PDF(Pubmed)
Abstract：
Nicotinamide adenine dinucleotide (NAD) levels are essential for the normal physiology of the cell and are strictly regulated to prevent pathological conditions. NAD functions as a coenzyme in redox reactions, as a substrate of regulatory proteins, and as a mediator of protein-protein interactions. The main objectives of this study were to identify the NAD-binding and NAD-interacting proteins, and to uncover novel proteins and functions that could be regulated by this metabolite. It was considered if cancer-associated proteins were potential therapeutic targets. Using multiple experimental databases, we defined datasets of proteins that directly interact with NAD - the NAD-binding proteins (NADBPs) dataset - and of proteins that interact with NADBPs - the NAD-protein-protein interactions (NAD-PPIs) dataset. Pathway enrichment analysis revealed that NADBPs participate in several metabolic pathways, while NAD-PPIs are mostly involved in signalling pathways. These include disease-related pathways, namely, three major neurodegenerative disorders: Alzheimer\'s disease, Huntington\'s disease, and Parkinson\'s disease. Then, the complete human proteome was further analysed to select potential NADBPs. TRPC3 and isoforms of diacylglycerol (DAG) kinases, which are involved in calcium signalling, were identified as new NADBPs. Potential therapeutic targets that interact with NAD were identified, that have regulatory and signalling functions in cancer and neurodegenerative diseases.
摘要：
烟酰胺腺嘌呤二核苷酸（NAD）水平对于细胞的正常生理至关重要，并受到严格的调节以预防病理状况。NAD在氧化还原反应中充当辅酶，作为调节蛋白的底物，作为蛋白质-蛋白质相互作用的媒介。这项研究的主要目的是鉴定NAD结合和NAD相互作用蛋白，并发现可以被这种代谢物调节的新蛋白质和功能。认为癌症相关蛋白是否是潜在的治疗靶标。使用多个实验数据库，我们定义了与NAD直接相互作用的蛋白质的数据集-NAD结合蛋白（NADBPs）数据集-以及与NADBPs相互作用的蛋白质-NAD-蛋白质相互作用（NAD-PPIs）数据集。通路富集分析表明，NADBP参与了几种代谢通路，而NAD-PPIs主要参与信号通路。这些包括疾病相关途径，即,三大神经退行性疾病：阿尔茨海默病，亨廷顿病,和帕金森病。然后，进一步分析完整的人类蛋白质组以选择潜在的NADBP。TRPC3和二酰基甘油（DAG）激酶的同工型，参与钙信号传导，被鉴定为新的NADBP。确定了与NAD相互作用的潜在治疗靶点，在癌症和神经退行性疾病中具有调节和信号功能。
