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In the presence of thiols such as glutathione or dithiothreitol, choleragen catalyzes the NAD-dependent ADP-ribosylation of arginine and proteins; thiols reduce the disulfide linking the A1 and A2 peptides of the A protomer of the toxin, releasing the active A1 peptide. Homogeneous thiol:protein disulfide oxidoreductase from bovine liver, in the presence of limiting concentrations of glutathione or dithiothreitol, increased the rate of activation of choleragen and its A protomer. The ability of oxidoreductase preparations to activate choleragen co-chromatographed with oxidoreductase protein on gel permeation columns and was proportional to the concentration of oxidoreductase in the assay. In the presence of oxidoreductase, the concentrations of glutathione and dithiothreitol necessary for activation were reduced. Thiol:protein disulfide oxidoreductase could play a role in the reduction of choleragen and release of the catalytically active A1 peptide.