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Metals in Redox Biology
Rotem Engelman Cristina Alvarez Bharathi Krishnan Shelbi Christgen
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.
Fenton Reaction: Fe2+ + H2O2 → Fe3+ + OH· + OH-
Cu+ + H2O2 → Cu2+ + OH· + OH-
How do mammalian cells import/export metals?
METAL ION UPTAKE by different metal transporters
- Divalent metal transporter (DMT1) - High affinity copper transporter (CTR1) - Ferritin - Hemosiderine
- Transferrin
METAL ION EXPORT: cell type specific proteins are required
- Ferroportin (FPN) - Iron Regulated Transporter (IREG 1) - Cu-transporting ATPase Secretory
- Metal Transport Protein (MTP)
Mobiliza=on from diet
Intes=nal absor=on
Transport and uptake at the organs
a.Storage b. Distribu=on c. Export
IRON METABOLISM
IRON METABOLISM IN THE ENTEROCYTE
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
How are import and export systems used to protect against stress?
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
Give an example of a metalloprotein that is involved in oxygen or redox sensing. Describe the mechanism of response
• 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
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
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
Oxidative Stress Alters Zn2+ Binding
Chim, N.; Johnson, P.; Goulding, C. (2014) Journal of Inorganic Biochemistry 133: 118-26
σL Target Genes
Dainese, E.; et. al. (2006) Infection and Immunity 74(4):2457
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