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首页> 外文期刊>Bioprocess and Biosystems Engineering >Enhancing the production of tacrolimus by engineering target genes identified in important primary and secondary metabolic pathways and feeding exogenous precursors
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Enhancing the production of tacrolimus by engineering target genes identified in important primary and secondary metabolic pathways and feeding exogenous precursors

机译：通过工程化在重要的一级和二级代谢途径中鉴定的靶标基因来增加他克莫司的生产并喂养外源性前体

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摘要

Tacrolimus has been widely used as a powerful novel immunosuppressant. The objective of this study was to improve the production of tacrolimus by engineering the target genes of important primary and secondary metabolic pathways and feeding exogenous precursors. Based on the metabonomics analysis, the shikimic acid pathway is an important primary metabolic pathway for the producing tacrolimus. Combined overexpression of shikimate kinase and dehydroquinic acid synthetase genes led to a 33.1% enhancement of tacrolimus production compared to parent strain. To predict the most efficient targets in secondary metabolic pathways for improving the production of tacrolimus, a genome-scale dynamic metabolic network model was used. A knockout of the d-lactate dehydrogenase gene, combined with the overexpression of tryptophane synthase and aspartate 1-decarboxylase genes, led to a 29.8% enhancement of tacrolimus production compared to the parent strain. Finally, we investigated the impact of the genetic manipulations on transcription levels, cell growth, cell morphology and production of tacrolimus by qRT-PCR and scanning electron microscopy to reveal the relationship between the growth of strains, the effects of engineering and fermentation. As the efficient synthesis of tacrolimus requires a rich supply of external substrates, the efficiency of the metabolic pathways that convert these substances is extremely important. The combined addition of three external substrates such as shikimic acid, alanine and the n-dodecane increased tacrolimus production by 49.5%. The insights obtained in this study will help further elucidate the mechanisms by which the identified target genes promote the activity of important primary and secondary metabolic pathways for tacrolimus biosynthesis and provide a new feeding strategy to improve tacrolimus production.
机译：他克莫司已被广泛用作功能强大的新型免疫抑制剂。这项研究的目的是通过工程化重要的一级和二级代谢途径的靶基因并喂养外源性前体来提高他克莫司的生产。基于代谢组学分析，the草酸途径是生产他克莫司的重要主要代谢途径。与亲本菌株相比，sh草酸激酶和脱氢奎尼酸合成酶基因的联合过表达导致他克莫司的产量提高了33.1％。为了预测次生代谢途径中最有效的靶点，以改善他克莫司的产生，使用了基因组规模的动态代谢网络模型。与亲本菌株相比，d-乳酸脱氢酶基因的敲除，加上色氨酸合酶和天冬氨酸1-脱羧酶基因的过表达，导致他克莫司的产量提高了29.8％。最后，我们通过qRT-PCR和扫描电子显微镜研究了遗传操作对他克莫司的转录水平，细胞生长，细胞形态和产量的影响，以揭示菌株生长，工程改造和发酵之间的关系。由于他克莫司的有效合成需要大量外部底物，因此转换这些物质的代谢途径的效率极为重要。三种外部底物（如sh草酸，丙氨酸和正十二烷）的共同添加使他克莫司的产量增加了49.5％。在这项研究中获得的见识将有助于进一步阐明所鉴定的靶基因促进他克莫司生物合成的重要的一级和二级代谢途径的活性的机制，并为提高他克莫司的生产提供新的喂养策略。

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  • 来源
    《Bioprocess and Biosystems Engineering》 |2019年第7期|1081-1098|共18页
  • 作者

    Li Yang; Liang Shaoxiong; Wang Junhua; Ma Dongxu; Wen Jianping;

  • 作者单位

    Tianjin Univ, Minist Educ, Key Lab Syst Bioengn, Tianjin 300072, Peoples R China|Collaborat Innovat Ctr Chem Sci & Engn Tianjin, SynBio Res Platform, Tianjin 300072, Peoples R China;

    Huaqiao Univ, Coll Lab Chem Engn, Xiamen 361021, Fujian, Peoples R China;

    Tianjin Univ, Minist Educ, Key Lab Syst Bioengn, Tianjin 300072, Peoples R China|Collaborat Innovat Ctr Chem Sci & Engn Tianjin, SynBio Res Platform, Tianjin 300072, Peoples R China;

    Tianjin Univ, Minist Educ, Key Lab Syst Bioengn, Tianjin 300072, Peoples R China|Collaborat Innovat Ctr Chem Sci & Engn Tianjin, SynBio Res Platform, Tianjin 300072, Peoples R China;

    Tianjin Univ, Minist Educ, Key Lab Syst Bioengn, Tianjin 300072, Peoples R China|Collaborat Innovat Ctr Chem Sci & Engn Tianjin, SynBio Res Platform, Tianjin 300072, Peoples R China;

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  • 正文语种 eng
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  • 关键词

    Tacrolimus; Primary and secondary metabolic pathways; Target genes; qRT-PCR; Scanning electron microscopy; Exogenous substances;

    机译：他克莫司;主要和次要代谢途径;靶基因;qRT-PCR;扫描电镜;外源物质;

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