The role of a formaldehyde dehydrogenase-glutathione pathway in protein S-nitrosation in mammalian cells

  1. Get@NRC: The role of a formaldehyde dehydrogenase-glutathione pathway in protein S-nitrosation in mammalian cells (Opens in a new window)
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Journal titleNitric.Oxide.
Pages172181; # of pages: 10
SubjectAcetylcysteine; Affect; Aldehyde Oxidoreductases; analogs & derivatives; analysis; Animals; antagonists & inhibitors; assay; Brain; Buthionine Sulfoximine; Canada; cell; Cell Line; CELLS; Cells,Cultured; Cysteine; Dehydroepiandrosterone; donor; drug effects; Endothelial Cells; ENZYME; genetics; Glutathione; Glutathione Reductase; Hela Cells; Humans; inverse; metabolism; Mice; Nitric Oxide; Nitric Oxide Donors; Nitrogen; Nitroprusside; Nitrosation; PATHWAY; PATHWAYS; pharmacology; physiology; POTENTIAL; protein; Proteins; Rna; RNA,Small Interfering; Role; S-Nitrosoglutathione; S-Nitrosothiols; TARGET
AbstractIntracellular sulfhydryls, both protein and non-protein, are potential targets of nitric oxide-related species. S-Nitrosation of proteins can occur in vivo and can affect their activity. Metabolic pathways that regulate protein S-nitrosation are therefore likely to be biologically important. We now report that formaldehyde dehydrogenase, an enzyme that decomposes S-nitrosoglutathione, can indirectly regulate the level of cellular protein S-nitrosation. Nitrogen oxide donors induced high levels of protein S-nitrosation in HeLa cells and lower levels in Mutatect fibrosarcoma cells, as determined by Saville-Griess assay and Western-dot-blot analysis. Depletion of glutathione by treatment with buthionine sulfoximine markedly increased protein S-nitrosation in both cell lines. Glutathione depletion also increased cytokine-induced S-nitrosation in brain endothelial cells. Formaldehyde dehydrogenase activity was 2-fold higher in Mutatect than in HeLa cells. We downregulated formaldehyde dehydrogenase activity in Mutatect cells by stably expressing antisense RNA and short-interfering RNA. In these cells, both protein S-nitrosation and S-nitrosoglutathione levels were significantly enhanced after exposure to nitrogen oxide donors as compared to parental cells. Overall, strong inverse correlation between total S-nitrosothiols and formaldehyde dehydrogenase activity was seen. Inhibition of glutathione reductase, the enzyme that converts oxidized to reduced glutathione, by dehydroepiandrosterone similarly increased protein S-nitrosation and S-nitrosoglutathione levels in both cell lines. Our results provide the first evidence that formaldehyde dehydrogenase-dependent decomposition of S-nitrosoglutathione plays a role in protecting against nitrogen oxide-mediated protein S-nitrosation. We propose that formaldehyde dehydrogenase and glutathione reductase participate in a glutathione-dependent metabolic cycle that decreases protein S-nitrosation following exposure of cells to nitric oxide
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AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberHAQQANI2003
NPARC number9388965
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Record identifier3e246177-0ef7-42f2-8e96-627cd2ef16d0
Record created2009-07-10
Record modified2016-05-09
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