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首页> 外文期刊>Biotechnology Progress >Production of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate using carbonyl reductase coupled with glucose dehydrogenase with high space-time yield
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Production of tert-butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate using carbonyl reductase coupled with glucose dehydrogenase with high space-time yield

机译：使用羰基还原酶与葡萄糖脱氢酶偶联的叔丁基（3R，5S）-6-氯-3,5-二羟基己酸酯的生产产生高空间产量

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摘要

tert-Butyl (3R,5S)-6-chloro-3,5-dihydroxyhexanoate ((3R,5S)-CDHH) is an important chiral intermediate for the synthesis of rosuvastatin. The biotechnological production of (3R,5S)-CDHH is catalyzed from tert-butyl (S)-6-chloro-5-hydroxy-3-oxohexanoate ((S)-CHOH) by a carbonyl reductase, and this synthetic pathway is becoming a primary route for (3R,5S)-CDHH production due to its high enantioselectivity, mild reaction conditions, low cost, process safety, and environmental friendship. However, the requirement of the pyridine nucleotide cofactors, reduced nicotinamide adenine dinucleotide (NADH) or reduced nicotinamide adenine dinucleotide phosphate (NADPH) limits its economic flexibility. In the present study, a recombinant Escherichia coli strain harboring carbonyl reductase R9M and glucose dehydrogenase (GDH) was constructed with high carbonyl reduction activity and cofactor regeneration efficiency. The recombinant E. coli cells were applied for the efficient production of (3R,5S)-CDHH with a substrate conversion of 98.8%, a yield of 95.6% and an enantiomeric excess (e.e.) of >99.0% under 350 g/L of (S)-CHOH after 12 hr reaction. A substrate fed-batch strategy was further employed to increase the substrate concentration to 400 g/L resulting in an enhanced product yield to 98.5% after 12 hr reaction in a 1 L bioreactor. Meanwhile, the space-time yield was 1,182.3 g L-1 day(-1), which was the highest value ever reported by a coupled system of carbonyl reductase and glucose dehydrogenase.
机译：叔丁基（3r，5s）-6-氯-3,5-二羟基己酸酯（（3R，5s）-cdhh）是合成罗苏伐他汀的重要手性中间体。通过羰基还原酶从叔丁基（S）-6-氯-5-羟基-3-氧己酸甲酯（（S）-CHOH）催化（3R，5S）-CHHH的生物技术生产，并且这种合成途径正在变成（3R，5S）-CDHH生产的主要途径由于其高对映射性，温和的反应条件，低成本，工艺安全和环境友谊。然而，吡啶核苷酸辅因子的要求，减少烟酰胺腺嘌呤二核苷酸（NADH）或降低的烟酰胺腺嘌呤二核苷酸磷酸酯（NADPH）限制了其经济柔性。在本研究中，用高羰基还原活性和辅因子再生效率构建含羰基还原酶R9M和葡萄糖脱氢酶（GDH）的重组大肠杆菌菌株。施用重组大肠杆菌细胞用于高效生产（3R，5S）-CHHH，底物转化为98.8％，产率为95.6％，对映体过量（EE）的产率为99.0％以下350克/升（S）-12小时后的核酸。进一步使用底物送入批次策略以将底物浓度增加到400g / l，得到1μl生物反应器中12小时反应后增强产量为98.5％。同时，时空产量为1,182.3g L-1天（-1），其是羰基还原酶和葡萄糖脱氢酶的偶联系统报告的最高值。

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  • 来源
    《Biotechnology Progress》 |2020年第1期|共7页
  • 作者

    Zhang Xiao-Jian; Zheng Ling; Wu Di; Zhou Rong; Liu Zhi-Qiang; Zheng Yu-Guo;

  • 作者单位

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

    Zhejiang Univ Technol Natl &

    Local Joint Engn Res Ctr Biomfg Chiral Che Hangzhou 310014 Zhejiang Peoples R China;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 生物科学;
  • 关键词

    carbonyl reductase; co-expression; glucose dehydrogenase; tert-butyl (3R; 5S)-6-chloro-3; 5-dihydroxyhexanoate;

    机译：羰基还原酶;共表达;葡萄糖脱氢酶;叔丁基（3r;5s）-6-氯-3;5-二羟基己酸酯;

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