Production of <i>myo</i>‐inositol: Recent advance and prospective

Li, Yunjie; Han, Pingping; Wang, Juan; Shi, Ting; You, Chun

doi:10.1002/bab.2181

Cited by 22 publications

(11 citation statements)

References 51 publications

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“…Microbial biosynthesis of inositol has been regarded as one of the most promising alternatives to the phytate hydrolysis method. Numerous studies have been reported for metabolic engineering of different strains for inositol production [ 35 ]. To date, E. coli is the most efficient host for inositol biosynthesis, and high inositol production and yield were achieved in this strain [ 14 , 18 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

et al. 2022

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Background The methylotrophic budding yeast Pichia pastoris GS115 is a powerful expression system and hundreds of heterologous proteins have been successfully expressed in this strain. Recently, P. pastoris has also been exploited as an attractive cell factory for the production of high-value biochemicals due to Generally Recognized as Safe (GRAS) status and high growth rate of this yeast strain. However, appropriate regulation of metabolic flux distribution between cell growth and product biosynthesis is still a cumbersome task for achieving efficient biochemical production. Results In this study, P. pastoris was exploited for high inositol production using an effective dynamic regulation strategy. Through enhancing native inositol biosynthesis pathway, knocking out inositol transporters, and slowing down carbon flux of glycolysis, an inositol-producing mutant was successfully developed and low inositol production of 0.71 g/L was obtained. The inositol production was further improved by 12.7% through introduction of heterologous inositol-3-phosphate synthase (IPS) and inositol monophosphatase (IMP) which catalyzed the rate-limiting steps for inositol biosynthesis. To control metabolic flux distribution between cell growth and inositol production, the promoters of glucose-6-phosphate dehydrogenase (ZWF), glucose-6-phosphate isomerase (PGI) and 6-phosphofructokinase (PFK1) genes were replaced with a glycerol inducible promoter. Consequently, the mutant strain could be switched from growth mode to production mode by supplementing glycerol and glucose sequentially, leading to an increase of about 4.9-fold in inositol formation. Ultimately, the dissolved oxygen condition in high-cell-density fermentation was optimized, resulting in a high production of 30.71 g/L inositol (~ 40-fold higher than the baseline strain). Conclusions The GRAS P. pastoris was engineered as an efficient inositol producer for the first time. Dynamic regulation of cell growth and inositol production was achieved via substrate-dependent modulation of glycolysis and pentose phosphate pathways and the highest inositol titer reported to date by a yeast cell factory was obtained. Results from this study provide valuable guidance for engineering of P. pastoris for the production of other high-value bioproducts.

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Section: Discussionmentioning

confidence: 99%

Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

et al. 2022

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“…Furthermore, inositol also finds application for the synthesis of inositol nitrate, found in explosives and solid rocket propellants, or glucaric acid, a biopolymer precursor [ 20 ]. This results in a world market of 15,000 tons per year and a global market of USD 60 million by 2020 [ 21 ]. It is mainly produced from phytate (inositol hexakisphosphate, IP6), the main phosphorous storage of plants.…”

Section: Industrially Relevant Enzyme Cascades For Api Synthesismentioning

confidence: 99%

“…It is mainly produced from phytate (inositol hexakisphosphate, IP6), the main phosphorous storage of plants. After its extraction, phytate is chemically dephosphorylated, which suffers from various drawbacks such as phosphorous waste, high production costs and difficult myo -inositol separation [ 21 ]. An alternative route is a cell-based production by metabolically engineered microorganisms such as Escherichia coli with a titer of 106.3 g L −1 (590.5 mM) and a yield of 0.82 mol mol −1 glucose in 23 h [ 51 ].…”

Section: Industrially Relevant Enzyme Cascades For Api Synthesismentioning

confidence: 99%

Industrially Relevant Enzyme Cascades for Drug Synthesis and Their Ecological Assessment

Siedentop

Rosenthal

2022

IJMS

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Environmentally friendly and sustainable processes for the production of active pharmaceutical ingredients (APIs) gain increasing attention. Biocatalytic synthesis routes with enzyme cascades support many stated green production principles, for example, the reduced need for solvents or the biodegradability of enzymes. Multi-enzyme reactions have even more advantages such as the shift of the equilibrium towards the product side, no intermediate isolation, and the synthesis of complex molecules in one reaction pot. Despite the intriguing benefits, only a few enzyme cascades have been applied in the pharmaceutical industry so far. However, several new enzyme cascades are currently being developed in research that could be of great importance to the pharmaceutical industry. Here, we present multi-enzymatic reactions for API synthesis that are close to an industrial application. Their performances are comparable or exceed their chemical counterparts. A few enzyme cascades that are still in development are also introduced in this review. Economic and ecological considerations are made for some example cascades to assess their environmental friendliness and applicability.

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“…Therefore, in the co-cultivation process of recombinant strains, it was obvious that the metabolic reactions of B. subtilis were drastically altered, including multiple pathways, while the biochemical process of E. coli was relatively simple. Furthermore, in the co-culture system, B. subtilis and E. coli needed to enhance stress tolerance to balance the cells to reduce damage in response to environmental stress, and changing the lipid composition of cell components to regulate membrane fluidity may be a For example, myo-inositol is a precursor substance of many compounds, a type of inositol derivative formed after lipid-dependent phosphorylation, which is both an important membrane structure and signal substance (Li et al 2021). In this study, the upregulation of myoinositol abundance in the co-culture system provides more precursors for lipid synthesis to achieve a cellular stress response.…”

Section: Metabolic Network Analysismentioning

confidence: 99%

A novel strategy for D-psicose and lipase co-production using a co-culture system of engineered Bacillus subtilis and Escherichia coli and bioprocess analysis using metabolomics

Luo

Wang

Chen

et al. 2021

Bioresour. Bioprocess.

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To develop an economically feasible fermentation process, this study designed a novel bioprocess based on the co-culture of engineered Bacillus subtilis and Escherichia coli for the co-production of extracellular D-psicose and intracellular lipase. After optimizing the co-culture bioprocess, 11.70 g/L of D-psicose along with 16.03 U/mg of lipase was obtained; the glucose and fructose were completely utilized. Hence, the conversion rate of D-psicose reached 69.54%. Compared with mono-culture, lipase activity increased by 58.24%, and D-psicose production increased by 7.08%. In addition, the co-culture bioprocess was explored through metabolomics analysis, which included 168 carboxylic acids and derivatives, 70 organooxygen compounds, 34 diazines, 32 pyridines and derivatives, 30 benzene and substituted derivatives, and other compounds. It also could be found that the relative abundance of differential metabolites in the co-culture system was significantly higher than that in the mono-culture system. Pathway analysis revealed that, tryptophan metabolism and β-alanine metabolism had the highest correlation and played an important role in the co-culture system; among them, tryptophan metabolism regulates protein synthesis and β-alanine metabolism, which is related to the formation of metabolic by-products. These results confirm that the co-cultivation of B. subtilis and E. coli can provide a novel idea for D-psicose and lipase biorefinery, and are beneficial for the discovery of valuable secondary metabolites such as turanose and morusin.

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Production of myo‐inositol: Recent advance and prospective

Cited by 22 publications

References 51 publications

Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

Metabolic engineering of Pichia pastoris for myo-inositol production by dynamic regulation of central metabolism

Industrially Relevant Enzyme Cascades for Drug Synthesis and Their Ecological Assessment

A novel strategy for D-psicose and lipase co-production using a co-culture system of engineered Bacillus subtilis and Escherichia coli and bioprocess analysis using metabolomics

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