Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery.
Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery.
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DOI：
10.1016/j.drudis.2013.07.014
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发表时间：
2014-02
影响因子：
7.4
通讯作者：
Goodacre, Royston
中科院分区：
文献类型：
--
作者：
Kell, Douglas B.;Goodacre, Royston
我们现在有代谢网络模型;代谢组由它们的节点表示。代谢物水平对酶活性的变化敏感。药物通过代谢物转运体进入和离开细胞。共识网络Recon 2代表了目前的技术水平，并具有预测能力。基于约束的建模将网络结构与代谢通量联系起来。代谢代表了系统生物学的“尖端”，因为代谢物浓度的变化相对于转录组、蛋白质组和酶活性的变化必然会被放大，而这些变化可以通过药物来调节。为了理解这种行为，我们需要（并且越来越多地拥有）可靠的人类代谢网络共识（社区）模型，其中包括重要的转运蛋白。小分子“药物”转运蛋白实际上是代谢物转运蛋白，因为药物与从网络重建和代谢物组测量中已知的代谢物具有结构相似性。Recon 2代表了目前最先进的人类代谢网络重建;它可以预测：（i）先天性代谢缺陷的影响;（ii）哪些代谢物是外代谢的，以及（iii）代谢如何在组织和细胞区室之间变化。然而，即使是这些定性的网络模型还不完整。随着我们的理解的提高，我们更清楚地认识到需要一个系统（多）药理学。
We now have metabolic network models; the metabolome is represented by their nodes. Metabolite levels are sensitive to changes in enzyme activities. Drugs hitchhike on metabolite transporters to get into and out of cells. The consensus network Recon2 represents the present state of the art, and has predictive power. Constraint-based modelling relates network structure to metabolic fluxes. Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology.
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影响因子：
7.4
作者：
Auray-Blais, Christiane;Boutin, Michel;Clarke, Joe T. R.
通讯作者：
Clarke, Joe T. R.
DOI：
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发表时间：
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