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通过定量异源途径设计揭示代谢工程策略

Unveiling Metabolic Engineering Strategies by Quantitative Heterologous Pathway Design.

作者信息

Wei Fan, Cai Jingyi, Mao Yufeng, Wang Ruoyu, Li Haoran, Mao Zhitao, Liao Xiaoping, Li Aonan, Deng Xiaogui, Li Feiran, Yuan Qianqian, Ma Hongwu

机构信息

Biodesign Center, Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.

National Technology Innovation Center for Synthetic Biology, Tianjin, 300308, China.

出版信息

Adv Sci (Weinh). 2024 Dec;11(45):e2404632. doi: 10.1002/advs.202404632. Epub 2024 Oct 16.

DOI:10.1002/advs.202404632
PMID:39413026
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11615770/
Abstract

Constructing efficient cell factories requires the rational design of metabolic pathways, yet quantitatively predicting the potential pathway for breaking stoichiometric yield limit in hosts remains challenging. This leaves it uncertain whether the pathway yield of various products can be enhanced to surpass the stoichiometric yield limit and whether common strategies exist. Here, a high-quality cross-species metabolic network model (CSMN) and a quantitative heterologous pathway design algorithm (QHEPath) are developed to address this challenge. Through systematic calculations using CSMN and QHEPath, 12,000 biosynthetic scenarios are evaluated across 300 products and 4 substrates in 5 industrial organisms, revealing that over 70% of product pathway yields can be improved by introducing appropriate heterologous reactions. Thirteen engineering strategies, categorized as carbon-conserving and energy-conserving, are identified, with 5 strategies effective for over 100 products. A user-friendly web server is developed to quantitatively calculate and visualize the product yields and pathways, which successfully predicts biologically plausible strategies validated in literature for multiple products.

摘要

构建高效的细胞工厂需要合理设计代谢途径，但定量预测突破宿主化学计量产率限制的潜在途径仍然具有挑战性。这使得各种产品的途径产率能否提高以超过化学计量产率限制以及是否存在通用策略变得不确定。在此，开发了一种高质量的跨物种代谢网络模型（CSMN）和一种定量异源途径设计算法（QHEPath）来应对这一挑战。通过使用CSMN和QHEPath进行系统计算，对5种工业生物体中300种产品和4种底物的12000种生物合成场景进行了评估，结果表明，通过引入适当的异源反应，超过70%的产品途径产率可以提高。确定了13种工程策略，分为碳节约型和能量节约型，其中5种策略对100多种产品有效。开发了一个用户友好的网络服务器，用于定量计算和可视化产品产率和途径，该服务器成功预测了文献中针对多种产品验证的生物学上合理的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/523fb2c2d950/ADVS-11-2404632-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/830a3544cc41/ADVS-11-2404632-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/e13f53b6f277/ADVS-11-2404632-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/fbc6ed4129fb/ADVS-11-2404632-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/8efec25bb3bf/ADVS-11-2404632-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/0c1713837ae2/ADVS-11-2404632-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/523fb2c2d950/ADVS-11-2404632-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/830a3544cc41/ADVS-11-2404632-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/e13f53b6f277/ADVS-11-2404632-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/fbc6ed4129fb/ADVS-11-2404632-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/8efec25bb3bf/ADVS-11-2404632-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/0c1713837ae2/ADVS-11-2404632-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e737/11615770/523fb2c2d950/ADVS-11-2404632-g005.jpg

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本文引用的文献

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Production and secretion of recombinant spider silk in Bacillus megaterium.巨大芽孢杆菌中重组蜘蛛丝的生产与分泌
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Functional decomposition of metabolism allows a system-level quantification of fluxes and protein allocation towards specific metabolic functions.
代谢的功能分解允许对通量和蛋白质分配到特定代谢功能的系统水平进行定量。
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CAVE: a cloud-based platform for analysis and visualization of metabolic pathways.CAVE：一个基于云的代谢通路分析和可视化平台。
Nucleic Acids Res. 2023 Jul 5;51(W1):W70-W77. doi: 10.1093/nar/gkad360.
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Metabolic Engineering: Methodologies and Applications.代谢工程：方法与应用。
Chem Rev. 2023 May 10;123(9):5521-5570. doi: 10.1021/acs.chemrev.2c00403. Epub 2022 Dec 30.
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Designing Microbial Cell Factories for the Production of Chemicals.设计用于化学品生产的微生物细胞工厂。
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An interactive metabolic map of bio-based chemicals.基于生物的化学品交互式代谢图谱。
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Highly efficient biosynthesis of spermidine from L-homoserine and putrescine using an engineered Escherichia coli with NADPH self-sufficient system.利用具有 NADPH 自给自足系统的工程化大肠杆菌，从 L-高丝氨酸和腐胺高效生物合成亚精胺。
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