Cellular metabolism encompasses a complex array of interconnected biochemical pathways that are required for cellular homeostasis. When dysregulated, metabolism underlies multiple human pathologies. At the heart of metabolic networks are enzymes that have been historically studied through a reductionist lens, and more recently, using high throughput approaches including genomics and proteomics. Merging these two divergent viewpoints are chemical proteomic technologies, including activity-based protein profiling, which combines chemical probes specific to distinct enzyme families or amino acid residues with proteomic analysis. This enables the study of metabolism at the network level with the precision of powerful biochemical approaches. Herein, we provide a primer on how chemical proteomic technologies custom-built for studying metabolism have unearthed fundamental principles in metabolic control. In parallel, these technologies have leap-frogged drug discovery through identification of novel targets and drug specificity. Collectively, chemical proteomics technologies appear to do the impossible: uniting systematic analysis with a reductionist approach.

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研究新陈代谢的化学蛋白质组学，一种在系统水平上应用的还原论方法

细胞代谢包含细胞稳态所需的一系列复杂的相互关联的生化途径。当新陈代谢失调时，新陈代谢会成为多种人类病理的基础。代谢网络的核心是酶，历史上一直通过还原论的视角进行研究，最近又使用基因组学和蛋白质组学等高通量方法进行研究。化学蛋白质组学技术将这两种不同的观点融合在一起，包括基于活性的蛋白质分析，它将特定于不同酶家族或氨基酸残基的化学探针与蛋白质组学分析相结合。这使得能够利用强大的生化方法精确地在网络水平上研究新陈代谢。在此，我们提供了关于为研究代谢而定制的化学蛋白质组学技术如何揭示代谢控制的基本原理的入门读物。与此同时，这些技术通过识别新靶点和药物特异性，实现了跨越式的药物发现。总的来说，化学蛋白质组学技术似乎完成了不可能的任务：将系统分析与还原论方法结合起来。