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Ammonium sulfate supplementation enhances erythromycin biosynthesis by augmenting intracellular metabolism and precursor supply in Saccharopolyspora erythraea

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Abstract

In this study, the cellular metabolic mechanisms regarding ammonium sulfate supplementation on erythromycin production were investigated by employing targeted metabolomics and metabolic flux analysis. The results suggested that the addition of ammonium sulfate stimulates erythromycin biosynthesis. Targeted metabolomics analysis uncovered that the addition of ammonium sulfate during the late stage of fermentation resulted in an augmented intracellular amino acid metabolism pool, guaranteeing an ample supply of precursors for organic acids and coenzyme A-related compounds. Therefore, adequate precursors facilitated cellular maintenance and erythromycin biosynthesis. Subsequently, an optimal supplementation rate of 0.02 g/L/h was determined. The results exhibited that erythromycin titer (1311.1 μg/mL) and specific production rate (0.008 mmol/gDCW/h) were 101.3% and 41.0% higher than those of the process without ammonium sulfate supplementation, respectively. Moreover, the erythromycin A component proportion increased from 83.2% to 99.5%. Metabolic flux analysis revealed increased metabolic fluxes with the supplementation of three ammonium sulfate rates.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was financially supported by the National Key Research and Development Program of China (Grant No. 2019YFA0904300), National Natural Science Foundation of China (Grant No. 32071461), and the National Key Research and Development Program of China (Grant No. 2018YFA0900300).

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  1. Yujie Yuan and Feng Xu have contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, People’s Republic of China

    Yujie Yuan, Feng Xu, **ang Ke, Ju Lu, Mingzhi Huang & Ju Chu

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  1. Yujie Yuan
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  3. **ang Ke
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Contributions

Conceptualization: [Mingzhi Huang, Ju Chu]; methodology: [Yujie Yuan, Feng Xu]; formal analysis and investigation: [Yujie Yuan, **ang Ke, Ju Lu, Feng Xu]; writing—original draft preparation: [Yujie Yuan, Feng Xu]; writing—review and editing: [Feng Xu, Mingzhi Huang, Ju Chu]; funding acquisition: [Mingzhi Huang, Ju Chu]; supervision: [Mingzhi Huang, Ju Chu].

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Correspondence to Mingzhi Huang or Ju Chu.

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Yuan, Y., Xu, F., Ke, X. et al. Ammonium sulfate supplementation enhances erythromycin biosynthesis by augmenting intracellular metabolism and precursor supply in Saccharopolyspora erythraea. Bioprocess Biosyst Eng 46, 1303–1318 (2023). https://doi.org/10.1007/s00449-023-02898-x

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