Metabolite Sensing and Regulation of Protein Function

代谢物感觉与蛋白质功能的调节 在人类基因组测序后，生物医学研究中最重要的挑战之一是 了解基因表达如何随着各种信号和压力的变化而变化。换句话说， 了解细胞信号转导机制对于理解生命过程至关重要。这项建议 重点研究哺乳动物细胞如何感知某些代谢物，并利用这些信息来调节蛋白质功能。 常见的细胞代谢物，如辅酶A、谷胱甘肽和烟酰胺腺嘌呤二核苷酸，发挥作用 在各种代谢途径中发挥重要作用。许多蛋白质翻译后修饰也使用这些 代谢物。因此，维持这些代谢物的浓度至关重要。细胞和生物体 必须能够感觉到这些代谢物，并使用这些信息来调节生物过程。然而， 人们对这些代谢物的感知机制知之甚少。在这个Mira应用程序中，我将重点放在 利用化学生物学技术鉴定哺乳动物细胞如何感知共同代谢物进行调节 蛋白质的功能。初步结果表明，这是一个非常有趣和令人兴奋的领域，值得 更多的调查。这对我的实验室来说是一个全新的研究方向，与我以前的 以及HHMI支持的研究。这项拟议的研究将确定许多新的蛋白质调节机制。 通过小分子代谢物发挥作用。这将反过来提供对细胞信号的更好的理解和 应对后基因组时代生物医学科学中最重要的挑战之一。这些监管规定 机制也可以直接影响治疗学的发展，因为它们将有助于发展变构 蛋白质的抑制剂或激活剂。

Metabolite Sensing and Regulation of Protein Function After the human genome is sequenced, one of the most important challenges in biomedical research is to understand how gene expression changes in response to various signals and stresses. In other words, understanding cell signaling mechanisms is of critical importance to understand life processes. This proposal focuses on how mammalian cells sense certain metabolites and use that information to regulate protein function. Common cellular metabolites, such as co-enzyme A, glutathione, and nicotinamide adenine dinucleotides, play important roles in various metabolic pathways. Many protein post-translational modifications also use these metabolites. Maintaining the concentrations of these metabolites is thus critically important. Cells and organisms must be able to sense these metabolites and use the information to regulate biological processes. However, very little is known about the sensing mechanisms for these metabolites. In this MIRA application, I will focus on using chemical biology techniques to identify how mammalian cells sense common metabolites to regulate protein function. Preliminary results indicate that this is a highly interesting and exciting area that warrant much more investigation. This a completely new research direction for my laboratory and is distinct from my previous and HHMI-supported research. The proposed research will identify many novel regulatory mechanisms of protein function by small molecule metabolites. This will in turn provide a better understanding of cell signaling and address one of the most important challenges in biomedical sciences in the postgenomic era. These regulatory mechanisms can also directly impact the development of therapeutics as they will help to develop allosteric inhibitors or activators of proteins.