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Engineering Saccharomyces cerevisiae for geranylgeraniol overproduction by combinatorial design
Tian-Qing Song1,2, Ming-Zhu Ding1,2, Fang Zhai1,2
1Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin, 300072, P.R. China.
Scientific Reports
|November 10, 2017
Summary
Combinatorial design in yeast successfully optimized geranylgeraniol (GGOH) production by fine-tuning metabolic pathways and fermentation conditions. This strategy significantly enhanced GGOH yields, demonstrating its potential for complex natural product biosynthesis.
Area of Science:
- Metabolic Engineering
- Synthetic Biology
- Biotechnology
Background:
- Combinatorial design is crucial for optimizing complex biological systems.
- Geranylgeraniol (GGOH) is a valuable diterpene precursor with diverse applications.
- Engineering microbial hosts for natural product overproduction requires sophisticated strategies.
Purpose of the Study:
- To explore the combined effects of pathway engineering, promoter strength, copy number, and integration locus on GGOH production in Saccharomyces cerevisiae.
- To establish an optimized GGOH biosynthetic pathway using combinatorial design principles.
- To demonstrate the scalability of the engineered strain for industrial applications.
Main Methods:
- Construction of two distinct GGOH biosynthetic pathway branches.
- Utilized 10 promoter combinations to regulate gene expression, including a fusion gene (BTS1-ERG20), a heterologous enzyme (GGPPSsa), and a truncated endogenous enzyme (tHMGR).
- Employed δ-integration for gene insertion and optimized fermentation conditions, including medium composition and carbon restriction.
Main Results:
- Achieved GGOH yields ranging from 18.45 mg/L to 161.82 mg/L through initial pathway engineering.
- Optimized fermentation medium increased yield to 437.52 mg/L.
- Carbon restriction strategy in a 5-L fermenter resulted in a final GGOH yield of 1315.44 mg/L.
Conclusions:
- Combinatorial pathway optimization is a powerful strategy for engineering microbes for high-level production of complex natural products like GGOH.
- The developed yeast strains and optimized processes offer significant potential for downstream diterpene production.
- This study validates the efficacy of integrating diverse genetic elements and fermentation strategies for microbial biosynthesis.
