Metabolic Engineering of Yarrowia lipolytica for Enhanced De Novo Biosynthesis of Icaritin

IF 3.7 2区生物学 Q1 BIOCHEMICAL RESEARCH METHODS

ACS Synthetic Biology Pub Date : 2025-03-19 DOI:10.1021/acssynbio.4c0075410.1021/acssynbio.4c00754

Wen-Zhuo Sun, Xin Wang, Meng-Yu Fu, Le-Fan Liu, Ping Zhang, Bin-Cheng Yin, Wei-Bing Liu* and Bang-Ce Ye*,

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引用次数: 0

Abstract

Icaritin (ICT) is a naturally occurring flavonoid compound with notable anticancer properties, recently recognized for its efficacy in treating advanced hepatic carcinoma. Traditional methods of ICT production, including plant extraction and chemical synthesis, face challenges such as low yield and environmental concerns. This study leverages synthetic biology to construct a microbial cell factory using Yarrowia lipolytica for de novo ICT synthesis. We engineered the yeast by integrating the ICT synthesis pathway involving EsPT from Epimedium sagittatum and OsOMTm from Oryza sativa. By optimizing the metabolic pathways, including enhancing the supply of DMAPP via mevalonate pathway modifications, and fine-tuning the expression and catalytic efficiency of EsPT through truncation strategies, we significantly improved ICT yield to 247.02 mg/L─the highest microbial ICT titer reported to date. These findings lay a solid foundation for the large-scale industrial production of ICT and offer valuable insights into the biosynthesis of other flavonoid plant natural products.

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淫羊藿苷 (ICT) 是一种天然黄酮类化合物，具有显著的抗癌特性，最近因其治疗晚期肝癌的疗效而得到认可。传统的 ICT 生产方法，包括植物提取和化学合成，面临着产量低和环境问题等挑战。本研究利用合成生物学技术，构建了一个微生物细胞工厂，使用脂肪溶解酵母（Yarrowia lipolytica）从头合成 ICT。我们通过整合 Epimedium sagittatum 的 EsPT 和 Oryza sativa 的 OsOMTm 参与的 ICT 合成途径，设计了这种酵母。通过优化新陈代谢途径，包括通过甲羟戊酸途径的修饰来增加 DMAPP 的供应，以及通过截短策略来微调 EsPT 的表达和催化效率，我们将 ICT 产量显著提高到 247.02 mg/L--这是迄今为止报道的最高微生物 ICT 滴度。这些发现为大规模工业化生产 ICT 奠定了坚实的基础，并为其他黄酮类植物天然产物的生物合成提供了宝贵的见解。

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来源期刊

ACS Synthetic Biology 生物-

CiteScore

8.00

自引率

10.60%

发文量

380

审稿时长

6-12 weeks

期刊介绍： The journal is particularly interested in studies on the design and synthesis of new genetic circuits and gene products; computational methods in the design of systems; and integrative applied approaches to understanding disease and metabolism. Topics may include, but are not limited to: Design and optimization of genetic systems Genetic circuit design and their principles for their organization into programs Computational methods to aid the design of genetic systems Experimental methods to quantify genetic parts, circuits, and metabolic fluxes Genetic parts libraries: their creation, analysis, and ontological representation Protein engineering including computational design Metabolic engineering and cellular manufacturing, including biomass conversion Natural product access, engineering, and production Creative and innovative applications of cellular programming Medical applications, tissue engineering, and the programming of therapeutic cells Minimal cell design and construction Genomics and genome replacement strategies Viral engineering Automated and robotic assembly platforms for synthetic biology DNA synthesis methodologies Metagenomics and synthetic metagenomic analysis Bioinformatics applied to gene discovery, chemoinformatics, and pathway construction Gene optimization Methods for genome-scale measurements of transcription and metabolomics Systems biology and methods to integrate multiple data sources in vitro and cell-free synthetic biology and molecular programming Nucleic acid engineering.