基于图论和约束优化的异源代谢途径设计方法及应用  

Graph-based and constraint-based heterologous metabolic pathway design methods and application

作　　者：余文童 袁倩倩[2] 马红武[2] 王智文[1] YU Wentong;YUAN Qianqian;MA Hongwu;WANG Zhiwen(School of Chemical Engineering and Technology,Tianjin University,Tianjin 300350,China;Biodesign Center,Tianjin Institute of Industrial Biotechnology,Chinese Academy of Sciences,Tianjin 300308,China)

机构地区：[1]天津大学化工学院,天津300350 [2]中国科学院天津工业生物技术研究所生物设计中心,天津300308

出　　处：《生物工程学报》2022年第4期1390-1407,共18页Chinese Journal of Biotechnology

基　　金：国家重点研发计划项目(2018YFA0901400);国家自然科学基金(21908239)。

摘　　要：构建高产高附加值产品的微生物细胞工厂是代谢工程的研究目标之一,设计高效的产品合成途径是实现这一目标的重要方式。不同微生物底盘因其代谢能力有所差异,故而可以利用的底物和生产的产品范围有限。为了扩大其生产能力,需要进行代谢途径从无到有的设计。传统代谢工程基于经验进行异源途径设计的方式低效且无法确保结果的全面性,而系统生物学技术的蓬勃发展,为途径设计提供了新的方法。异源代谢途径设计方法主要包括基于图论的途径设计和基于约束优化的途径设计,这些方法利用包含丰富代谢反应信息的数据库,通过图论搜索策略或约束算法,计算出多条产品合成途径,进而筛选出最优途径指导菌株改造。本文将对途径设计所依赖的数据库、途径设计算法及其在代谢工程中的应用进行详细介绍,并讨论现有算法在实际应用中存在的不足和挑战,为研究者选择不同方法进行产品合成途径设计提供指导。It is among the goals in metabolic engineering to construct microbial cell factories producing high-yield and high value-added target products,and an important solution is to design efficient synthetic pathway for the target products.However,due to the difference in metabolic capacity among microbial chassises,the available substrate and the yielded products are limited.Therefore,it is urgent to design related metabolic pathways to improve the production capacity.Existing metabolic engineering approaches to designing heterologous pathways are mainly based on biological experience,which are inefficient.Moreover,the yielded results are in no way comprehensive.However,systems biology provides new methods for heterologous pathway design,particularly the graph-based and constraint-based methods.Based on the databases containing rich metabolism information,they search for and uncover possible metabolic pathways with designated strategy(graph-based method)or algorithm(constraint-based method)and then screen out the optimal pathway to guide the modification of strains.In this paper,we reviewed the databases and algorithms for pathway design,and the applications in metabolic engineering and discussed the strengths and weaknesses of existing algorithms in practical application,hoping to provide a reference for the selection of optimal methods for the design of product synthesis pathway.

关 键 词：途径设计 代谢网络 代谢工程 图论方法 约束方法 

分 类 号：Q78[生物学—分子生物学]