Metals in Redox Biology
Kadri Valter Jordan Frederick Morreall
Friederike Ewald Anjan Motamarry Michelle Palmer Jeremy Forsberg
Redox Course 20 May 2015
Which metals are the major contributors to hydroxyl radical forma;on in cells?
1. iron
2. copper
3. Chromium
4. Zinc
Valko M, et al. Free radicals, metals and anKoxidants in oxidaKve stress-‐induced cancer. Chem Biol Interact. 2006 Mar 10;160(1):1-‐40
2
What are the intracellular concentra;ons of these metals in mammals?
[Fe] = 0.2–0.5 μM1 [Cu] = 0.5-‐1.0 μM2
[Cr] = 0.03 μM3
[Zn] = 100 μM4 1Konijn AM, et al. The cellular labile iron pool and intracellular ferriKn in K562 cells. Blood. 1999 Sep 15;94(6):
2128-‐34. 2Kuivaniemi H, et al. Abnormal copper metabolism and deficient lysyl oxidase acKvity in a heritable connecKve
Kssue disorder. J Clin Invest. 1982 Mar;69(3):730-‐3. 3Minoia C & Cavalleri A. Chromium in urine, serum and red blood cells in the biological monitoring of workers
exposed to different chromium valency states. Sci Total Environ. 1988 Jun 1;71(3):323-‐7. 4Vallee, BL & Falchuk, KH. Physiol Rev. 1993. 73, 79-‐118.
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Possible reac;ons with metals
O2.-‐ + Mn+ → O2 + M(n-‐1)+
H2O2 + M(n-‐1)+ → OH. + OH-‐ + Mn+
Net: O2.-‐ + H2O2 → O2 + OH-‐ + OH.
4
Reac;ons which form hydroxyl radicals The Fenton ReacKon H2O2 + Fe2+ → OH. + OH-‐ + Fe3+ H2O2 + Cu+ → OH. + OH-‐ + Cu2+ H2O2 + Cr5+ → OH. + OH-‐ + Cr6+ The metal ion-‐catalyzed Haber-‐Weiss reacKon O2
.-‐ + Fe3+ → O2 + Fe2+ O2
.-‐ + Cu2+ → O2 + Cu+ The metal ion-‐catalyzed Haber-‐Weiss reacKon O2
.-‐ + H2O2 O2 + OH-‐ + OH.
M B Yim et al, Copper, zinc superoxide dismutase catalyzes hydroxyl radical producKon from hydrogen
peroxide. Proc Natl Acad Sci U S A. 1990 Jul; 87(13): 5006–5010 Si-‐xue Chen and Peter Schopfer, Hydroxyl-‐radical producKon in physiological reacKons. Eur. J. Biochem. 260,
726±735 (1999) 5
How mammalian cells import/export metals? Metal ion uptake ● Specific transport system mediates uptake of metal ions
o Divalent metal transporter (DMT1) o Transferin Receptor (TfR) o Copper transporter 1 (Ctr1)
Metal export ● Cell type specific proteins are required
o Cu-‐transporKng P-‐type ATPase (secretory compartment of plasma membrane)
o WND Cu transporKng ATPase (liver) o FerroporKn
Andrews NC, The iron transporter DMT1. Int J Biochem Cell Biol. 1999 Oct;31(10):991-‐4
R'zik S et al, ReKculocyte transferrin receptor (TfR) expression and contribuKon to soluble TfR levels. Haematologica. 2001 Mar;86(3):244-‐51
Yien-‐Ming Kuo et al, The copper transporter CTR1 provides an essenKal funcKon in mammalian embryonic development. PNAS vol. 98 no. 12, 6836–6841
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Iron transport in enterocytes
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Copper transport
Festa, R. A., & Thiele, D. J. (2011). Copper: an essenKal metal in biology. Current Biology, 21(21)
Mechanisms of iron import & export
Sukru Gulec et al. Am J Physiol Gastrointest Liver Physiol 2014;307:G397-G409
©2014 by American Physiological Society
Matthias W. Hentze , Martina U. Muckenthaler , Bruno Galy , Clara Camaschella; Two to Tango: Regulation of Mammalian Iron Metabolism; Cell, Volume 142, Issue 1, 2010, 24 – 38
Use of import/export systems of Iron in response to stress
Control and Func;on of Zn(II) Ion Increasing free [Zn2+] Zn2+ as a signal
MTF = metal-‐response element-‐binding TF 1
Maret W. 2013. Adv Nutr. hqp://advances.nutriKon.org/content/4/1/82.full
Metallothionein: a redox sensor
A) 4 Zn-‐clusters in the alpha subunit; B) 3 Zn-‐clusters in the beta-‐subunit of metallothionein
Maret W. 1997. PNAS. hqp://www.pnas.org/content/94/6/2233/F1.expansion.html DeMoor J, et al. 2001. Toxicol. Sci. hqp://toxsci.oxfordjournals.org/content/64/1/67.full
Sensing Mechanism
Oqaviani M. 2014. Flipper e Nuvola. hqp://flipper.diff.org/app/items/6366 Takahashi. 2012. J Hemat Oncol. hqp://www.jhoonline.org/content/5/1/41/figure/F1
MTs Protec;ve Role in Metal Toxicity
Pretreatment with ZnCl2 protects against intracellular stress. 24-‐h pretreatment with 100 μM ZnSO4 lessens toxic effects of MeHg exposure.
Aschner M. 1998. Brain Res. hqp://dx.doi.org/10.1016/S0006-‐8993(98)00947-‐0
Addi8onal References: Gaetke, L. M., & Chow, C. K. (2003). Copper toxicity, oxidaKve stress, and anKoxidant nutrients. Toxicology, 189(1), 147-‐163. Song, I. S., Chen, H. H., Aiba, I., Hossain, A., Liang, Z. D., Klomp, L. W., & Kuo, M. T. (2008). TranscripKon factor Sp1 plays an important role in the regulaKon of copper homeostasis in mammalian cells. Molecular pharmacology, 74(3), 705-‐713. Festa, R. A., & Thiele, D. J. (2011). Copper: an essenKal metal in biology. Current Biology, 21(21), R877-‐R883.
Ques;ons?
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