ArticleProceedings of the National Academy of Sciences of the United States of America2015
Yeast homologous recombination-based promoter engineering for the activation of silent natural product biosynthetic gene clusters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 111 citations in OpenAlex.
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- CRISETR: an efficient technology for multiplexed refactoring of biosynthetic gene clusters.Nucleic acids research · 2024Article
- Heterologous expression facilitates the discovery and characterization of marine microbial natural products.Engineering microbiology · 2024Review
- Heterologous overproduction of oviedomycin by refactoring biosynthetic gene cluster and metabolic engineering of host strain Streptomyces coelicolor.Microbial cell factories · 2023Article
- Refactoring the architecture of a polyketide gene cluster enhances docosahexaenoic acid production in Yarrowia lipolytica through improved expression and genetic stability.Microbial cell factories · 2023Article
- Parallelized gene cluster editing illuminates mechanisms of epoxyketone proteasome inhibitor biosynthesis.Nucleic acids research · 2023Article
- Leveraging yeast to characterize plant biosynthetic gene clusters.Current opinion in plant biology · 2023Review
- Genomics-Guided Efficient Identification of 2,5-Diketopiperazine Derivatives from Actinobacteria.Chembiochem : a European journal of chemical biology · 2023Article
- The modular pYT vector series employed for chromosomal gene integration and expression to produce carbazoles and glycolipids inFEMS microbes · 2023Article
- Improving candidate Biosynthetic Gene Clusters in fungi through reinforcement learning.Bioinformatics (Oxford, England) · 2022Article
- Recent Advances in the Heterologous Expression of Biosynthetic Gene Clusters for Marine Natural Products.Marine drugs · 2022Review
- Multiplying the heterologous production of spinosad through tandem amplification of its biosynthetic gene cluster in Streptomyces coelicolor.Microbial biotechnology · 2022Article
- Advances in Biosynthesis of Natural Products from Marine Microorganisms.Microorganisms · 2021Review
- High-Throughput Transcriptional Characterization of Regulatory Sequences from Bacterial Biosynthetic Gene Clusters.ACS synthetic biology · 2021Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Large-scale sequencing of prokaryotic (meta)genomic DNA suggests that most bacterial natural product gene clusters are not expressed under common laboratory culture conditions. Silent gene clusters represent a promising resource for natural product discovery and the development of a new generation of therapeutics. Unfortunately, the characterization of molecules encoded by these clusters is hampered owing to our inability to express these gene clusters in the laboratory. To address this bottleneck, we have developed a promoter-engineering platform to transcriptionally activate silent gene clusters in a model heterologous host. Our approach uses yeast homologous recombination, an auxotrophy complementation-based yeast selection system and sequence orthogonal promoter cassettes to exchange all native promoters in silent gene clusters with constitutively active promoters. As part of this platform, we constructed and validated a set of bidirectional promoter cassettes consisting of orthogonal promoter sequences, Streptomyces ribosome binding sites, and yeast selectable marker genes. Using these tools we demonstrate the ability to simultaneously insert multiple promoter cassettes into a gene cluster, thereby expediting the reengineering process. We apply this method to model active and silent gene clusters (rebeccamycin and tetarimycin) and to the silent, cryptic pseudogene-containing, environmental DNA-derived Lzr gene cluster. Complete promoter refactoring and targeted gene exchange in this "dead" cluster led to the discovery of potent indolotryptoline antiproliferative agents, lazarimides A and B. This potentially scalable and cost-effective promoter reengineering platform should streamline the discovery of natural products from silent natural product biosynthetic gene clusters.
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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.