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  • Title: Cathepsin B responsiveness to glutathione and lipoic acid redox.
    Author: Lockwood TD.
    Journal: Antioxid Redox Signal; 2002 Aug; 4(4):681-91. PubMed ID: 12230881.
    Abstract:
    Some subcomponents of cell protein degradation exhibit an unexplained reductive energy requirement; and diverse cysteine proteases are among multiple effector mechanisms requiring reduction. Present studies investigated whether cathepsin B activity is graded in response to (a) reduced glutathione (GSH) and dihydrolipoic acid (DHLA) concentrations, (b) their redox ratios, and (c) their differential potencies and efficacies. Purified bovine cathepsin B activity was assayed with carbobenzyloxy-Arg-Arg-aminomethylcoumarin by standard methods following inactivation by spontaneous air oxidation. Endogenous GSH concentration (2-3 mM) maintained 30-40% of the maximal cathepsin B reaction rate observed under dithiothreitol (5 mM). Following activation with GSH, the cathepsin B reaction rate was inhibited in proportion to nonphysiologic GSH:GSSG redox ratio above 1% oxidized (e.g., 85% inhibited at 3 mM:2 mM). Thus, cathepsin B can be redox buffered by the GSH:GSSG ratio. DHLA was identified as a potent cathepsin activator with threshold near 1 microM and 80% maximal activation near 10 microM. Conversely, oxidized lipoamide disulfide inhibited cathepsin B over 5-250 microM. DHLA at 5-50 microM superimposed severalfold additional activation upon the stable submaximal cathepsin B reaction rate maintained by endogenous GSH concentration (2-3 mM). Cell protein degradation was bioassayed by release of [3H] leucine from the biosynthetically labeled rat heart under nonrecirculating perfusion. The pro-oxidant, diamide (100 microM), reversibly inhibited 80% of basal proteolysis. Supraphysiologic extracellular DHLA (80 microM) doubled the basal rate of averaged cell protein degradation in 15 min. Thus, the cell redox system buffers an intermediate rate of protein degradation, which can be decreased by supraphysiologic exposure to diamide pro-oxidant or increased by DHLA reductant.
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