Peroxiredoxin 6 as an Anti-oxidant Enzyme

Summary

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

Top Publications

  1. pmc Identification of the amino acid sequence that targets peroxiredoxin 6 to lysosome-like structures of lung epithelial cells
    Elena 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
  2. pmc Comparison of glutathione peroxidase 1 and peroxiredoxin 6 in protection against oxidative stress in the mouse lung
    Geng Liu
    Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Free Radic Biol Med 49:1172-81. 2010
  3. pmc Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A₂ activities
    Aron B Fisher
    Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Antioxid Redox Signal 15:831-44. 2011
  4. pmc Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke–mediated lung inflammatory response and injury
    Isaac 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
  5. pmc Increased phospholipase A2 activity with phosphorylation of peroxiredoxin 6 requires a conformational change in the protein
    Hamidur Rahaman
    Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 6068, United States
    Biochemistry 51:5521-30. 2012
  6. pmc Functional interaction of glutathione S-transferase pi and peroxiredoxin 6 in intact cells
    Suiping 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
  7. pmc Keratinocyte growth factor and glucocorticoid induction of human peroxiredoxin 6 gene expression occur by independent mechanisms that are synergistic
    Ibrul Chowdhury
    1 Institute for Environmental Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Antioxid Redox Signal 20:391-402. 2014

Research Grants

  1. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
  2. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  3. Role of Prdx6 in the activation of NADPH oxidase
    Aron B Fisher; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc Identification of the amino acid sequence that targets peroxiredoxin 6 to lysosome-like structures of lung epithelial cells
    Elena 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...
  2. pmc Comparison of glutathione peroxidase 1 and peroxiredoxin 6 in protection against oxidative stress in the mouse lung
    Geng 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...
  3. pmc Peroxiredoxin 6: a bifunctional enzyme with glutathione peroxidase and phospholipase A₂ activities
    Aron B Fisher
    Institute for Environmental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
    Antioxid Redox Signal 15:831-44. 2011
    ....
  4. pmc Peroxiredoxin 6 differentially regulates acute and chronic cigarette smoke–mediated lung inflammatory response and injury
    Isaac 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
    ....
  5. pmc Increased phospholipase A2 activity with phosphorylation of peroxiredoxin 6 requires a conformational change in the protein
    Hamidur Rahaman
    Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104 6068, United States
    Biochemistry 51:5521-30. 2012
    ....
  6. pmc Functional interaction of glutathione S-transferase pi and peroxiredoxin 6 in intact cells
    Suiping 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...
  7. pmc Keratinocyte growth factor and glucocorticoid induction of human peroxiredoxin 6 gene expression occur by independent mechanisms that are synergistic
    Ibrul 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...

Research Grants30

  1. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  2. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley 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. ..
  3. Role of Prdx6 in the activation of NADPH oxidase
    Aron 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. ..