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A genetic analysis of nitrosative stress.
Biochemistry. 2009 Feb 03; 48(4):792-9.B

Abstract

Nitrosative stress is induced by pathophysiological levels of nitric oxide (NO) and S-nitrosothiols (e.g., S-nitrosoglutathione, GSNO) and arises, at least in significant part, from the nitrosylation of critical protein Cys thiols (S-nitrosylation) and metallocofactors. However, the mechanisms by which NO and GSNO mediate nitrosative stress are not well understood. Using yeast Saccharomyces cerevisiae strains lacking NO- and/or GSNO-consuming enzymes (flavohemoglobin and GSNO reductase, respectively), we measured the individual and combined effects of NO and GSNO on both cell growth and the formation of protein-bound NO species. Our results suggest an intracellular equilibrium between NO and GSNO, dependent in part on cell-catalyzed release of NO from GSNO (i.e., "SNO-lyase" activity). However, whereas NO induces multiple types of protein-based modifications, levels of which correlate with inhibition of cell growth, GSNO mainly affects protein S-nitrosylation, and the relationship between S-nitrosylation and nitrosative stress is more complex. These data support the idea of multiple classes of protein-SNO, likely reflected in divergent routes of synthesis and degradation. Indeed, a significant fraction of protein S-nitrosylation by NO occurs in the absence of O(2), which is commonly assumed to drive this reaction but instead is apparently dependent in substantial part upon protein-bound transition metals. Additionally, our findings suggest that nitrosative stress is mediated principally via the S-nitrosylation of a subset of protein targets, which include protein SNOs that are stable to cellular glutathione (and thus are not metabolized by GSNO reductase). Collectively, these results provide new evidence for the mechanisms through which NO and GSNO mediate nitrosative stress as well as the cellular pathways of protein S-nitrosylation and denitrosylation involving metalloproteins, SNO lyase(s) and GSNO reductase.

Authors+Show Affiliations

Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

19138101

Citation

Foster, Matthew W., et al. "A Genetic Analysis of Nitrosative Stress." Biochemistry, vol. 48, no. 4, 2009, pp. 792-9.
Foster MW, Liu L, Zeng M, et al. A genetic analysis of nitrosative stress. Biochemistry. 2009;48(4):792-9.
Foster, M. W., Liu, L., Zeng, M., Hess, D. T., & Stamler, J. S. (2009). A genetic analysis of nitrosative stress. Biochemistry, 48(4), 792-9. https://doi.org/10.1021/bi801813n
Foster MW, et al. A Genetic Analysis of Nitrosative Stress. Biochemistry. 2009 Feb 3;48(4):792-9. PubMed PMID: 19138101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A genetic analysis of nitrosative stress. AU - Foster,Matthew W, AU - Liu,Limin, AU - Zeng,Ming, AU - Hess,Douglas T, AU - Stamler,Jonathan S, PY - 2009/1/14/entrez PY - 2009/1/14/pubmed PY - 2009/2/26/medline SP - 792 EP - 9 JF - Biochemistry JO - Biochemistry VL - 48 IS - 4 N2 - Nitrosative stress is induced by pathophysiological levels of nitric oxide (NO) and S-nitrosothiols (e.g., S-nitrosoglutathione, GSNO) and arises, at least in significant part, from the nitrosylation of critical protein Cys thiols (S-nitrosylation) and metallocofactors. However, the mechanisms by which NO and GSNO mediate nitrosative stress are not well understood. Using yeast Saccharomyces cerevisiae strains lacking NO- and/or GSNO-consuming enzymes (flavohemoglobin and GSNO reductase, respectively), we measured the individual and combined effects of NO and GSNO on both cell growth and the formation of protein-bound NO species. Our results suggest an intracellular equilibrium between NO and GSNO, dependent in part on cell-catalyzed release of NO from GSNO (i.e., "SNO-lyase" activity). However, whereas NO induces multiple types of protein-based modifications, levels of which correlate with inhibition of cell growth, GSNO mainly affects protein S-nitrosylation, and the relationship between S-nitrosylation and nitrosative stress is more complex. These data support the idea of multiple classes of protein-SNO, likely reflected in divergent routes of synthesis and degradation. Indeed, a significant fraction of protein S-nitrosylation by NO occurs in the absence of O(2), which is commonly assumed to drive this reaction but instead is apparently dependent in substantial part upon protein-bound transition metals. Additionally, our findings suggest that nitrosative stress is mediated principally via the S-nitrosylation of a subset of protein targets, which include protein SNOs that are stable to cellular glutathione (and thus are not metabolized by GSNO reductase). Collectively, these results provide new evidence for the mechanisms through which NO and GSNO mediate nitrosative stress as well as the cellular pathways of protein S-nitrosylation and denitrosylation involving metalloproteins, SNO lyase(s) and GSNO reductase. SN - 1520-4995 UR - https://www.unboundmedicine.com/medline/citation/19138101/A_genetic_analysis_of_nitrosative_stress_ L2 - https://doi.org/10.1021/bi801813n DB - PRIME DP - Unbound Medicine ER -