School of Food and Health, Beijing Technology and Business University, Bejing, China.
Department of Engineering Science, University of Oxford, Oxford, United Kingdom.
PLoS Comput Biol. 2023 Aug 24;19(8):e1011391. doi: 10.1371/journal.pcbi.1011391. eCollection 2023 Aug.
In microorganisms, different from primary metabolism for cellular growth, secondary metabolism is for ecological interactions and stress responses and an important source of natural products widely used in various areas such as pharmaceutics and food additives. With advancements of sequencing technologies and bioinformatics tools, a large number of biosynthetic gene clusters of secondary metabolites have been discovered from microbial genomes. However, due to challenges from the difficulty of genome-scale pathway reconstruction and the limitation of conventional flux balance analysis (FBA) on secondary metabolism, the quantitative modeling of secondary metabolism is poorly established, in contrast to that of primary metabolism. This review first discusses current efforts on the reconstruction of secondary metabolic pathways in genome-scale metabolic models (GSMMs), as well as related FBA-based modeling techniques. Additionally, potential extensions of FBA are suggested to improve the prediction accuracy of secondary metabolite production. As this review posits, biosynthetic pathway reconstruction for various secondary metabolites will become automated and a modeling framework capturing secondary metabolism onset will enhance the predictive power. Expectedly, an improved FBA-based modeling workflow will facilitate quantitative study of secondary metabolism and in silico design of engineering strategies for natural product production.
在微生物中，与细胞生长的初级代谢不同，次级代谢是为了生态相互作用和应激反应，是广泛应用于制药和食品添加剂等各个领域的天然产物的重要来源。随着测序技术和生物信息学工具的进步，已经从微生物基因组中发现了大量的次级代谢生物合成基因簇。然而，由于基因组规模途径重建的困难以及传统通量平衡分析（FBA）对次级代谢的限制，与初级代谢相比，次级代谢的定量建模还没有很好地建立起来。
本综述首先讨论了在基因组规模代谢模型（GSMM）中重建次级代谢途径的最新进展，以及相关的基于 FBA 的建模技术。此外，还提出了 FBA 的潜在扩展，以提高次生代谢产物生产的预测准确性。正如本综述所指出的，各种次生代谢物的生物合成途径的重建将实现自动化，并且捕捉次生代谢起始的建模框架将提高预测能力。预计，改进的基于 FBA 的建模工作流程将有助于对次级代谢进行定量研究，并进行天然产物生产的工程策略的计算机设计。
