Genomes and Genes
Peroxiredoxin 6 as an Anti-oxidant Enzyme
Principal Investigator: Aron B Fisher
Abstract: DESCRIPTION (provided by applicant): This project will evaluate the properties of a novel glutathione peroxidase enzyme that is considerably enriched in lungs and plays an important role in lung antioxidant defense and lung surfactant metabolism. This recently described protein called peroxiredoxin 6 (Prdx6 or 1-cys Peroxiredoxin) represents the only non-selenium glutathione peroxidase of relatively high specific activity. An important characteristic in the activity spectrum for this enzyme is its ability, unlike classical glutathione peroxidase, to reduce phospholipid hydroperoxides as, for example, peroxidation of membrane phospholipids during oxidant stress. During the past 4 years of support as a component project of a P-01 grant, we have demonstrated that Prdx6 plays a seminal role in defense of lungs against oxidant stress (hyperoxia, paraquat), that the promoter of the gene contains an antioxidant response element that is sensitive to the transcription factor Nrf2, and have developed a model based on lipid binding studies for the coordination of the peroxidase (Prx) and phospholipase (PLA2) activities of the protein. We are now seeking 5 years of support to extend these studies. Specific Aim 1 will utilize "knock-in" technology in the Prdx6 null cells to evaluate the respective contributions of the 2 activities (Prx, PLA2) to antioxidant protection. This aim will also directly compare the relative roles of Prdx6 and the other major glutathione peroxidase (GPx1) in antioxidant protection. Specific Aim 2 will study induction of Prdx6 by combined KGF and dexamethasone treatment, which our preliminary data indicate have a synergistic effect on Prdx6 expression. Specific Aim 3 will continue studies to evaluate structure-function characteristics of the protein with a special focus on phospholipid binding as a requirement for the phospholipid hydroperoxide peroxidase activity and the role of Prdx6 post-translational modifications. Specific Aim 4 will utilize cellular systems for analysis of the role of pGST in activation of Prdx6 activity. The proposed studies will provide a coordinated effort to investigate the role of this novel antioxidant enzyme in lung defense against oxidant stress and will provide new information concerning the biochemical regulation of its enzymatic activity. This information could lead to new approaches to increasing the ability of the lung to tolerate oxidant stress.
Funding Period: 2010-05-01 - 2015-04-30
more information: NIH RePORT
- Identification of the amino acid sequence that targets peroxiredoxin 6 to lysosome-like structures of lung epithelial cellsElena M Sorokina
Institute for Environmental Medicine, University of Pennsylvania, One John Morgan Bldg, 3620 Hamilton Walk, Philadelphia, PA 19104, USA
Am J Physiol Lung Cell Mol Physiol 297:L871-80. 2009..These studies indicate that the localization of Prdx6 in acidic organelles and consequent PLA2 activity depend on a novel 10-aa peptide located at positions 31-40 of the protein...
- Comparison of glutathione peroxidase 1 and peroxiredoxin 6 in protection against oxidative stress in the mouse lungGeng Liu
Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
Free Radic Biol Med 49:1172-81. 2010..Thus, Prdx6-null mice are significantly more sensitive to oxidant stress compared to GPx1 null, suggesting that scavenging of phospholipid hydroperoxides by Prdx6 plays a major role in lung antioxidant defense...
- Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A₂ activitiesAron B Fisher
Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
Antioxid Redox Signal 15:831-44. 2011....
- Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke–mediated lung inflammatory response and injuryIsaac K Sundar
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester, NY 14642, USA
Exp Lung Res 36:451-62. 2010....
- Increased phospholipase A2 activity with phosphorylation of peroxiredoxin 6 requires a conformational change in the proteinHamidur Rahaman
Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 6068, United States
Biochemistry 51:5521-30. 2012....
- Functional interaction of glutathione S-transferase pi and peroxiredoxin 6 in intact cellsSuiping Zhou
Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104 6068, United States
Int J Biochem Cell Biol 45:401-7. 2013..These data are consistent with the hypothesis that oxidation of the catalytic cysteine in Prdx6 is required for its interaction with πGST and that the interaction plays an important role in regenerating the peroxidase activity of Prdx6...
- Keratinocyte growth factor and glucocorticoid induction of human peroxiredoxin 6 gene expression occur by independent mechanisms that are synergisticIbrul Chowdhury
1 Institute for Environmental Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Antioxid Redox Signal 20:391-402. 2014..This study determined the mechanism by which keratinocyte growth factor (KGF) and the glucocorticoid analogue, dexamethasone (Dex), induce increased Prdx6 expression...
- DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITYSamuel Hawgood; Fiscal Year: 2013..abstract_text> ..
- DEGENERATIVE AND DEMENTING DISEASES OF AGINGStanley B Prusiner; Fiscal Year: 2013..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
- Role of Prdx6 in the activation of NADPH oxidaseAron B Fisher; Fiscal Year: 2013..A novel and non-toxic agent (MJ33) that inhibits the production of ROS by the pathway will be evaluated for its ability to prevent lung injury associated with ischemia and reperfusion. ..