Oxidative Stress and the CNS

Re: Symposium 216

Bernhard H.J. Juurlink
juurlink@duke.usask.ca

Dear Dr. Grover, What sets a cell's GSH level are a number of factors. These include: 1) Actions that consume GSH such as glutathione transferase activity, glutathione peroxidase activity resulting in the formation of GSSG, oxidation of protein thiols yielding protein-SG adducts etc. So, of course, one important mechanism of maintaining GSH concentration is 2) glutathione reductase activity that is dependent upon NADPH for the reducing equivalents. NADPH is produced mainly via glucose-6-phosphate dehydrogenase activity and in some cells by a significant NADP-dependent isocitrate dehydrogenase activity. 3) GSH synthesis also plays an important role (note the transferase activity results in ultimate GSH consumption). The rate-limiting amino acid is cysteine. Cysteine is readily oxidized in the blood to cystine. Cystine is taken up into cells using an antiporter in exchange for glutamate; hence, intracellular glutamate concentrations play a role in determining how much cystine is taken up. This antiporter may be present in very different numbers in the plasmalemma of various cells. The cystine taken up must be reduced to 2 cysteines which is dependent upon NADPH for the electrons. Glutamylcysteine synthase forms glutamylcysteine. GSH provides feedback inhibition to this enzyme. This feedback inhibition by GSH is alleviated by glutamate; hence, glutamate levels play several important roles in GSH synthesis: i) it is an amino acid used in the synthesis of GSH, ii) the glutamate concentration gradient drives cystine uptake, and iii) increasing levels of intracellular glutamate moe efficiently alleviate the GSH-mediated feedback inhibition of glutamylcysteine synthase. The second enzyme involved in GSH synthesis is glutathione synthase; it does not seem to be affected by feed back inhibition.
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Sun Dec 13