The sesquiterpene lactone parthenolide is a promising anticancer drug. Its biosynthesis via a microbial cell factory has been considered as a sustainable alternative to plant extraction. Herein, systematic metabolic engineering approaches, as well as the introduction of a novel noncanonical tricarboxylic acid (TCA) cycle, were employed to enhance the production of the key precursor germacrene A. By identifying two new dehydrogenases and controlling the expression of parthenolide synthase, we further achieved the elimination of byproducts and enhanced parthenolide production. A two-stage fermentation approach and in situ product extraction using macroreticular resin were further applied to relieve the nocuous effect of costunolide and parthenolide on the growth of yeast cell factories, ultimately achieving a titer of 549.7 mg/L for parthenolide and 972.7 mg/L for costunolide in a 10 L fermenter, which represents the highest reported titer obtained by microbial fermentation. The strategies should also contribute to the microbial cell factory-construction for other natural products exhibiting toxicity.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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