Selvarasu Suresh, Karimi Iftekhar A, Ghim Ghi-Hoon, Lee Dong-Yup
Department of Chemical and Biomolecular Engineering, National University of Singapore, Engineering Drive 4, Singapore.
Mol Biosyst. 2010 Jan;6(1):152-61. doi: 10.1039/b912865d. Epub 2009 Sep 2.
Genome-scale metabolic modeling has been successfully applied to a multitude of microbial systems, thus improving our understanding of their cellular metabolisms. Nevertheless, only a handful of works have been done for describing mammalian cells, particularly mouse, which is one of the important model organisms, providing various opportunities for both biomedical research and biotechnological applications. Presented herein is a genome-scale mouse metabolic model that was systematically reconstructed by improving and expanding the previous generic model based on integrated biochemical and genomic data of Mus musculus. The key features of the updated model include additional information on gene-protein-reaction association, and improved network connectivity through lipid, amino acid, carbohydrate and nucleotide biosynthetic pathways. After examining the model predictability both quantitatively and qualitatively using constraints-based flux analysis, the structural and functional characteristics of the mouse metabolism were investigated by evaluating network statistics/centrality, gene/metabolite essentiality and their correlation. The results revealed that overall mouse metabolic network is topologically dominated by highly connected and bridging metabolites, and functionally by lipid metabolism that most of essential genes and metabolites are from. The current in silico mouse model can be exploited for understanding and characterizing the cellular physiology, identifying potential cell engineering targets for the enhanced production of recombinant proteins and developing diseased state models for drug targeting.
基因组规模代谢建模已成功应用于众多微生物系统，从而增进了我们对其细胞代谢的理解。然而，针对哺乳动物细胞，特别是小鼠（作为重要的模式生物之一，为生物医学研究和生物技术应用提供了各种机会）的相关研究却寥寥无几。本文展示了一个基因组规模的小鼠代谢模型，该模型是在整合小家鼠生化和基因组数据的基础上，通过改进和扩展先前的通用模型系统重建而成。更新后模型的关键特征包括基因 - 蛋白质 - 反应关联的额外信息，以及通过脂质、氨基酸、碳水化合物和核苷酸生物合成途径改善的网络连通性。在使用基于约束的通量分析对模型预测性进行定量和定性检验后，通过评估网络统计/中心性、基因/代谢物必需性及其相关性，对小鼠代谢的结构和功能特征进行了研究。结果表明，总体而言，小鼠代谢网络在拓扑结构上由高度连接和起桥梁作用的代谢物主导，在功能上由脂质代谢主导，大多数必需基因和代谢物都来自脂质代谢。当前的计算机模拟小鼠模型可用于理解和表征细胞生理学、识别增强重组蛋白生产的潜在细胞工程靶点，以及开发用于药物靶向的疾病状态模型。
