Discovery metabolite profiling of the prolyl peptidases

摘要 阐明疾病背后的分子机制对于开发新的 治疗剂。研究人员最近开发了许多方法来识别这些基因， 蛋白质和与疾病相关的代谢物。然而，定义连接的补充方法 这些分子之间的联系是疾病生物学模型的基础，也是有针对性的 事实证明，药物的开发要困难得多。因此，仍然有巨大的需求 揭示体内疾病分子成分之间相互作用的创新方法。这个 以下提案概述了一种称为发现的方法的持续开发和应用 代谢物分析(DMP)，用于将内源底物分配给酪氨酸氨基转移酶 酵素。DMP集成了一系列生物和化学方法，包括遗传学、药理学和 分析化学，以确定真正的生理性酶-底物相互作用。重要的是，通过使用 DMP用于研究一种酶家族，这些酶实际上缺乏已知的内源底物，但可以调节 表型的巨大生物医学兴趣，这项研究将开始认识到令人难以置信的潜力 医学中的脯氨酸肽酶。此外，DMP在多肽酶中的应用将证明 这一方法对于未来医学相关酶和信号转导特性的一般性 小路。

Abstract Elucidation of the molecular mechanisms that underlie disease is crucial for the development of new therapeutic agents. Researchers have recently developed a number of methods to identify the genes, proteins, and metabolites associated with disease. However, complementary methods that define connections between these molecules¿connections that are the foundation of biological models of disease and targeted medicine¿have proven much more difficult to develop. As a result, there remains a tremendous need for innovative new approaches that reveal interactions between the molecular components of disease in vivo. The following proposal outlines the continued development and application of one such method, termed discovery metabolite profiling (DMP), for the assignment of endogenous substrates to the prolyl peptidase family of enzymes. DMP integrates an array of biological and chemical methods, including genetics, pharmacology, and analytical chemistry to identify bona fide physiological enzyme-substrate interactions. Importantly, by using DMP to study a family of enzymes that are virtually lacking in known endogenous substrates, but regulate phenotypes of tremendous biomedical interest, this research will begin to realize the incredible potential of the prolyl peptidases in medicine. Furthermore, the application of DMP to peptidases will demonstrate the generality of this approach for the future characterization of medically relevant enzymes and signaling pathways.