Transition Metals, Metalloenzymes, and Oxidative Stress

Copper-Zinc Superoxide Dismutase and Lou Gehrig’s Disease: Copper-containing proteins play important roles in organisms ranging from bacteria and yeast to plants and animals. Our objectives in this area are to understand the properties and biological functions of wild type copper-zinc superoxide dismutases (CuZnSOD) and to understand why mutant human CuZnSOD proteins cause familial amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease). Approximately 70 different single mutations in human CuZnSOD have individually been linked to an inherited form of ALS. Human ALS mutant CuZnSODs have been prepared in our laboratory and have been found to have lost several of the properties characteristic of wild type CuZnSOD other than its SOD activity. These properties are highly likely to be essential to CuZnSOD in performing its normal biological functions. Moreover, the loss of these properties in the ALS mutant enzymes will likely prove to be linked to the gain of the new toxic property that is involved in the mechanism of causation of the disease. Preparation and characterization of these human mutant ALS CuZnSOD proteins for the purpose of identifying their disease-causing properties is a major objective of this project.

Yeast Studies of Oxidative Stress and Antioxidants: Life in air is possible because uncatalyzed reactions of dioxygen in living organisms are usually slow. In addition, oxidative damage to components of healthy cells is frequently prevented or repaired by antioxidant, replacement, or repair systems that exist in the cells for the purpose of maintaining and restoring redox balance. Our approach in this area is to study the roles of superoxide, hydrogen peroxide, metal ions, and small molecule antioxidants in bakers yeast S. cerevisiae. Extensive genetics and molecular biology exist for this simple eukaryoles and the entire genome is sequenced. Many genes from higher organisms have been shown to substitute functionally for their yeast analogs, and more are expected. When grown on a non-fermentable carbon source, yeast cells metabolize dioxygen in a fashion similar to human cells, and the cellular systems for prevention, repair, and replacement of oxidatively damaged cell components are also similar. Yeast is thus an excellent system in which to study how redox balance is maintained in healthy eucaryotic cells. These studies are expected to lead to a better understanding of redox balance in eucaryotic organisms and the role of "oxidative stress" in processes leading to human aging, cell death, and disease.

207. How do ALS-associated mutations in Superoxide Dismutase 1 promote aggregation of the protein? Shaw, B. F.; Valentine, J. S. Trends in Biochem. Sci., 2007, 32(2), 78-85.

206. Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials. Ferri, A., Cozzolino, M., Crosio, C., Nencini, M., Casciati, A., Gralla, E.B., Rotilli, G., Valentine, J.S., Carri, M.T. Proc. Natl. Acad. Sci., 2006, 103 (37), 13860-13865.

205. Local unfolding in a destabilized, Pathogenic Variant of Superoxide Dismuase 1 observed with H/D exchange and mass spectrometry. Shaw, B.F., Durazo, A., Nersissian, A.M., Whitelegge, J.P., Faull, K.F. J. Biol. Chem., 2006, 286 (26) 18167-18176.

204. Superoxide dismutase 1 modulates expression of transferrin receptor. Danzeisen, R., Achsel, T.; Bederke, U., Cozzolino, M., Crosio, C., Ferri, A., Frenzel,M., Gralla, E.B., Huber, L., Ludolph, A., Nencini, M., Rotilio, G., Valentine, J.S., Carri, M.T. J. Bio. Chem., 2006, 11(4), 489-498.

203. Variable Metallation of Human Superoxide Dismutase: Atomic Resolution Crystal Structures of Cu-Zn, Zn-Zn and as-isolated Wild-type Enzymes. Strange, R.W., Antonyuk, S.V., Hough, M.A., Doucette, P.A., Valentine, J.S., Hasnain, S.S.. J. Mol. Biol., 2006, 356(5), 1152-1162.

202. Metal-deficient copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis: Pathogenic SOD1 oligomerization through non-native protein-protein interactions. Hart, P. J, Valentine, J.S. ACS Symposium Series, 2005, No. 903 (Medicinal Inorganic Chemistry), 348-365.

201. Fully Metallated S134N Cu,Zn-Superoxide Dismutase Displays Abnormal Mobility and Intermolecular Contacts in Solution. Banci, L., Bertini, I., D'Amelio, N.; Gaggelli, E., Libralesso, E., Matecko, I., Turano, P., Valentine, J.S. J. Biol. Chem., 2005, 280(43), 35815-35821.

200. Exogenous manganous ion at millimolar levels rescues all known dioxygen-sensitive phenotypes of yeast lacking CuZnSOD. Sanchez, R. J., Srinivasan, C., Munroe, W. H., Wallace, M. A., Martins, J., Kao, T. Y., Le, K.; Gralla, E. B., Valentine, J. S. J. Biol. Chem., 2005, 10(8), 913-923.

199. Copper-Zinc Superoxide Dismutase and Amyotrophic Lateral Sclerosis. Valentine, J. S., Doucette, P. A., Potter, S. Z. Ann. Rev. Biochem., 2005, 74, 563-93.

198. Induction of Phenotypes Resembling CuZn-Superoxide Dismutase Deletion in Wild-Type Yeast Cells: An in vivo Assay for Role of Superoxide in the Toxicity of Redox-Cycling Compounds. Wallace, M. A., Bailey, S., Fukuto, J. M., Valentine, J.S., Gralla, E.B. Chem. Res. Toxicology, 2005, 18, 1279-1286.

197. Destabilization of Apoprotein is Insufficient to Explain Cu,Zn-Superoxide Dismutase-linked ALS Pathogenesis. Rodriguez, J.A., Shaw, B. F., Durazo, A., Sohn, S. H., Doucette, P. A., Nersissian, A.M., Faull, K. F., Eggers, D.K., Tiwari, A., Hayward, L.J., Valentine J.S. Proc. Natl. Acad. Sci., 2005, 102, 10516-10521.

196. Structural Consequences of the Familial Amyotrophic Lateral Sclerosis SOD1 Mutant His46Arg. Antonyuk, S, Elam, J. S., Hough, M. A., Strange, R. W., Doucette, P. A., Rodriguez, J. A., Hayward, L.J., Valentine, J. S., Hart, P. J., Hasnain, S. S., Prot. Sci., 2005, 14, 1201-1213.

195. Dissociation of Human Copper-Zinc Superoxide Dismutase Dimers Using Chaotrope and Reductant: Insights Into the Molecular Basis for Diner Stability. Doucette, P. A.; Whitson, L. J.; Cao, X.; Schirf, V.; Demeler, B.; Valentine, J. S.; Hansen, J. C.; Hart, P. J., J. Biol. Chem., 2004, 279, 54558-54566.

194. Local Nanomechanical Motion of the Cell Wall of Saccharomyces cerevisiae. Pelling, A. E.; Sehati, S.; Gralla, E. B.; Valentine, J. S.; Gimzewski, J. K. Science, 2004, 305, 1147-1150.

193. Superoxide Inhibits 4Fe-4S Cluster Enzymes Involved in Amino Acid Biosynthesis: Cross-Compartment Protection by CuZn-Superoxide Dismutase. Wallace, M. A.; Liou, L.-L.; Martins, J.; Clement, M. H. S.; Bailey, S.; Longo, V. D.; Valentine, J. S.; Gralla, E. B., J. Biol. Chem. 2004, 279, 32055-32062.

192. Mutations in Saccharomyces cerevisiae Iron Sulfur Cluster Assembly Genes and Oxidative Stress Relevant to Cu/Zn Superoxide Dismutase. Jensen, L. T., Sanchez, R. J., Srinivasan, C., Valentine, J. S., and Culotta, V. C. J. Biol. Chem. 2004, 279, 29938-29943.

191. Dimer Destabilization in Superoxide Dismutase May Result in Disease-Causing Properties: Structures of Motor Neuron Disease Mutants. Hough, M. A.; Grossman, J. G.; Antonyuk, S. V.; Strange, R. W.; Doucette, P. A.; Rodriguez, J. A.; Whitson, L. J.; Hart, P. J.; Hayward, L.J.; Valentine, J.S.; Hasnain, S.S. Proc. Natl. Acad. Sci. USA, 2004, 101, 5976-5981.

190. Mechanisms for Activating Cu- and Zn-Containing Superoxide Dismutase in the Absence of the CCS Cu Chaperone. Carroll, M. C.; Girouard, J. B.; Ulloa, J. L.; Subramaniam, J. R.; Wong, P. C.; Valentine, J. S.; Culotta, V.C. Proc. Natl. Acad. Sci. USA, 2004, 101, 5964-5969.

189. SOD2 Functions Downstream of Sch9 to Extend Longevity in Yeast. Fabrizio, Paola; Liou, Lee-Loung; Moy, V. N.; Diaspro, A.; Valentine, J. S.; Gralla, E. B.; Longo, V. D. Genetics, 2003, 163, 35-46.

188. Dynamic Properties of the G93A Mutant of Copper-Zinc Superoxide Dismutase as Detected by NMR Spectroscopy: Implications for the Pathology of Familial Amyotrophic Lateral Sclerosis. Shipp, E. L.; Cantini, F.; Bertini, I.; Valentine, J. S.; Banci, L. Biochemistry, 2003, 42, 1890-1899.

187. An Alternative Mechanism of Bicarbonate-Mediated Peroxidation by Copper-Zinc Superoxide Dismutase: Rates Enhanced via Proposed Enzyme-Associated Peroxicarbonate Intermediate. Elam, J. S.; Malek, K.; Rodriguez, J. A.; Doucette, P. A.; Taylor, A. B.; Hayward, L. J.; Cabelli, D. E.; Valentine, J. S.; Hart, P. John. J. Biol. Chem., 2003, 278, 21032-21039.

186. Spectroscopic Investigation of Stellacyanin Mutants: Axial Ligand Interactions at the Blue Copper Site. DeBeer George, S.; Basumallick, L.; Szilagyi, R. K.; Randall, D. W.; Hill, Michael G.; Nersissian, A. M.; Valentine, J. S.; Hedman, B.; Hodgson, K. O.; Solomon, E. I., J. Am. Chem. Soc., 2003, 125, 11314-11328.

185. Manganese. Valentine, J. S. Chem & Engr News, 2003, 81, 76.

184. Amyloid-Like Filaments and Water-Filled Nanotubes Formed by SOD1 Mutant Proteins Linked to Familial ALS. Elam, J. S.; Taylor, A. B.; Strange, R.; Antonyuk, S.; Doucette, P. A.; Rodriguez, J. A.; Hasnain, S. S.; Hayward, L. J.; Valentine, J. S.; Yeates, T. O.; Hart, P. J. Nat. Struct. Biol., 2003, 10, 461-467.

183. The Structure of Holo and Metal-Deficient Wild-Type Human Cu, Zn Superoxide Dismutase and its Relevance to Familial Amyotrophic Lateral Sclerosis. Strange, R. W.; Antonyuk, S.; Hough, M. A.; Doucette, P. A.; Rodriguez, J. A.; Hart, P. J.; Hayward, L. J.; Valentine, J. S.; Hasnain, S. S.. J. Mol. Biol. 2003, 328, 877-891.

182. The Perplexing Role of Copper-Zinc Superoxide Dismutase in Amyotrophic Lateral Sclerosis (Lou Gehrig's disease). Potter, S. Z.; Valentine, J. S., J. Biol. Inorg. Chem., 2003, 8, 373-380.

181. Misfolded CuZnSOD and Amyotrophic Lateral Sclerosis. Valentine, J.S. , Hart, P.J. Proc. Natl. Acad. Sci. U.S.A., 2003, 100, 3617-3622.

BOOKS

Biological Inorganic Chemistry: Structure and Reactivity, Bertini, I., Gray, H.B., Stiefel, E.I. and Valentine, J.S., eds., University Science Books, Sausalito, CA 2006.

Advances in Protein Chemistry: Copper Containing Molecules (Advances in Protein Chemistry), Valentine, J.S. and Gralla, E. B., eds., Elsevier Science, USA, 2002.

Active Oxygen in Biochemistry. Valentine, J. S.; Foote, C. S.; Greenberg, A.; Liebman, J. F., eds., Blackie Academic & Professional, Chapman & Hall, Glasgow, 1995.

Active Oxygen in Chemistry. Foote, C. S.; Valentine, J. S.; Greenberg, A.; Liebman, J. F., eds., Blackie Academic & Professional, Chapman & Hall, Glasgow, 1995.

Bioinorganic Chemistry (textbook). Bertini, I.; Gray, H. B.; Lippard, S. J.; Valentine, J. S. University Science Books, Mill Valley, California, 1994.

Complete List of Publications

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