Glutathione (GSH), whose IUPAC name is
2-amino-5-{[2-[(carboxymethyl)amino]-1-(mercaptomethyl)-2-oxoethyl]amino}-5-oxopenta
noic acid, is gamma-glutamylcysteinylglycine, a tripeptide. It contains an unusual
peptide linkage between the amine group of cysteine and the carboxyl group of the
glutamate side chain.
Sulfhydryl groups are kept in a reduced state within ~5 mM in animal cells. In
effect, glutathione reduces any disulfide bonds formed within cytoplasmic proteins
to cysteines by acting as an electron donor. Glutathione is found almost exclusively
in its reduced form, as the enzyme which reverts it from its oxidized form (GSSG),
glutathione reductase, is constitutively active and inducible upon oxidative stress.
In fact, the ratio of reduced to oxidized glutathione within cells is often used
scientifically as a measure of cellular toxicity.
Glutathione participates in leukotriene synthesis and is a cofactor for the enzyme
glutathione peroxidase. It is also important as a hydrophilic molecule that is added
to lipophilic toxins and waste in the liver during biotransformation before they can
become part of the bile. Glutathione is also needed for the detoxification of
methylglyoxal, a toxin produced as a by-product of metabolism. This detoxification
reaction is carried out by the glyoxalase system. Glyoxalase I catalyzes the
conversion of methylglyoxal and reduced glutathione to S-D-Lactoyl-glutathione.
Gluoxalase II catalyzes the conversion of S-D-Lactoyl Glutathione to Reduced
Glutathione and D-lactate.
GSH is known as a cofactor in both conjugation reactions and reduction reactions,
catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and
mitochondria. However, it is capable of participating in non-enzymatic conjugation
with some chemicals, as it is hypothesized to do to a significant extent with
n-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450 reactive
metabolite formed by toxic overdose of acetaminophen. Glutathione in this capacity
binds to NAPQI as a suicide substrate and in the process detoxifies it, taking the
place of cellular protein sulfhydryl groups which would otherwise be toxically
adducted. The preferred medical treatment to an overdose of this nature, whose
efficacy has been consistently supported in literature, is the administration
(usually in atomized form) of N-acetylcysteine, which is used by cells to replace
spent GSSG and allow a usable GSH pool.
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