Improving riboflavin production by modifying related metabolic pathways in
            <i>Ba</i>
            <i>cillus subtilis</i>

Xu, Jingyu; Wang, C.; Ban, Rui

doi:10.1111/lam.13584

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…This result was consistent with Xu et al . 's (2022) study published in 2022, in which riboflavin production was enhanced by overexpressing ykgB . Notably, PRPP is also a precursor of riboflavin.…”

Section: Resultsmentioning

confidence: 99%

Metabolic engineering of Bacillus subtilis for high-level production of uridine from glucose

Wang

Ban

2022

Letters in Applied Microbiology

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As an intermediate in drug synthesis, uridine has practical applications in the pharmaceutical field. Bacillus subtilis is used as a host to boost uridine yield by manipulating its uridine biosynthesis pathway. In this study, we engineered a high‐uridine‐producing strain of B. subtilis by modifying its metabolic pathways in vivo. Overexpression of the aspartate ammonia‐lyase (ansB) gene increased the relative transcriptional level of ansB in B. subtilis TD320 by 13·18 times and improved uridine production to 15·13 g l−1 after 72‐h fermentation. Overexpression of the putative 6‐phosphogluconolactonase (ykgB) gene increased uridine production by the derivative strain TD325 to 15·43 g l−1. Reducing the translation of the amido phosphoribosyl transferase (purF) gene and inducing expression of the subtilisin E (aprE) gene resulted in a 1·99‐fold increase in uridine production after 24 h shaking. Finally, uridine production in the optimal strain B. subtilis TD335, which exhibited reduced urease expression, reached 17·9 g l−1 with a yield of 314 mg of uridine g−1 glucose. To our knowledge, this is the first study to obtain high‐yield uridine‐producing B. subtilis in a medium containing only three components (80 g l−1 glucose, 20 g l−1 yeast powder, and 20 g l−1 urea).

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Section: Resultsmentioning

confidence: 99%

Metabolic engineering of Bacillus subtilis for high-level production of uridine from glucose

Wang

Ban

2022

Letters in Applied Microbiology

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“…By reducing the metabolic flux in the pyrimidine pathway, Xu et al successfully increased riboflavin production to 7.01 g/L using 80 g/L of glucose, resulting in a yield of 0.089 g riboflavin/g glucose [46]. Zhang et al also enhanced riboflavin production and yield through in vitro and in vivo modifications of the PP pathway, raising the yield from 0.065 g riboflavin/g glucose to 0.084 g riboflavin/g gluconate [47].…”

Section: Discussionmentioning

confidence: 99%

De novo engineering riboflavin production Bacillus subtilis by overexpressing the downstream genes in the purine biosynthesis pathway

Liu,

Xia,

Fang

et al. 2024

Microb Cell Fact

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Background Bacillus subtilis is widely used in industrial-scale riboflavin production. Previous studies have shown that targeted mutagenesis of the ribulose 5-phosphate 3-epimerase in B. subtilis can significantly enhance riboflavin production. This modification also leads to an increase in purine intermediate concentrations in the medium. Interestingly, B. subtilis exhibits remarkable efficiency in purine nucleoside synthesis, often exceeding riboflavin yields. These observations highlight the importance of the conversion steps from inosine-5’-monophosphate (IMP) to 2,5-diamino-6-ribosylamino-4(3 H)-pyrimidinone-5’-phosphate (DARPP) in riboflavin production by B. subtilis. However, research elucidating the specific impact of these reactions on riboflavin production remains limited. Result We expressed the genes encoding enzymes involved in these reactions (guaB, guaA, gmk, ndk, ribA) using a synthetic operon. Introduction of the plasmid carrying this synthetic operon led to a 3.09-fold increase in riboflavin production compared to the control strain. Exclusion of gmk from the synthetic operon resulted in a 36% decrease in riboflavin production, which was further reduced when guaB and guaA were not co-expressed. By integrating the synthetic operon into the genome and employing additional engineering strategies, we achieved riboflavin production levels of 2702 mg/L. Medium optimization further increased production to 3477 mg/L, with a yield of 0.0869 g riboflavin per g of sucrose. Conclusion The conversion steps from IMP to DARPP play a critical role in riboflavin production by B. subtilis. Our overexpression strategies have demonstrated their effectiveness in overcoming these limiting factors and enhancing riboflavin production.

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“…Therefore, G. thermoglucosidasius DSM 2542 is emerging as an attractive platform for biofermentation. Other strategies, including deletion of the regulatory gene ccpN (gene encoding the lactic dehydrogenase) and certain genes involved in the purine metabolic network, 17,41 engineering of the riboswitches of pur and rib operons, 42 and the RBS regions of genes involved in riboflavin biosynthesis, 43 introducing mutations in the transcriptional regulators CcpN and YvrH, 44 and overexpression genes involved in the pentose-phosphate pathway including zwf, gnd, ykgB, and gntZ, 45 have also been successful in increasing the production of riboflavin. These approaches might be integrated with our GCR-DC strategy to further improve the capacity of this robust host, G. thermoglucosidasius DSM 2542, to utilize natural carbon sources for the production of riboflavin in future.…”

Section: ■ Discussionmentioning

confidence: 99%

Dynamic Control Strategy to Produce Riboflavin with Lignocellulose Hydrolysate in the Thermophile Geobacillus thermoglucosidasius

Wang

et al. 2022

ACS Synth. Biol.

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The e cient utilization of both glucose and xylose, the two most abundant sugars in biomass hydrolysates, is one of the main objectives of biofermentation with lignocellulosic materials. The utilization of xylose is commonly inhibited by glucose, which is known as glucose catabolite repression (GCR). Here we report a GCR-based dynamic control (GCR-DC) strategy aiming at a better co-utilization of glucose and xylose, by decoupling the cell growth and biosynthesis of ribo avin as a product. Using the thermophilic strain Geobacillus thermoglucosidasius DSM2542 as a host, we constructed extra ribo avin biosynthetic pathways that were activated by xylose but not glucose. The engineered strains showed a two-stage fermentation process. In the rst stage, glucose was preferentially used for cell growth and no production of ribo avin was observed, while in the second stage where glucose was nearly depleted, xylose was effectively utilized for ribo avin biosynthesis. Using the corn cob hydrolysate as a carbon source, the optimized ribo avin yields of strains DSM2542-DCall-MSS (full pathway dynamic control strategy) and DSM2542-DCrib (single module dynamic control strategy) were 5.26 and 2.26 folds higher than that of the control strain DSM2542 Rib-Gtg constitutively producing ribo avin, respectively. This GCR-DC strategy should also be applicable to the construction of cell factories that can e ciently use natural carbon sources with multiple sugar components for the production of high-value chemicals in future.

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Improving riboflavin production by modifying related metabolic pathways in Ba cillus subtilis

Cited by 6 publications

References 20 publications

Metabolic engineering of Bacillus subtilis for high-level production of uridine from glucose

Metabolic engineering of Bacillus subtilis for high-level production of uridine from glucose

De novo engineering riboflavin production Bacillus subtilis by overexpressing the downstream genes in the purine biosynthesis pathway

Dynamic Control Strategy to Produce Riboflavin with Lignocellulose Hydrolysate in the Thermophile Geobacillus thermoglucosidasius

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