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  • Print publication year: 2007
  • Online publication date: October 2013

10 - Metal stress and the single yeast cell: Berkeley Award Lecture

from IV - Fungal bioremediation

Summary

Introduction

Overview

This paper explores the mechanisms of metal toxicity towards cells, specifically some advances being made in this area through work with the unicellular fungus, Saccharomyces cerevisiae. The two principal questions addressed here are:

Is oxidative damage the cause of cellular metal toxicity?

Why do individual cells exhibit widely differing metal resistances?

Several powerful experimental tools are unique to S. cerevisiae among eukaryotes, and are being exploited to help elucidate the mechanism(s) of metal toxicity. Furthermore, in conjunction with its unicellular morphology, S. cerevisiae provides an ideal system with which to explore the topical problem of cell individuality, applied here to metal toxicity. This chapter provides an overview of these fields, illustrated with key findings from the author's laboratory.

Metals in the environment and relevance to fungi

A wide range of industrial activities give rise to metal pollutants, which continue to be released into the environment at potentially harmful levels. Localized concentration of certain metals may also arise naturally. For example, toxic levels of the biologically essential metal copper are often associated with certain mineral ores as well as industrial or agricultural discharges. Cadmium is used widely in electroplating and galvanizing industries, as a colour pigment in paints and in batteries, and as a by-product of zinc and lead mining and smelting. Zinc, lead and other metals also may be released from similar types of sources.

References
Allen, J., Davey, H. M., Broadhurst, D., Heald, J. K., Rowland, J. J., Oliver, S. G. & Kell, D. B. (2003). High-throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nature Biotechnology, 21, 692–6.
Assmann, S., Sigler, K. & Hofer, M. (1996). Cd2 +-induced damage to yeast plasma membrane and its alleviation by Zn2 +: studies on Schizosaccharomyces pombe cells and reconstituted plasma membrane vesicles. Archives of Microbiology, 165, 279–84.
Avery, S. V. (1995). Caesium accumulation by microorganisms: uptake mechanisms, cation competition, compartmentalization and toxicity. Journal of Industrial Microbiology, 14, 76–84.
Avery, S. V. (2001). Metal toxicity in yeasts and the role of oxidative stress. Advances in Applied Microbiology, 49, 111–42.
Avery, S. V. (2005a). Cell individuality: the bistability of competence development. Trends in Microbiology, 13, 459–62.
Avery, S. V. (2005b). Phenotypic diversity and fungal fitness. The Mycologist, 19, 74–80.
Avery, S. V. & Tobin, J. M. (1993). Mechanism of adsorption of hard and soft metal ions to Saccharomyces cerevisiae and influence of hard and soft anions. Applied and Environmental Microbiology, 59, 2851–6.
Avery, A. M. & Avery, S. V. (2001). Saccharomyces cerevisiae expresses three phospholipid hydroperoxide glutathione peroxidases. Journal of Biological Chemistry, 276, 33730–5.
Avery, S. V., Howlett, N. G. & Radice, S. (1996). Copper toxicity towards Saccharomyces cerevisiae: dependence on plasma-membrane fatty acid composition. Applied and Environmental Microbiology, 62, 3960–6.
Avery, A. M., Willetts, S. A. & Avery, S. V. (2004). Genetic dissection of the phospholipid hydroperoxidase activity of yeast Gpx3 reveals its functional importance. Journal of Biological Chemistry, 279, 46652–8.
Baryla, A., Laborde, C., Montillet, J. L., Triantaphylides, C. & Chagvardieff, P. (2000). Evaluation of lipid peroxidation as a toxicity bioassay for plants exposed to copper. Environmental Pollution, 109, 131–5.
Basu, U., Southron, J. L., Stephens, J. L. & Taylor, G. J. (2004). Reverse genetic analysis of the glutathione metabolic pathway suggests a novel role of PHGPX and URE2 genes in aluminum resistance in Saccharomyces cerevisiae. Molecular Genetics and Genomics, 271, 627–37.
Beckman, K. B. & Ames, B. N. (1997). Oxidative decay of DNA. Journal of Biological Chemistry, 272, 19633–66.
Bergman, A. & Siegal, M. L. (2003). Evolutionary capacitance as a general feature of complex gene networks. Nature, 424, 549–52.
Blake, W. J., Kaern, M., Cantor, C. R. & Collins, J. J. (2003). Noise in eukaryotic gene expression. Nature, 10, 633–7.
Brennan, R. J. & Schiestl, R. H. (1996). Cadmium is an inducer of oxidative stress in yeast. Mutation Research – Fundamental Molecular Mechanisms of Mutagenesis, 356, 171–8.
Cabiscol, E., Piulats, E., Echave, P., Herrero, E. & Ros, J. (2000). Oxidative stress promotes specific protein damage in Saccharomyces cerevisiae. Journal of Biological Chemistry, 275, 27393–8.
Cakmak, I. (2000). Possible roles of zinc in protecting plant cells from damage by reactive oxygen species. New Phytologist, 146, 185–205.
Casalino, E., Sblano, C. & Landriscina, C. (1997). Enzyme activity alteration by cadmium administration to rats – the possibility of iron involvement in lipid peroxidation. Archives of Biochemistry and Biophysics, 346, 171–9.
Chen, C. Y., Su, Y. J., Wu, P. F. & Shyu, M. M. (2002). Nickel-induced plasma lipid peroxidation and effect of antioxidants in human blood: involvement of hydroxyl radical formation and depletion of alpha-tocopherol. Journal of Toxicology and Environmental Health, Part A, 65, 843–52.
Chiang, K. T., Shinyashiki, M., Switzer, C. H., Valentine, J. S., Gralla, E. B., Thiele, D. J. & Fukuto, J. M. (2000). Effects of nitric oxide on the copper-responsive transcription factor Ace1 in Saccharomyces cerevisiae: cytotoxic and cytoprotective actions of nitric oxide. Archives of Biochemistry and Biophysics, 377, 296–303.
Cooke, M. S., Evans, M. D., Dizdaroglu, M. & Lunec, J. (2003). Oxidative DNA damage: mechanisms, mutation, and disease. FASEB Journal, 17, 1195–214.
Costa, W. M. V., Amorim, M. A., Quintanilha, A. & Moradas-Ferreira, P. (2002). Hydrogen peroxide-induced carbonylation of key metabolic enzymes in Saccharomyces cerevisiae: the involvement of the oxidative stress response regulators Yap1 and Skn7. Free Radical Biology and Medicine, 33, 1507–15.
Culotta, V. C., Joh, H.-D., Lin, S.-J., Slekar, K. H. & Strain, J. (1995). A physiological role for Saccharomyces cerevisiae copper/zinc superoxide dismutase in copper buffering. Journal of Biological Chemistry, 270, 29991–7.
Davey, H. M. & Kell, D. B. (1996). Flow cytometry and cell sorting of heterogeneous microbial populations: the importance of single-cell analyses. Microbiological Reviews, 60, 641–96.
Deutschbauer, A. M., Jaramillo, D. F., Proctor, M., Kumm, J., Hillenmeyer, M. E., Davis, R. W., Nislow, C. & Giaever, G. (2005). Mechanisms of haploinsufficiency revealed by genome-wide profiling in yeast. Genetics, 169, 1915–25.
Delaunay, A., Pflieger, D., Barrault, M. B., Vinh, J. & Toledano, M. B. (2002). A thiol peroxidase is an H2O2 receptor and redox-transducer in gene activation. Cell, 111, 471–81.
Vos, C. H. R., Bookum, W. M. Y., Vooijs, R., Schat, H. & Kok, L. J. (1993). Effects of copper on fatty acid composition and peroxidation of lipids in the roots of copper tolerant and sensitive Silene cucabalus. Plant Physiology and Biochemistry, 31, 151–8.
Dix, T. A. & Aikens, J. (1993). Mechanisms and biological relevance of lipid peroxidation initiation. Chemical Research in Toxicology, 6, 2–18.
Drakulic, T., Temple, M. D., Guido, R., Jarolim, S., Breitenbach, M., Attfield, P. V. & Dawes, I. W. (2005). Involvement of oxidative stress response genes in redox homeostasis, the level of reactive oxygen species, and ageing in Saccharomyces cerevisiae. FEMS Yeast Research, 5, 1215–28.
Dunning, J. C., Ma, Y. & Marquis, R. E. (1998). Anaerobic killing of oral streptococci by reduced, transition metal cations. Applied and Environmental Microbiology, 64, 27–33.
Elowitz, M. B., Levine, A. J., Siggia, E. D. & Swain, P. S. (2002). Stochastic gene expression in a single cell. Science, 297, 1183–6.
Fortuniak, A., Zadzinski, R., Bilinski, T. & Bartosz, G. (1996). Glutathione depletion in the yeast Saccharomyces cerevisiae. Biochemistry and Molecular Biology International, 38, 901–10.
Fraser, H. B., Hirsh, A. E., Giaever, G., Kumm, J. & Eisen, M. B. (2004). Noise minimization in eukaryotic gene expression. PLOS Biology, 2, 834–8.
Gadd, G. M. (1993). Interactions of fungi with toxic metals. New Phytologist, 124, 25–60.
Gadd, G. M. (2000). Bioremedial potential of microbial mechanisms of metal mobilization and immobilization. Current Opinion in Biotechnology, 11, 271–9.
Gadd, G. M. & Mowll, J. L. (1983). The relationship between cadmium uptake, potassium release and viability in Saccharomyces cerevisiae. FEMS Microbiology Letters, 16, 45–8.
Galiazzo, F., Cirilio, M. R., Carri, M. T., Civitareale, P., Marcocci, L., Marmocchi, F. & Rotilio, G. (1991). Activation and induction by copper of Cu/Zn superoxide dismutase in Saccharomyces cerevisiae – presence of an inactive proenzyme in anaerobic yeast. European Journal of Biochemistry, 196, 545–9.
Gralla, E. B. (1997). Superoxide dismutase: studies in the yeast Saccharomyces cerevisiae. In Oxidative Stress and the Molecular Biology of Antioxidant Defenses, ed. Scandialos, J. G.. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, pp. 495–525.
Greco, M. A., Hrab, D. I., Magner, W. & Kosman, D. J. (1990). Cu, Zn superoxide-dismutase and copper deprivation and toxicity in Saccharomyces cerevisiae. Journal of Bacteriology, 172, 317–25.
Halliwell, B. & Gutteridge, J. M. C. (1990). Role of free radicals and catalytic metal ions in human disease: an overview. Methods in Enzymology, 186, 1–88.
Halliwell, B. & Gutteridge, J. M. C. (1999). Free Radicals in Biology and Medicine, 3rd edn. Oxford, UK: Oxford University Press.
Harris, Z. L. & Gitlin, J. D. (1996). Genetic and molecular basis for copper toxicity. American Journal of Clinical Nutrition, 63, S836–S841.
Hepburn, D. D. D., Burney, J. M., Woski, S. A. & Vincent, J. B. (2003). The nutritional supplement chromium picolinate generates oxidative DNA damage and peroxidized lipids in vivo. Polyhedron, 22, 455–63.
Hippeli, S. & Elstner, E. F. (1999). Transition metal ion-catalyzed oxygen activation during pathogenic processes. FEBS Letters, 443, 1–7.
Howlett, N. G. & Avery, S. V. (1997a). Induction of lipid peroxidation during heavy metal stress in Saccharomyces cerevisiae and influence of plasma membrane fatty acid unsaturation. Applied and Environmental Microbiology, 63, 2971–6.
Howlett, N. G. & Avery, S. V. (1997b). Relationship between cadmium sensitivity and degree of plasma membrane fatty acid unsaturation in Saccharomyces cerevisiae. Applied Microbiology and Biotechnology, 48, 539–45.
Howlett, N. G. & Avery, S. V. (1999). Flow cytometric investigation of heterogeneous copper sensitivity in asynchronously-grown Saccharomyces cerevisiae. FEMS Microbiology Letters, 176, 379–86.
Hughes, M. N. & Poole, R. K. (1991). Metal speciation and microbial growth – the hard (and soft) facts. Journal of General Microbiology, 137, 725–34.
Hughes, T. R., Marton, M. J., Jones, A. R., Roberts, C. J., Stoughton, R., Armour, C. D., Bennett, H. A., Coffey, E., Dai, H. Y., He, Y. D. D., Kidd, M. J., King, A. M., Meyer, M. R., Slade, D., Lum, P. Y., Stepaniants, S. B., Shoemaker, D. D., Gachotte, D., Chakraburtty, K., Simon, J., Bard, M. & Friend, S. H. (2000). Functional discovery via a compendium of expression profiles. Cell, 102, 109–26.
Inoue, Y., Matsuda, T., Sugiyama, K.-I., Izawa, S. & Kimura, A. (1999). Genetic analysis of glutathione peroxidase in oxidative stress response of Saccharomyces cerevisiae. Journal of Biological Chemistry, 274, 27002–9.
Jin, Y. H., Clark, A. B., Slebos, R. J. C., Al-Refai, H., Taylor, J. A., Kunkel, T. A., Resnick, M. A. & Gordenin, D. A. (2003). Cadmium is a mutagen that acts by inhibiting mismatch repair. Nature Genetics, 34, 326–9.
Jungmann, J., Reins, H. A., Schobert, C. & Jentsch, S. (1993). Resistance to cadmium mediated by ubiquitin-dependent proteolysis. Nature, 361, 369–71.
Kaern, M., Elston, T. C., Blake, W. J. & Collins, J. J. (2005). Stochasticity in gene expression: from theories to phenotypes. Nature Reviews Genetics, 6, 451–64.
Kale, S. P. & Jazwinski, S. M. (1996). Differential response to UV stress and DNA damage during the yeast replicative life span. Developmental Genetics, 18, 154–60.
Karlstrom, A. R. & Levine, R. L. (1991). Copper inhibits the protease from human immunodeficiency virus-1 by both cysteine-dependent and cysteine-independent mechanisms. Proceedings of the National Academy of Sciences of the USA, 88, 5552–6.
Kasprzak, K. S. (2002). Oxidative DNA and protein damage in metal-induced toxicity and carcinogenesis. Free Radical Biology and Medicine, 32, 958–67.
Kryukov, G. V., Kumar, R. A., Koc, A., Sun, Z. H. & Gladyshev, V. N. (2002). Selenoprotein R is a zinc-containing stereo-specific methionine sulfoxide reductase. Proceedings of the National Academy of Sciences of the USA, 99, 4245–50.
Larison, J. R., Likens, G. E., Fitzpatrick, J. W. & Crock, J. G. (2000). Cadmium toxicity among wildlife in the Colorado Rocky Mountains. Nature, 406, 181–3.
Lee, J. K., Kim, J. M., Kim, S. W., Nam, D. H., Yong, C. S. & Huh, K. (1996). Effect of copper-ion damage in superoxide dismutase-deficient Saccharomyces cerevisiae. Archives of Pharmaceutical Research, 19, 178–82.
Lehmann, M., Reidel, K., Adler, K. & Kunze, G. (2000). Amperometric measurement of copper ions with a deputy substrate using a novel Saccharomyces cerevisiae sensor. Biosensors and Bioelectronics, 15, 211–19.
Leonard, S. S., Bower, J. J. & Shi, X. L. (2004). Metal-induced toxicity, carcinogenesis, mechanisms and cellular responses. Molecular and Cellular Biochemistry, 255, 3–10.
Li, Z. S., Lu, Y. P., Zhen, R. G., Szczypka, M., Thiele, D. J. & Rea, P. A. (1997). A new pathway for vacuolar cadmium sequestration in Saccharomyces cerevisiae: YCF1-catalyzed transport of bis(glutathionato)cadmium. Proceedings of the National Academy of Sciences USA, 94, 42–7.
Lin, C.-M., Crawford, B. F. & Kosman, D. J. (1993). Distribution of Cu64 in Saccharomyces cerevisiae: cellular locale and metabolism. Journal of General Microbiology, 139, 1605–15.
Liochev, S. I. & Fridovich, I. (1999). Superoxide and iron: partners in crime. IUBMB Life, 48, 157–61.
Llanos, R. M. & Mercer, J. F. B. (2002). The molecular basis of copper homeostasis and copper-related disorders. DNA and Cell Biology, 21, 259–70.
Lloyd, D. R., Phillips, D. H. & Carmichael, P. L. (1997). Generation of putative intrastrand cross-links and strand breaks in DNA by transition metal ion-mediated oxygen radical attack. Chemical Research in Toxicology, 10, 393–400.
Lu, Y., Roe, J. A., Bender, C. J., Peisach, J., Banci, L., Bertini, I., Gralla, E. B. & Valentine, J. S. (1996). New type 2 copper-cysteinate proteins. Copper site histidine-to-cysteine mutants of yeast copper-zinc superoxide dismutase. Inorganic Chemistry, 35, 1692–700.
Lum, P. Y., Armour, C. D., Stepaniants, S. B., Cavet, G., Wolf, M. K., Butler, J. S., Hinshaw, J. C., Garnier, P., Prestwich, G. D., Leonardson, A., Garrett-Engele, P., Rush, C. M., Bard, M., Schimmack, G., Phillips, J. W., Roberts, C. J. & Shoemaker, D. D. (2004). Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes. Cell, 116, 121–37.
Malik, A. (2004). Metal bioremediation through growing cells. Environment International, 30, 261–78.
Mastrolorenzo, A., Scozzafava, A. & Supuran, C. T. (2000). Antifungal activity of silver and zinc complexes of sulfadrug derivatives incorporating arylsulfonylureido moieties. European Journal of Pharmaceutical Sciences, 11, 99–107.
Mukhopadhyay, R., Shi, J. & Rosen, B. P. (2000). Purification and characterization of Acr2p, the Saccharomyces cerevisiae arsenate reductase. Journal of Biological Chemistry, 275, 21149–57.
Murakami, K. & Yoshino, M. (1999). Dipicolinic acid as an antioxidant: protection of glutathione reductase from the inactivation by copper. Biomedical Research – Tokyo, 20, 321–6.
Naganuma, A., Miura, N., Kaneko, S., Mishina, T., Hosoya, S., Miyairi, S., Furuchi, T. & Kuge, S. (2000). GFAT as a target molecule of methylmercury toxicity in Saccharomyces cerevisiae. FASEB Journal, 14, 968–72.
Nicoletti, G., Domalewska, E. & Borland, R. (1999). Fungitoxicity of oxine and copper oxinate: activity spectrum, development of resistance and synergy. Mycological Research, 103, 1073–84.
Ohsumi, Y., Kitamoto, K. & Anraku, Y. (1988). Changes induced in the permeability barrier of the yeast plasma membrane by cupric ion. Journal of Bacteriology, 170, 2676–82.
Ozbudak, E. M., Thattai, M., Kurtser, I., Grossman, A. D. & Oudenaarden, A. (2002). Regulation of noise in the expression of a single gene. Nature Genetics, 31, 69–73.
Park, J. I., Grant, C. M., Davies, M. J. & Dawes, I. W. (1998). The cytoplasmic Cu, Zn superoxide dismutase of Saccharomyces cerevisiae is required for resistance to freeze-thaw stress. Generation of free radicals during freezing and thawing. Journal of Biological Chemistry, 273, 22921–8.
Pereira, M. D., Herdeiro, R. S., Fernandes, P. N., Eleutherio, E. C. & Panek, A. D. (2003). Targets of oxidative stress in yeast sod mutants. Biochimica et Biophysica Acta, 1620, 245–51.
Pourahmad, J. & O'Brien, P. J. (2000). A comparison of hepatocyte cytotoxic mechanisms for Cu2 + and Cd2 +. Toxicology, 143, 263–73.
Predki, P. F. & Sarkar, B. (1992). Effect of replacement of zinc finger zinc on estrogen-receptor DNA interactions. Journal of Biological Chemistry, 267, 5842–6.
Rae, T. D., Schmidt, P. J., Pufahl, R. A., Culotta, V. C. & O'Halloran, T. V. (1999). Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science, 284, 805–8.
Raser, J. M. & O'Shea, E. K. (2004). Control of stochasticity in eukaryotic gene expression. Science, 304, 1811–14.
Requena, J. R., Groth, D., Legname, G., Stadtman, E. R., Prusiner, S. B. & Levine, R. L. (2001). Copper-catalyzed oxidation of the recombinant SHa(29–231) prion protein. Proceedings of the National Academy of Sciences of the USA, 98, 7170–5.
Rotilio, G., Rossi, L., Demartino, A., Ferreira, A. M. D. S. & Ciriolo, M. R. (1995). Free-radicals, metal-ions and oxidative stress – chemical mechanisms of damage and protection in living systems. Journal of the Brazilian Chemical Society, 6, 221–7.
Rutherford, J. C. & Bird, A. J. (2004). Metal-responsive transcription factors that regulate iron, zinc, and copper homeostasis in eukaryotic cells. Eukaryotic Cell, 3, 1–13.
Sarkar, S., Poonam, Y. & Bhatnagar, D. (1997). Cadmium-induced lipid peroxidation and the antioxidant enzymes in rat tissues – role of vitamin E and selenium. Trace Elements and Electrolytes, 14, 41–5.
Shanmuganathan, A., Avery, S. V., Willetts, S. A. & Houghton, J. E. (2004). Copper-induced oxidative stress in Saccharomyces cerevisiae targets enzymes of the glycolytic pathway. FEBS Letters, 556, 253–9.
Shenton, D. & Grant, C. M. (2003). Protein S-thiolation targets glycolysis and protein synthesis in response to oxidative stress in the yeast Saccharomyces cerevisiae. Biochemical Journal, 374, 513–19.
Shringarpure, R., Grune, T. & Davies, K. J. A. (2001). Protein oxidation and 20S proteasome-dependent proteolysis in mammalian cells. Cellular and Molecular Life Sciences, 58, 1442–50.
Srinivasan, C., Liba, A., Imlay, J. A., Valentine, J. S. & Gralla, E. B. (2000). Yeast lacking superoxide dismutase(s) show elevated levels of ‘free iron’ as measured by whole cell electron paramagnetic resonance. Journal of Biological Chemistry, 275, 29187–92.
Stohs, S. J. & Bagchi, D. (1995). Oxidative mechanisms in the toxicity of metal ions. Free Radical Biology and Medicine, 18, 321–36.
Strain, J. & Culotta, V. C. (1996). Copper ions and the regulation of Saccharomyces cerevisiae metallothionein genes under aerobic and anaerobic conditions. Molecular and General Genetics, 251, 139–45.
Sumner, E. R. & Avery, S. V. (2002). Phenotypic heterogeneity: differential stress resistance among individual cells of the yeast Saccharomyces cerevisiae. Microbiology, 148, 345–51.
Sumner, E. R., Avery, A. M., Houghton, J. E., Robins, R. A. & Avery, S. V. (2003). Cell cycle- and age-dependent activation of Sod1p drives the formation of stress-resistant cell subpopulations within clonal yeast cultures. Molecular Microbiology, 50, 857–70.
Sumner, E. R., Shanmuganathan, A., Sideri, T. C., Willetts, S. A., Houghton, J. E. & Avery, S. V. (2005). Oxidative protein damage causes chromium toxicity in yeast. Microbiology, 151, 1939–48.
Szuster-Ciesielska, A., Stachura, A., Slotwinska, M., Kaminska, T., Sniezko, R., Paduch, R., Abramczyk, D., Filar, J. & Kandefer-Szerszen, M. (2000). The inhibitory effect of zinc on cadmium-induced cell apoptosis and reactive oxygen species (ROS) production in cell cultures. Toxicology, 145, 159–71.
Tamai, K. T., Gralla, E. B., Ellerby, L. M., Valentine, J. S. & Thiele, D. J. (1993). Yeast and mammalian metallothioneins functionally substitute for yeast copper-zinc superoxide dismutase. Proceedings of the National Academy of Sciences of the USA, 90, 8013–17.
Thattai, M. & Oudenaarden, A. (2004). Stochastic gene expression in fluctuating environments. Genetics, 167, 523–30.
Tolker-Nielsen, T., Holmstrom, K., Boe, L. & Molin, S. (1998). Non-genetic population heterogeneity studied by in situ polymerase chain reaction. Molecular Microbiology, 27, 1099–105.
Uetz, P., Giot, L., Cagney, G., Mansfield, T. A., Judson, R. S., Knight, J. R., Lockshon, D., Narayan, V., Srinivasan, M., Pochart, P., Qureshi-Emili, A., Li, Y., Godwin, B., Conover, D., Kalbfleisch, T., Vijayadamodar, G., Yang, M. J., Johnston, M., Fields, S. & Rothberg, J. M. (2000). A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature, 403, 623–7.
Ginkel, G. & Sevanian, A. (1994). Lipid peroxidation-induced membrane structural alterations. Methods in Enzymology, 233, 273–88.
Verma, N. & Singh, M. (2005). Biosensors for heavy metals. Biometals, 18, 121–9.
Viarengo, A., Burlando, B., Ceratto, N. & Panfoli, I. (2000). Antioxidant role of metallothioneins: A comparative review. Cellular and Molecular Biology, 46, 407–17.
Watabe, S., Hasegawa, H., Takimoto, K., Yamamoto, Y. & Takahashi, S. Y. (1995). Possible function of SP-22, a substrate of mitochondrial ATP-dependent protease, as radical scavenger. Biochemical and Biophysical Research Communications, 213, 1010–16.
Wei, J. P. J., Srinivasan, C., Han, H., Valentine, J. S. & Gralla, E. B. (2001). Evidence for a novel role of copper-zinc superoxide dismutase in zinc metabolism. Journal of Biological Chemistry, 276, 44798–803.
Wemmie, J. A., Szczypka, M. S., Thiele, D. J. & Moye-Rowley, W. S. (1994). Cadmium tolerance mediated by the yeast AP-1 protein requires the presence of an ATP-binding cassette transporter-encoding gene, YCF1. Journal of Biological Chemistry, 269, 32592–7.
White, C., Sharman, A. K. & Gadd, G. M. (1998). An integrated microbial process for the bioremediation of soil contaminated with toxic metals. Nature Biotechnology, 16, 572–5.
Winzeler, E. A.et al. (1999). Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science, 285, 901–6.