completed the heterologous microbial production of verazine (biosynthetic precursor to cyclopamine) from simple sugars (i.e., glucose and galactose) in engineered Saccharomyces cerevisiae (S. cerevisiae) through the inducible upregulation of the native yeast mevalonate and lanosterol biosynthetic pathways, diversion of biosynthetic flux from ergosterol (i.e., native sterol in S. cerevisiae) to cholesterol (i.e., biosynthetic precursor to verazine), and expression of a refactored five-step verazine biosynthetic pathway. The engineered S. cerevisiae strain that produced verazine contains eight heterologous enzymes sourced from seven different species. Importantly, S. cerevisiae-produced verazine was indistinguishable via liquid chromatography-mass spectrometry from both a commercial standard (Veratrum spp. plant-produced) and Nicotiana benthamiana-produced verazine. To the best of our knowledge, this is the first report describing the heterologous production of a steroidal alkaloid in an engineered yeast. Verazine production was ultimately increased through design-build-test-learn cycles to a final titer of 83 ± 3 μg/L (4.1 ± 0.1 μg/g DCW). Together, this research lays the groundwork for future microbial biosynthesis of cyclopamine, (bio)synthetic derivatives of cyclopamine, and other steroidal alkaloid natural products.

Indexed as

Metabolic EngineeringSaccharomyces cerevisiaeVeratrum AlkaloidsSugarscyclopamineSugarsVeratrum AlkaloidsMetabolic engineeringMicrobial biosynthesisNatural productSteroidal alkaloidSynthetic biologyVerazine

Identifiers

PMID39074544
PMCPMC11421371

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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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.