Glutathione (GSH) a tripeptide.
Containing a sulfhydryl group, is a highly distinctive amino acid derivative
with several important roles. It contains an unusual peptide linkage between
the amino group of cysteine and the carboxyl group of the glutamate side chain
(Chen, 2007) Glutathione, an antioxidant, protects red cells from oxidative
stress ( free radicals).
SYNTHESIS
OF GLUTATHIONE
Figure: Synthesis of glutathione from glutamate.
The first
step in the synthesis of glutathione is the formation of a peptide linkage
between the γ- carboxyl group of glutamate and the amino group of cysteine, in
a reaction catalysed by γ – glutamylcysteine synthetase. Formation of this
peptide bond requires activation of the γ – carboxyl group, which is achieved
by ATP. The resulting acyl – phosphate intermediate is then attacked by the
amino group of cysteine. This reaction is a feedback inhibition by glutathione
(Stryer, 2000). In the second step, which is catalysed by glutathione
synthetase, ATP activates the carboxyl group of cysteine to enable it to
condense with the amino group of glycine.
FUNCTIONS OF GLUTATHIONE
Glutathione
exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the
thiol group of cysteine is able to donate a reducing equivalent (H+
+ e-) to other unstable molecules, such as reactive oxygen species
(chen, 2007).
In
donating an election, glutathione itself becomes reactive, but readily reacts
with another reactive glutathione to form glutathione disulfide (GSSG). Such a
reaction is possible due to the relatively high concentration of glutathione in
cells (up to 5mm in the liver). GSH can be regenerated from GSSG by the enzyme
glutathione reductase which is constitutively active and inducible upon
oxidative stress (chen, 2007) in fact, the ration of reduced glutathione to
oxidized glutathione within cells is often used scientifically as a measure of
cellular toxicity.
GSH is
known as a substrate in both conjugation reactions and reduction reactions,
catalyzed by glutathione S-transferase enzymes in cytosol, microsomes and
mitochondria.
However,
it is also capable of participating in non – enzymatic conjugation with some
chemicals, as in the case of N-acetyl – p – benzoquinone immune (NAPQI), the
reactive cytochrome p450 – reactive metabolite formed by paracetamol
(acetaminophen), that becomes toxic when GSH is depleted by an overdose of
acetaminophen (styrt, 2000) Glutathione conjugates to NAPQI and helps to
detoxify it, in this capacity protects cellular protein thiol groups, which
would other wise become covalently modified, when all GSH has been spent, NAPQI
begins to react with the cellular proteins, killing the cells in the process
(styrt, 2000).