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