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<p>D-chiro-inositol (DCI) is a pharmacologically active inositol isomer with promising applications in treating insulin resistance and polycystic ovary syndrome (PCOS), yet efficient microbial synthesis remains a significant challenge. This study aimed to establish efficient de novo DCI biosynthesis from glucose by constructing and optimizing heterologous pathways and systematically remodeling the central carbon metabolic network of <i>Escherichia coli</i>. First, we evaluated three distinct biosynthetic pathways, identifying the alfalfa-derived enzymes OEPa and OEPb as the most effective. Introducing and optimizing these heterologous genes enabled de novo synthesis with a DCI titer of 1.18&#xa0;g/L. Subsequently, considering the diversion of the precursor G6P via the hexose monophosphate pathway (HMP), the competitive <i>zwf</i> node was finely downregulated. This strategy effectively reconciled the metabolic trade-off between cell growth and product synthesis, increasing the DCI titer by 31.36% to 1.55&#xa0;g/L. To further alleviate substrate uptake limitations, we synergistically reinforced transmembrane glucose transport and intracellular phosphorylation. This substantially enhanced the glucose uptake rate, further boosting the DCI titer by 14.84% to 1.78&#xa0;g/L. Ultimately, the engineered strain G21 demonstrated excellent performance in a 5 L bioreactor, achieving a DCI titer of 6.43&#xa0;g/L—the highest level reported in the literature to date—while co-producing 63.31&#xa0;g/L of <i>myo</i>-inositol (MI). These results not only demonstrate the construction of a highly competitive cell factory for DCI production but also lay a solid foundation for the efficient biomanufacturing of MI and its derivatives.</p>

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Reprogramming central carbon metabolism for the efficient de novo biosynthesis of D-chiro-inositol in Escherichia coli

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Kaiyang Zhao,
  • Yaokang Wu,
  • Xueqin Lv,
  • Jianghua Li,
  • Long Liu,
  • Guocheng Du,
  • Jian Chen,
  • Yanfeng Liu

摘要

D-chiro-inositol (DCI) is a pharmacologically active inositol isomer with promising applications in treating insulin resistance and polycystic ovary syndrome (PCOS), yet efficient microbial synthesis remains a significant challenge. This study aimed to establish efficient de novo DCI biosynthesis from glucose by constructing and optimizing heterologous pathways and systematically remodeling the central carbon metabolic network of Escherichia coli. First, we evaluated three distinct biosynthetic pathways, identifying the alfalfa-derived enzymes OEPa and OEPb as the most effective. Introducing and optimizing these heterologous genes enabled de novo synthesis with a DCI titer of 1.18 g/L. Subsequently, considering the diversion of the precursor G6P via the hexose monophosphate pathway (HMP), the competitive zwf node was finely downregulated. This strategy effectively reconciled the metabolic trade-off between cell growth and product synthesis, increasing the DCI titer by 31.36% to 1.55 g/L. To further alleviate substrate uptake limitations, we synergistically reinforced transmembrane glucose transport and intracellular phosphorylation. This substantially enhanced the glucose uptake rate, further boosting the DCI titer by 14.84% to 1.78 g/L. Ultimately, the engineered strain G21 demonstrated excellent performance in a 5 L bioreactor, achieving a DCI titer of 6.43 g/L—the highest level reported in the literature to date—while co-producing 63.31 g/L of myo-inositol (MI). These results not only demonstrate the construction of a highly competitive cell factory for DCI production but also lay a solid foundation for the efficient biomanufacturing of MI and its derivatives.