Reactive oxygen species (ROS) are continuously generated in aerobic organisms as byproducts of metabolism. In man, damage from ROS has been associated with various disorders including cancer and aging. To protect against oxygen related toxicity, eukaryotes contain a mitochondrial superoxide dismutase (Sod2) enzyme that guards against respiratory ROS, and also a cytosolic Sod 1. However, the precise role of Sod 1 is unclear and also quite controversial. The hypothesis of this research is that Sod 1 protects against non-mitochondrial metabolic sources of ROS and that this enzyme functions broadly to maintain the reduced environment of the cell. The goals of this research have been to utilize the simple eukaryote, S. cerevisiae (bakers yeast) to understand the impact of Sod1 on cell metabolism. In the past funding period, a number of genes were identified that have the capacity to substitute for Sod1 (""""""""suppressors of Sod1 deficiency""""""""), and these were found to function in the metabolism of either transition metals, or the cellular reductant, NADPH. Through the following specific aims, the goals are now to understand how Sod1 and the suppressors of Sod1 deficiency affect metabolically produced ROS and also to identify targets and sources of oxygen toxicity relevant to Sod1.
Aim I : To understand how sod1 mutations and the suppressors of Sod 1 deficiency affect the homeostasis of ROS in vivo. Chemiluminescence and EPR techniques will be used to identify the radical species that predominate in sod1 mutants and to understand how the suppressors of Sod1 deficiency affect the profile of radicals generated during aerobic metabolism.
Aim II : To identify the molecular targets of metabolic oxidative damage in sod1 mutants: Cells lacking Sod1 are defective in lysine and methionine biosynthesis and the corresponding molecular target(s) of oxidative damage will now be explored through biochemical and molecular genetic approaches.
Aim III : To identify the metabolic sources of ROS responsible for oxidative damage: To delineate key origins of endogenous oxygen toxicity, known generators of ROS in the cytosol, peroxisome and microsomes will be systematically ablated through gene deletion studies. Secondly, two genetic selection procedures will be used to identify gene mutations that reduce metabolic oxidative stress. Overall, these studies promise to provide new information regarding the natural role of Sod1 in cell metabolism, and the findings obtained with yeast should be readily extrapolated to more complex organisms, including man.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Chemical Pathology Study Section (CPA)
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Johns Hopkins University
Public Health & Prev Medicine
Schools of Public Health
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Robinett, Natalie G; Peterson, Ryan L; Culotta, Valeria C (2018) Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains. J Biol Chem 293:4636-4643
Broxton, Chynna N; He, Bixi; Bruno, Vincent M et al. (2018) A role for Candida albicans superoxide dismutase enzymes in glucose signaling. Biochem Biophys Res Commun 495:814-820
Schatzman, Sabrina S; Culotta, Valeria C (2018) Chemical Warfare at the Microorganismal Level: A Closer Look at the Superoxide Dismutase Enzymes of Pathogens. ACS Infect Dis 4:893-903
Rossi, Diego C P; Gleason, Julie E; Sanchez, Hiram et al. (2017) Candida albicans FRE8 encodes a member of the NADPH oxidase family that produces a burst of ROS during fungal morphogenesis. PLoS Pathog 13:e1006763
Broxton, Chynna N; Culotta, Valeria C (2016) SOD Enzymes and Microbial Pathogens: Surviving the Oxidative Storm of Infection. PLoS Pathog 12:e1005295
Besold, Angelique N; Culbertson, Edward M; Culotta, Valeria C (2016) The Yin and Yang of copper during infection. J Biol Inorg Chem 21:137-44
Peterson, Ryan L; Galaleldeen, Ahmad; Villarreal, Johanna et al. (2016) The Phylogeny and Active Site Design of Eukaryotic Copper-only Superoxide Dismutases. J Biol Chem 291:20911-20923
Baron, J Allen; Chen, Janice S; Culotta, Valeria C (2015) Cu/Zn superoxide dismutase and the proton ATPase Pma1p of Saccharomyces cerevisiae. Biochem Biophys Res Commun 462:251-6
Li, Cissy X; Gleason, Julie E; Zhang, Sean X et al. (2015) Candida albicans adapts to host copper during infection by swapping metal cofactors for superoxide dismutase. Proc Natl Acad Sci U S A 112:E5336-42
Gleason, Julie E; Li, Cissy X; Odeh, Hana M et al. (2014) Species-specific activation of Cu/Zn SOD by its CCS copper chaperone in the pathogenic yeast Candida albicans. J Biol Inorg Chem 19:595-603

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