ArticleMicrobial cell factories2022
Bottom-up synthetic biology approach for improving the efficiency of menaquinone-7 synthesis in Bacillus subtilis.
Article in Microbial cell factories, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 22 citations in OpenAlex.
- Menaquinone biosynthesis inEngineering microbiology · 2026Review
- Development of Bacillus subtilis cell factories for nutraceuticals production.World journal of microbiology & biotechnology · 2026Review
- High-level production of vitamin K2 inSynthetic and systems biotechnology · 2026Article
- Directed screening and spatial coupling of farnesyl diphosphate synthase for enhancing menaquinone-7 production in Bacillus subtilis.Microbial cell factories · 2026Article
- Metabolic Engineering Strategy forFoods (Basel, Switzerland) · 2025Review
- Vitamin K (Menaquinone) from marine Kocuria sp. RAM1: optimization, characterization and potential in vitro biological activities.Microbial cell factories · 2025Article
- A bioprocess optimization study to enhance the production of Menaquinone-7 using Bacillus subtilis MM26.Microbial cell factories · 2025Article
- Engineering a PhrC-RapC-SinR quorum sensing molecular switch for dynamic fine-tuning of menaquinone-7 synthesis in Bacillus subtilis.Microbial cell factories · 2025Article
- Adaptive laboratory evolution for improved tolerance of vitamin K in Bacillus subtilis.Applied microbiology and biotechnology · 2024Article
- Increasing Vitamin KJournal of agricultural and food chemistry · 2024Article
- Functional Identification and Regulatory Active Site Screening of thePlants (Basel, Switzerland) · 2024Article
- Dynamic and Static Regulation of Nicotinamide Adenine Dinucleotide Phosphate: Strategies, Challenges, and Future Directions in Metabolic Engineering.Molecules (Basel, Switzerland) · 2024Review
- Enhancing menaquinone-7 biosynthesis through strengthening precursor supply and product secretion.Bioprocess and biosystems engineering · 2024Article
- Advances in regulating vitamin KWorld journal of microbiology & biotechnology · 2023Review
- Protein engineering and iterative multimodule optimization for vitamin BNature communications · 2023Article
- Application of cofactors in the regulation of microbial metabolism: A state of the art review.Frontiers in microbiology · 2023Review
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9 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundMenaquinone-7 (MK-7), which is associated with complex and tightly regulated pathways and redox imbalances, is produced at low titres in Bacillus subtilis. Synthetic biology provides a rational engineering principle for the transcriptional optimisation of key enzymes and the artificial creation of cofactor regeneration systems without regulatory interference. This holds great promise for alleviating pathway bottlenecks and improving the efficiency of carbon and energy utilisation.
resultsWe used a bottom-up synthetic biology approach for the synthetic redesign of central carbon and to improve the adaptability between material and energy metabolism in MK-7 synthesis pathways. First, the rate-limiting enzymes, 1-deoxyxylulose-5-phosphate synthase (DXS), isopentenyl-diphosphate delta-isomerase (Fni), 1-deoxyxylulose-5-phosphate reductase (DXR), isochorismate synthase (MenF), and 3-deoxy-7-phosphoheptulonate synthase (AroA) in the MK-7 pathway were sequentially overexpressed. Promoter engineering and fusion tags were used to overexpress the key enzyme MenA, and the titre of MK-7 was 39.01 mg/L. Finally, after stoichiometric calculation and optimisation of the cofactor regeneration pathway, we constructed two NADPH regeneration systems, enhanced the endogenous cofactor regeneration pathway, and introduced a heterologous NADH kinase (Pos5P) to increase the availability of NADPH for MK-7 biosynthesis. The strain expressing pos5P was more efficient in converting NADH to NADPH and had excellent MK-7 synthesis ability. Following three Design-Build-Test-Learn cycles, the titre of MK-7 after flask fermentation reached 53.07 mg/L, which was 4.52 times that of B. subtilis 168. Additionally, the artificially constructed cofactor regeneration system reduced the amount of NADH-dependent by-product lactate in the fermentation broth by 9.15%. This resulted in decreased energy loss and improved carbon conversion.
conclusionsIn summary, a "high-efficiency, low-carbon, cofactor-recycling" MK-7 synthetic strain was constructed, and the strategy used in this study can be generally applied for constructing high-efficiency synthesis platforms for other terpenoids, laying the foundation for the large-scale production of high-value MK-7 as well as terpenoids.
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