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<p>Microbial fermentation is one of the primary approaches for inosinic acid (IMP) production. However, most IMP-producing strains are non-model organisms, which limits the application of genetic engineering for further strain improvement. Additionally, these strains require expensive substrates as feedstock, increasing production costs. In this study, we engineered <i>Escherichia coli</i>, a well-characterized model microorganism, as the chassis for IMP biosynthesis from glucose by systematically optimizing its metabolic network. First, we reprogrammed the metabolic flux of the pentose phosphate pathway to increase the intracellular availability of phosphoribosyl pyrophosphate (PRPP), a key precursor of IMP, achieving an IMP titer of 484.6&#xa0;mg/L. Then, the alleviation of feedback inhibition in the purine biosynthetic pathway increased the IMP titer to 562.0&#xa0;mg/L. Furthermore, by identifying the rate-limiting steps in the purine synthesis pathway and knocking out competing pathways for IMP synthesis, we further increased the IMP titer to 1409.6&#xa0;mg/L. Finally, by enhancing the supply of cofactor N<sub>10</sub>-formyl-tetrahydrofolate, the titer of IMP reached 2.1&#xa0;g/L in shake-flasks and 3.1&#xa0;g/L in 5-L bioreactors. This study provides new insights for the construction of cell factories for the synthesis of nucleotide derivatives.</p>

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Metabolic engineering of Escherichia coli for biosynthesis of inosinic acid

  • 期刊论文

  • 发表日期：

    2025年8月18日

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  • Xiaoxi Li,
  • Wenwen Yu,
  • Baoyuan Guo,
  • Xutao Lang,
  • Xianhao Xu,
  • Yanfeng Liu,
  • Jianghua Li,
  • Guocheng Du,
  • Xueqin Lv,
  • Long Liu

摘要

Microbial fermentation is one of the primary approaches for inosinic acid (IMP) production. However, most IMP-producing strains are non-model organisms, which limits the application of genetic engineering for further strain improvement. Additionally, these strains require expensive substrates as feedstock, increasing production costs. In this study, we engineered Escherichia coli, a well-characterized model microorganism, as the chassis for IMP biosynthesis from glucose by systematically optimizing its metabolic network. First, we reprogrammed the metabolic flux of the pentose phosphate pathway to increase the intracellular availability of phosphoribosyl pyrophosphate (PRPP), a key precursor of IMP, achieving an IMP titer of 484.6 mg/L. Then, the alleviation of feedback inhibition in the purine biosynthetic pathway increased the IMP titer to 562.0 mg/L. Furthermore, by identifying the rate-limiting steps in the purine synthesis pathway and knocking out competing pathways for IMP synthesis, we further increased the IMP titer to 1409.6 mg/L. Finally, by enhancing the supply of cofactor N10-formyl-tetrahydrofolate, the titer of IMP reached 2.1 g/L in shake-flasks and 3.1 g/L in 5-L bioreactors. This study provides new insights for the construction of cell factories for the synthesis of nucleotide derivatives.