A major goal of systems biology is to decipher cellular responses to genetic perturbations or environmental changes. Network integration of high-throughput data sets such as transcriptomics, proteomics, and metabolomics ("3-omics") offers a powerful tool for understanding the regulation and organization of cellular functions and biological processes. Given that the ATM (the product of the ataxia-telangiectasia mutated) gene exhibits multifaceted functions involved in complex biological networks, we attempted to analyze "3-omics" data sets by utilizing a functional pathway analysis approach. ATM-mediated gene and protein expression and metabolite products were interrogated using a model system comprised of cells genetically similar but demonstrating ATM deficiency (AT5BIVA) or ATM proficiency (ATCL8). Here, we report an unprecedented finding from the results of this integrated analysis revealing that ATM dictates purine, pyrimidine, and urea cycle pathways through the regulation of adenosine monophosphate (AMP) activated protein kinase (AMPK), a major sensor and regulator of cellular energy homeostasis. Furthermore, our results support the feasibility of applying a systems approach for identification of specific cellular networks and understanding of pathway perturbations underlying the complex A-T clinical syndrome.