Biological Sciences Division
Novel Indicators of Oxidative Stress in Disease
Proteomics study offers clues to how diseases such as Parkinson's progress
Results: Scientists from Pacific Northwest National Laboratory and the UCLA School of Medicine have produced the first proteome survey of tyrosine modifications in mouse brain and heart tissues. The research team studied two oxidative modifications of the amino acid tyrosine (3, 4- dihydroxyphenylalanine [DOPA] and Dopaquinone) to examine a possible link to human diseases including Parkinson's disease, atherosclerosis, myocardial disease, and cataracts.
DOPA is a sensitive biomarker of neurological and cardiovascular diseases, and site-specific information on these modifications may lay the groundwork for enhanced prevention and treatment. The detailed results of this study may help establish more sensitive biomarkers for disease pathologies; they also complement current biomarkers by helping distinguish inflammatory from non-inflammatory physiological states.
Why It Matters: More accurate disease biomarkers open the door to earlier detection, more effective prevention, and better treatment. Oxidative modifications of amino acids such as tyrosine are often very low in abundance within complex proteomes, making it difficult to confidently identify and track them. In addition, while elevated DOPA levels have been linked to disease, the specific proteins DOPA modifies have not been identified or studied. Recent advances in proteomics—including higher resolution mass spectrometry—have made it possible to overcome the hurdles.
Methods: Using the world-class proteomics capabilities, at the Department of Energy's EMSL and two PNNL-developed software programs, the scientists performed a global proteomics survey of DOPA/Dopaquinone modifications on protein tyrosines.
Two post-translational modifications mediated by hydroxyl radical on protein tyrosine residue serve as novel markers of oxidative stress.
The results offer underlying, site-specific clues to how diseases progress. Specifically, the study showed that DOPA/Dopaquinone modifications serve as novel mitochondrially derived oxidative stress markers, where they may disrupt mitochondrial respiration and alter signaling pathways in brain tissue. Mitochondria are the power plants of cells, generating adenosine triphosphate as a source of chemical energy.
In addition to providing a useful model of how to apply advances in proteomics to the study of disease biomarkers, the team identified 85 unique tyrosine sites with DOPA modifications-a dataset that will allow vital insights on how these modifications affect cellular components and signaling pathways.
Acknowledgments: This research was supported by the National Institute of Health and Pacific Northwest National Laboratory. Lead author is Xu Zhang and senior author is Wei-Jun Qian, both of PNNL. EMSL is a DOE Office of Biological and Envrionmental Science national scientific user facility located at PNNL.
Reference: Zhang X, ME Monroe, B Chen, MH Chin, TH Heibeck, AA Schepmoes, F Yang, BO Petritis, DG Camp, II, JG Pounds, JM Jacobs, DJ Smith, DJ Bigelow, RD Smith, and W Qian. 2010. "Endogenous 3, 4- Dihydroxyphenylalanine and Dopaquinone Modifications on Protein Tyrosine." Molecular & Cellular Proteomics 9(6):1199-1208. doi: 10.1074/mcp.M900321-MCP200