Metals in Redox Biology - University of...
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Metals in Redox Biology
Rotem Engelman Cristina Alvarez Bharathi Krishnan Shelbi Christgen
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Which metals are the major contributors to hydroxyl radical formation in cells? Show the reaction by which these metals catalyze the formation of hydroxyl radicals.
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Fenton Reaction: Fe2+ + H2O2 → Fe3+ + OH· + OH-
Cu+ + H2O2 → Cu2+ + OH· + OH-
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How do mammalian cells import/export metals?
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METAL ION UPTAKE by different metal transporters
- Divalent metal transporter (DMT1) - High affinity copper transporter (CTR1) - Ferritin - Hemosiderine
- Transferrin
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METAL ION EXPORT: cell type specific proteins are required
- Ferroportin (FPN) - Iron Regulated Transporter (IREG 1) - Cu-transporting ATPase Secretory
- Metal Transport Protein (MTP)
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Mobiliza=on from diet
Intes=nal absor=on
Transport and uptake at the organs
a.Storage b. Distribu=on c. Export
IRON METABOLISM
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IRON METABOLISM IN THE ENTEROCYTE
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COPPER METABOLISM
Func=on and Regula=on of Human Copper-‐Transpor=ng ATPases Svetlana Lutsenko , Natalie L. Barnes , Mee Y. Bartee , Oleg Y. Dmitriev Physiological ReviewsPublished 1 July
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How are import and export systems used to protect against stress?
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Regulation of cellular iron metabolism
Matthlas W.Hentze, Martina U. Mukenthaler, Bruno Galy Clara Camaschella (2010) Two to Tango: Regulation of Mammalian Iron Metabolism.Cell 142: 24-38
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Give an example of a metalloprotein that is involved in oxygen or redox sensing. Describe the mechanism of response
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• SigL: Extracytoplasmic FuncIon Sigma Factor – Vital for virulence of
M. tuberculosis
SigL/RslA Complex
Hahn, M., Raman, S.; Anaya, M.; Husson, R. (2005) Journal of Bacteriology 187(20): 7062-71
– Co-‐transcribed with anI-‐σ factor RsIA
Redox-‐sensi=ve metal binding complex
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SigL/RslA Complex
Hahn, M., Raman, S.; Anaya, M.; Husson, R. (2005) Journal of Bacteriology 187(20): 7062-71
• RslA: Transmembrane anI-‐sigma factor – Contains a zinc binding moIf
Redox-sensitive metal binding complex
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Oxidative Stress Alters Zn2+ Binding
• RslA binding of Zn2+ is dependent on redox state
• OxidaIve Stress triggers Zn2+ release
• Zn2+ release triggers a conformaIonal change that breaks complex
Thankur, K.; Praveena, T.; Gopal, B. (2010) Journal of Molecular Biology 397: 1199-208
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Oxidative Stress Alters Zn2+ Binding
Chim, N.; Johnson, P.; Goulding, C. (2014) Journal of Inorganic Biochemistry 133: 118-26
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σL Target Genes
Dainese, E.; et. al. (2006) Infection and Immunity 74(4):2457
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References • Stohs, S.J.; Bagchi, D. (1994) Oxidative Mechanisms in the Toxicity of Metal Ions Free
Radical Biology and Medicine 18(2): 321-36 • Khalil M, Teunissen C, Langkanner C, (2011) Iron and Neurodegeneration in Multiple
Sclerosis, Multiple Sclerosis International, doi:10.1155/2011/606807. • Matthlas W.Hentze, Martina U. Mukenthaler, Bruno Galy Clara Camaschella (2010) Two to Tango: Regulation of Mammalian Iron Metabolism.Cell 142: 24-38. • Chim, N.; Johnson, P.; Goulding, C. (2014) Insights into Redox Sensing Metalloproteins in
Mycobacterium tuberculosis Journal of Inorganic Biochemistry 133: 118-26 • Hahn, M., Raman, S.; Anaya, M.; Husson, R. (2005) The Mycobacterium tuberculosis
Extracytoplasmic-Function Sigma Factor SigL Regulates Polyketide Synthases and Secreted or Membrane Proteins and is Required for Virulence Journal of Bacteriology 187(20): 7062-71
• Dainese, E.; Rodrigue, S.; Delogu, G.; Provvedi, R.; Laflamme, L.; Brzezinski, R.; Fadda, G.; Smith, I.; Gaudreau, L.; Palu, G.; Manganelli, R. (2006) Posttranslational Regulation of Mycobacterium tuberculosis Extracytoplasmic-Function Sigma Factor σL and Roles in Virulence and in Global Regulation of Gene Expression Infection and Immunity 74(4):2457
• Thakur, K.; Praveena, T.; Gopal, B. (2010) Strctural and Biochemical Bases for the Redox Sensitivity of Mycobacterium tuberculosis RslA Journal of Molecular Biology 397: 1199-208