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Abstract
Oxidation-reduction (redox) based regulation of signal transduction and gene expression
is emerging as a fundamental regulatory mechanism in cell biology. Electron flow through
side chain functional CH2-SH groups of conserved cysteinyl residues in proteins account
for their redox-sensing properties. Because in most intracellular proteins thiol groups
are strongly "buffered" against oxidation by the highly reduced environment inside
the cell, only accessible protein thiol groups with high thiol-disulfide oxidation
potentials are likely to be redox sensitive. The list of redox-sensitive signal transduction
pathways is steadily growing, and current information suggests that manipulation of
the cell redox state may prove to be an important strategy for the management of AIDS
and some forms of cancer. The endogenous thioredoxin and glutathione systems are of
central importance in redox signaling. Among the thiol agents tested for their efficacy
to modulate cellular redox status, N-acetyl-L-cysteine (NAC) and alpha-lipoic acid
hold promise for clinical use. A unique advantage of lipoate is that it is able to
utilize cellular reducing equivalents, and thus it harnesses the metabolic power of
the cell to continuously regenerate its reductive vicinal dithiol form. Because lipoate
can be readily recycled in the cell, it has an advantage over N-acetyl-L-cysteine
on a concentration:effect basis. Our current knowledge of redox regulated signal transduction
has led to the unfolding of the remarkable therapeutic potential of cellular thiol
modulating agents.