untargeted plasma metabolite profiling reveals the broad systemic consequences of xanthine oxidoreductase inactivation in mice没有针对性血浆代谢物分析揭示了广泛的系统性后果黄嘌呤氧化还原酶失活的老鼠.pdfVIP

Untargeted Plasma Metabolite Profiling Reveals the Broad Systemic Consequences of Xanthine Oxidoreductase Inactivation in Mice 1 2 2 2 3 Qiuying Chen , Hyeong-Cheon Park , Michael S. Goligorsky , Praveen Chander , Steven M. Fischer , Steven S. Gross1* 1 Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America, 2 Departments of Medicine, Pathology and Pharmacology, Renal Research Institute, New York Medical College, Valhalla, New York, United States of America, 3 Metabolomics Laboratory, Agilent Technologies, Santa Clara, California, United States of America Abstract A major challenge in systems biology is integration of molecular findings for individual enzyme activities into a cohesive high-level understanding of cellular metabolism and physiology/pathophysiology. However, meaningful prediction for how a perturbed enzyme activity will globally impact metabolism in a cell, tissue or intact organisms is precluded by multiple unknowns, including in vivo enzymatic rates, subcellular distribution and pathway interactions. To address this challenge, metabolomics offers the potential to simultaneously survey changes in thousands of structurally diverse metabolites within complex biological matrices. The present study assessed the capability of untargeted plasma metabolite profiling to discover systemic changes arising from inactivation of xanthine oxidoreductase (XOR), an enzyme that catalyzes the final steps in purine degradation. Using LC-MS coupled with a multivariate statistical data analysis platform, we confidently surveyed .3,700 plasma metabolites (50–1,000 Da) for differential expression in XOR wildtype vs. mice with inactivated XOR, aris