Engineering Corynebacterium glutamicum towards high yield vitamin A production
改造谷氨酸棒杆菌以实现高产维生素 A 生产
基本信息
- 批准号:421479496
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Fellowships
- 财政年份:2019
- 资助国家:德国
- 起止时间:2018-12-31 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
In the human body, Vitamin A plays an essential role for growth and development, the maintenance of the immune system and good vision. It refers to a group of vitamers, most notably β-carotene, which can be converted into the bioactive form of the vitamin by organisms. Vitamin A deficiency (VAD) is a worldwide issue, especially in developing countries. The severe consequences of VAD (blindness, night blindness, death) are estimated to affect approximately one third of all children younger than five around the world. Industrial large-scale production is mainly (90%) realized by chemical synthesis, but the demand for naturally produced carotenoids is increasing. As microorganisms are capable of forming different carotenoids via the carotenogenesis, a microbial production process could represent a promising alternative for synthesizing vitamin A. In order to provide high amounts of β-carotene, it is essential to reduce production costs and achieve higher productivity. Microbial production hosts are naturally equipped with a complex metabolism, which is undesirable in the non-natural environment of a bioreactor, as it can negatively impact fermentation processes and lead to unsatisfactory yields. By systematic deletion of dispensable genes, microbial chassis-strains with reduced metabolic pathways can be generated, which still maintain the genetic stability and stress tolerance as the parental strain. These strains represent a promising basis for further engineering towards highly efficient production strains for industrial biotechnology. Only recently, the strain Corynebacterium glutamicum C1* was constructed by combinatorial deletions based on a library of reduced genomes. The C1* genome is reduced by 13.4% (412 deleted genes), but in the course of systematically reducing the genome some gene cluster deletions were found to be incompatible. For this reason, further chassis optimization requires alternative strategies. The proposed project focuses on the construction of a minimal genome of C. glutamicum by de novo synthesis of genomic regions containing essential genes. In parallel, β-carotene biosynthesis will be optimized in an already established production strain. Subsequently, this optimized synthesis pathway should be introduced into the C. glutamicum chassis strain, to first demonstrate the advantages of a minimal genome strain as synthesis organism and at the same time obtain an efficient production strain for the industrial production of vitamin A. Based on this β-carotene platform strain, further production strains for the synthesis of relevant carotenoids like lutein, zeaxanthin or astaxanthin can be developed.
在人体中,维生素A对生长和发育,维持免疫系统和良好的视力起着至关重要的作用。它是指一组维生素,最著名的是β-胡萝卜素,它可以被生物体转化为维生素的生物活性形式。维生素A缺乏症(VAD)是一个世界性的问题,特别是在发展中国家。VAD(失明、夜盲、死亡)的严重后果估计影响到全世界五岁以下儿童的大约三分之一。工业化大规模生产主要(90%)通过化学合成实现,但对天然产生的类胡萝卜素的需求正在增加。由于微生物能够通过类胡萝卜素生成形成不同的类胡萝卜素,因此微生物生产过程可能代表合成维生素A的有希望的替代方案。为了提供大量的β-胡萝卜素,降低生产成本并实现更高的生产率是至关重要的。微生物生产宿主天然具有复杂的代谢,这在生物反应器的非天然环境中是不期望的,因为它可能对发酵过程产生负面影响并导致不令人满意的产率。通过系统性地删除代谢酶基因,可以产生代谢途径减少的微生物底盘菌株,这些菌株仍然保持亲本菌株的遗传稳定性和胁迫耐受性。这些菌株代表了进一步工程改造为工业生物技术的高效生产菌株的有希望的基础。仅在最近,菌株谷氨酸棒杆菌C1* 通过基于简化基因组文库的组合缺失构建。C1* 基因组减少了13.4%(412个缺失基因),但在系统地减少基因组的过程中,发现一些基因簇缺失是不相容的。因此,进一步的底盘优化需要替代策略。该项目的重点是构建C.通过从头合成含有必需基因的基因组区域来合成谷氨酸杆菌。同时,β-胡萝卜素的生物合成将在已经建立的生产菌株中进行优化。随后,这一优化的合成途径应被引入到C。谷氨酸底盘菌株,以首次证明最小基因组菌株作为合成生物体的优点,同时获得用于工业生产维生素A的有效生产菌株。基于该β-胡萝卜素平台菌株,可以开发用于合成相关类胡萝卜素如叶黄素、玉米黄质或虾青素的进一步生产菌株。
项目成果
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