Metabolic engineering of Saccharomyces cerevisiae for enhanced taxadiene production.
Saccharomyces cerevisiae
/ genetics
Metabolic Engineering
/ methods
Mevalonic Acid
/ metabolism
Alkenes
/ metabolism
Polyisoprenyl Phosphates
/ metabolism
Diterpenes
/ metabolism
Hydroxymethylglutaryl CoA Reductases
/ genetics
NADP
/ metabolism
Saccharomyces cerevisiae Proteins
/ genetics
Sesquiterpenes
S. cerevisiae
Metabolic engineering
Mevalonate pathway
Taxol
Terpenes
Journal
Microbial cell factories
ISSN: 1475-2859
Titre abrégé: Microb Cell Fact
Pays: England
ID NLM: 101139812
Informations de publication
Date de publication:
06 Sep 2024
06 Sep 2024
Historique:
received:
29
03
2024
accepted:
19
08
2024
medline:
7
9
2024
pubmed:
7
9
2024
entrez:
6
9
2024
Statut:
epublish
Résumé
Metabolic engineering enables the sustainable and cost-efficient production of complex chemicals. Efficient production of terpenes in Saccharomyces cerevisiae can be achieved by recruiting an intermediate of the mevalonate pathway. The present study aimed to evaluate the engineering strategies of S. cerevisiae for the production of taxadiene, a precursor of taxol, an antineoplastic drug. SCIGS22a, a previously engineered strain with modifications in the mevalonate pathway (MVA), was used as a background strain. This strain was engineered to enable a high flux towards farnesyl diphosphate (FPP) and the availability of NADPH. The strain MVA was generated from SCIGS22a by overexpressing all mevalonate pathway genes. Combining the background strains with 16 different episomal plasmids, which included the combination of 4 genes: tHMGR (3-hydroxy-3-methylglutaryl-CoA reductase), ERG20 (farnesyl pyrophosphate synthase), GGPPS (geranyl diphosphate synthase) and TS (taxadiene synthase) resulted in the highest taxadiene production in S. cerevisiae of 528 mg/L. Our study highlights the critical role of pathway balance in metabolic engineering, mainly when dealing with toxic molecules like taxadiene. We achieved significant improvements in taxadiene production by employing a combinatorial approach and focusing on balancing the downstream and upstream pathways. These findings emphasize the importance of minor gene expression modification levels to achieve a well-balanced pathway, ultimately leading to enhanced taxadiene accumulation.
Sections du résumé
BACKGROUND
BACKGROUND
Metabolic engineering enables the sustainable and cost-efficient production of complex chemicals. Efficient production of terpenes in Saccharomyces cerevisiae can be achieved by recruiting an intermediate of the mevalonate pathway. The present study aimed to evaluate the engineering strategies of S. cerevisiae for the production of taxadiene, a precursor of taxol, an antineoplastic drug.
RESULT
RESULTS
SCIGS22a, a previously engineered strain with modifications in the mevalonate pathway (MVA), was used as a background strain. This strain was engineered to enable a high flux towards farnesyl diphosphate (FPP) and the availability of NADPH. The strain MVA was generated from SCIGS22a by overexpressing all mevalonate pathway genes. Combining the background strains with 16 different episomal plasmids, which included the combination of 4 genes: tHMGR (3-hydroxy-3-methylglutaryl-CoA reductase), ERG20 (farnesyl pyrophosphate synthase), GGPPS (geranyl diphosphate synthase) and TS (taxadiene synthase) resulted in the highest taxadiene production in S. cerevisiae of 528 mg/L.
CONCLUSION
CONCLUSIONS
Our study highlights the critical role of pathway balance in metabolic engineering, mainly when dealing with toxic molecules like taxadiene. We achieved significant improvements in taxadiene production by employing a combinatorial approach and focusing on balancing the downstream and upstream pathways. These findings emphasize the importance of minor gene expression modification levels to achieve a well-balanced pathway, ultimately leading to enhanced taxadiene accumulation.
Identifiants
pubmed: 39242505
doi: 10.1186/s12934-024-02512-z
pii: 10.1186/s12934-024-02512-z
doi:
Substances chimiques
taxa-4(5),11(12)diene
0
Mevalonic Acid
S5UOB36OCZ
Alkenes
0
farnesyl pyrophosphate
79W6B01D07
Polyisoprenyl Phosphates
0
Diterpenes
0
Hydroxymethylglutaryl CoA Reductases
EC 1.1.1.-
NADP
53-59-8
Saccharomyces cerevisiae Proteins
0
Sesquiterpenes
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
241Subventions
Organisme : Scientific and Technological Research Council of Türkiye
ID : 117Z246
Organisme : Anadolu University Scientific Research Projects Commission
ID : 2008S091
Informations de copyright
© 2024. The Author(s).
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