GLUTATHIONE (GSH) is an important antioxidant in plants, animals,
fungi, and some bacteria and archaea.
Glutathione is capable of
preventing damage to important cellular components caused by reactive
oxygen species such as free radicals , peroxides , lipid peroxides ,
and heavy metals . It is a tripeptide with a gamma peptide linkage
between the carboxyl group of the glutamate side chain and the amine
group of cysteine , and the carboxyl group of cysteine is attached by
normal peptide linkage to a glycine .
Thiol groups are reducing agents , existing at a concentration around
5 mM in animal cells.
Glutathione reduces disulfide bonds formed
within cytoplasmic proteins to cysteines by serving as an electron
donor. In the process, glutathione is converted to its oxidized form,
glutathione disulfide (GSSG), also called L-(–)-glutathione.
Once oxidized, glutathione can be reduced back by glutathione
NADPH as an electron donor. The ratio of reduced
glutathione to oxidized glutathione within cells is often used as a
measure of cellular oxidative stress .
* 1 Biosynthesis
* 2 Function
* 2.1 Function in animals
* 2.2 Function in plants
Bioavailability and Supplementation
* 4 Methods to determine glutathione
* 4.1 Small molecule based glutathione probes
* 4.1.1 Ellman\'s reagent and Monobromobimane
* 4.1.2 Monochlorobimane
* 4.1.3 5-Chloromethylfluorescein diacetate (CMFDA)
* 4.1.4 ThiolQuant Green
* 4.1.5 Real
Protein based glutathione probes
* 5 Other biological implications
* 5.1 Lead
* 5.2 Cancer
* 5.3 Cystic fibrosis
* 5.4 Alzheimer\'s disease (AD)
* 6 Uses
* 6.1 Winemaking
* 6.2 Cosmetics
* 7 Importance of gamma-glutamylcysteine as a precursor for
* 8 See also
* 9 References
* 10 Further reading
* 11 External links
The biosynthesis pathway for glutathione is found in some bacteria,
such as cyanobacteria and proteobacteria , but is missing in many
other bacteria. Most eukaryotes, including humans, synthesize
glutathione, but some do not, such as
Entamoeba , and
Giardia . The only archaea that make glutathione are halobacteria .
Glutathione is not an essential nutrient for humans, since it can be
synthesized in the body from the amino acids L-cysteine , L-glutamic
acid , and glycine ; it does not have to be present as a supplement in
the diet. The sulfhydryl group (SH) of cysteine serves as a proton
donor and is responsible for its biological activity.
Cysteine is the
rate-limiting factor in cellular glutathione biosynthesis, since this
amino acid is relatively rare in foods.
Cells make glutathione in two adenosine triphosphate -dependent
* First, gamma-glutamylcysteine is synthesized from L-glutamate and
cysteine via the enzyme gamma-glutamylcysteine synthetase (glutamate
cysteine ligase, GCL). This reaction is the rate-limiting step in
* Second, glycine is added to the C-terminal of
gamma-glutamylcysteine via the enzyme glutathione synthetase .
Animal glutamate cysteine ligase (GCL) is a heterodimeric enzyme
composed of a catalytic and a modulatory subunit. The catalytic
subunit is necessary and sufficient for all GCL enzymatic activity,
whereas the modulatory subunit increases the catalytic efficiency of
the enzyme. Mice lacking the catalytic subunit (i.e., lacking all de
novo GSH synthesis) die before birth. Mice lacking the modulatory
subunit demonstrate no obvious phenotype, but exhibit marked decrease
in GSH and increased sensitivity to toxic insults.
While all animal cells are capable of synthesizing glutathione,
glutathione synthesis in the liver has been shown to be essential.
GCLC knockout mice die within a month of birth due to the absence of
hepatic GSH synthesis. Major transport into the blood stream is
driven by an electrochemical gradient , specifically through the
transport proteins RcGshT and RsGshT. Similarly, glutathione
S-conjugates, synthesized hepatically, feature preferential secretion
into bile .
The plant glutamate cysteine ligase (GCL) is a redox-sensitive
homodimeric enzyme , conserved in the plant kingdom. In an oxidizing
environment, intermolecular disulfide bridges are formed and the
enzyme switches to the dimeric active state. The midpoint potential of
the critical cysteine pair is -318 mV. In addition to the
redox-dependent control, the plant GCL enzyme is feedback inhibited by
glutathione. GCL is exclusively located in plastids , and glutathione
synthetase (GS) is dual-targeted to plastids and cytosol, thus GSH and
gamma-glutamylcysteine are exported from the plastids. Both
glutathione biosynthesis enzymes are essential in plants; knock-outs
of GCL and GS are lethal to embryo and seedling.
Glutathione exists in both 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 molecules, such as reactive
oxygen species to neutralize them, or to protein cysteines to maintain
their reduced forms. With donating an electron, glutathione itself
becomes reactive and readily reacts with another reactive glutathione
to form glutathione disulfide (GSSG). Such a reaction is probable due
to the relatively high concentration of glutathione in cells (up to 7
mM in the liver).
Generally, interactions between GSH and other molecules with higher
relative electrophilicity deplete GSH levels within the cell. An
exception to this case involves the sensitivity of GSH to the
electrophilic compound's relative concentration. In high
concentrations, the organic molecule Diethyl maleate fully depleted
GSH levels in cells. However, in low concentrations, a minor decrease
in cellular GSH levels was followed by a two-fold increase.
GSH can be regenerated from GSSG by the enzyme glutathione reductase
NADPH reduces FAD present in GSR to produce a transient
FADH-anion. This anion then quickly breaks a disulfide bond (Cys58 –
Cys63) and leads to Cys63's nucleophilically attacking the nearest
sulfide unit in the GSSG molecule (promoted by His467), which creates
a mixed disulfide bond (GS-Cys58) and a GS-anion. His467 of GSR then
protonates the GS-anion to form the first GSH. Next, Cys63
nucleophilically attacks the sulfide of Cys58, releasing a GS-anion,
which, in turn, picks up a solvent proton and is released from the
enzyme, thereby creating the second GSH. So, for every GSSG and NADPH,
two reduced GSH molecules are gained, which can again act as
antioxidants scavenging reactive oxygen species in the cell.
In healthy cells and tissue, more than 90% of the total glutathione
pool is in the reduced form (GSH) and less than 10% exists in the
disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered
indicative of oxidative stress .
Glutathione has multiple functions:
* It maintains levels of reduced glutaredoxin and glutathione
* It is one of the major endogenous antioxidants produced by the
cells, participating directly in the neutralization of free radicals
and reactive oxygen compounds, as well as maintaining exogenous
antioxidants such as vitamins C and E in their reduced (active) forms.
* Regulation of the nitric oxide cycle is critical for life, but can
be problematic if unregulated.
* It is used in metabolic and biochemical reactions such as DNA
synthesis and repair, protein synthesis, prostaglandin synthesis,
amino acid transport, and enzyme activation. Thus, every system in the
body can be affected by the state of the glutathione system,
especially the immune system, the nervous system, the gastrointestinal
system, and the lungs.
* It has a vital function in iron metabolism. Yeast cells depleted
of GSH or containing toxic levels of GSH show an intense iron
starvation-like response and impairment of the activity of
extramitochondrial ISC enzymes thus inhibiting oxidative endoplasmic
reticulum folding, followed by death.
* It has roles in progression of the cell cycle , including cell
death . GSH levels regulate redox changes to nuclear proteins
necessary for the initiation of cell differentiation . Differences in
GSH levels also determine the expressed mode of cell death, being
either apoptosis or cell necrosis . Manageably low levels result in
the systematic breakage of the cell whereas excessively low levels
result in rapid cell death.
FUNCTION IN ANIMALS
GSH is known as a substrate in conjugation reactions, which is
catalyzed by glutathione S-transferase enzymes in cytosol , microsomes
, and mitochondria . However, GSH is also capable of participating in
nonenzymatic conjugation with some chemicals.
In the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive
cytochrome P450 -reactive metabolite formed by paracetamol
(acetaminophen), which becomes toxic when GSH is depleted by an
overdose of acetaminophen, glutathione is an essential antidote to
Glutathione conjugates to
NAPQI and helps to detoxify it. In
this capacity, it protects cellular protein thiol groups, which would
otherwise become covalently modified; when all GSH has been spent,
NAPQI begins to react with the cellular proteins , killing the cells
in the process. The preferred treatment for an overdose of this
painkiller is the administration (usually in atomized form) of
N-acetyl-L-cysteine (often as a preparation called Mucomyst ), which
is processed by cells to L-cysteine and used in the de novo synthesis
Glutathione (GSH) 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 byproduct of metabolism.
This detoxification reaction is carried out by the glyoxalase system
Glyoxalase I (EC 22.214.171.124) catalyzes the conversion of methylglyoxal
and reduced glutathione to S-D-lactoyl-glutathione.
Glyoxalase II (EC
126.96.36.199) catalyzes the hydrolysis of S-D-lactoyl-glutathione to
glutathione and D-lactic acid .
Glutathione, along with oxidized glutathione (GSSG) and
S-nitrosoglutathione (GSNO), have been found to bind to the glutamate
recognition site of the NMDA and
AMPA receptors (via their γ-glutamyl
moieties), and may be endogenous neuromodulators . At millimolar
concentrations, they may also modulate the redox state of the NMDA
Glutathione has been found to bind to and activate
ionotropic receptors that are different from any other excitatory
amino acid receptor , and which may constitute glutathione receptors,
potentially making it a neurotransmitter .
Glutathione is also able
to activate the purinergic P2X7 receptor from Müller glia , inducing
acute calcium transient signals and GABA release from both retinal
neurons and glial cells.
FUNCTION IN PLANTS
In plants, glutathione is crucial for biotic and abiotic stress
management. It is a pivotal component of the glutathione-ascorbate
cycle , a system that reduces poisonous hydrogen peroxide . It is the
precursor of phytochelatins , glutathione oligomers that chelate heavy
metals such as cadmium .
Glutathione is required for efficient
defence against plant pathogens such as
Pseudomonas syringae and
Adenylyl-sulfate reductase , an enzyme of the
sulfur assimilation pathway, uses glutathione as an electron donor.
Other enzymes using glutathione as a substrate are glutaredoxins .
These small oxidoreductases are involved in flower development,
salicylic acid , and plant defence signalling.
BIOAVAILABILITY AND SUPPLEMENTATION
Systemic bioavailability of orally consumed glutathione is poor
because the molecule, a tripeptide, is the substrate of proteases
(peptidases) of the alimentary canal, and due to the absence of a
specific carrier of glutathione at the level of cell membrane.
Because direct supplementation of glutathione is not always
successful, supply of the raw nutritional materials used to generate
GSH, such as cysteine and glycine, may be more effective at increasing
glutathione levels. Other antioxidants such as ascorbic acid (vitamin
C) may also work synergistically with glutathione, preventing
depletion of either. The glutathione-ascorbate cycle , which works to
detoxify hydrogen peroxide (H2O2), is one very specific example of
Additionally, compounds such as
N-acetylcysteine (NAC) and alpha
lipoic acid (ALA, not to be confused with the unrelated
alpha-linolenic acid ) are both capable of helping to regenerate
glutathione levels. NAC in particular is commonly used to treat
overdose of acetaminophen , a type of potentially fatal poisoning
which is harmful in part due to severe depletion of glutathione
Calcitriol (1,25-dihydroxyvitamin D3), the active metabolite of
vitamin D3 , after being synthesized from calcifediol in the kidney,
increases glutathione levels in the brain and appears to be a catalyst
for glutathione production. It takes about ten days for the body to
process vitamin D3 into calcitriol.
S-adenosylmethionine (SAMe), a cosubstrate involved in methyl group
transfer, has also been shown to increase cellular glutathione content
in persons suffering from a disease-related glutathione deficiency.
Low glutathione is commonly observed in wasting and negative nitrogen
balance, as seen in cancer, HIV/AIDS, sepsis , trauma, burns, and
athletic overtraining. Low levels are also observed in periods of
starvation. These effects are hypothesized to be influenced by the
higher glycolytic activity associated with cachexia , which result
from reduced levels of oxidative phosphorylation.
METHODS TO DETERMINE GLUTATHIONE
SMALL MOLECULE BASED GLUTATHIONE PROBES
Ellman\'s Reagent And Monobromobimane
Reduced glutathione may be visualized using Ellman\'s reagent or
bimane derivatives such as monobromobimane . The monobromobimane
method is more sensitive. In this procedure, cells are lysed and
thiols extracted using a HCl buffer . The thiols are then reduced with
dithiothreitol and labelled by monobromobimane. Monobromobimane
becomes fluorescent after binding to GSH. The thiols are then
separated by HPLC and the fluorescence quantified with a fluorescence
Monochlorobimane can be used to quantify glutathione in vivo . The
quantification is done by confocal laser scanning microscopy after
application of the dye to living cells. This quantification process
relies on measuring the rates of fluorescence changes and is limited
to plant cells.
5-Chloromethylfluorescein Diacetate (CMFDA)
CMFDA was initially used as a cell tracker. Unfortunately, it has
also been mistakenly used as a glutathione probe. Unlike
monochlorobimane, whose fluorescence increases upon reacting with
glutathione, the fluorescence increase of CMFDA is due to the
hydrolysis of the acetate groups inside cells. Although CMFDA may
react with glutathione in cells, the fluorescence increase does not
reflect the reaction. Therefore, studies using CMFDA as a glutathione
probe should be revisited and re-interpreted.
The major limitation of these bimane based probes and many other
reported probes is that these probes are based on irreversible
chemical reactions with glutathione, which renders these probes
incapable of monitoring the real-time glutathione dynamics. Recently,
the first reversible reaction based fluorescent probe-ThiolQuant Green
(TQG)-for glutathione was reported. ThiolQuant Green can not only
perform high resolution measurements of glutathione levels in single
cells using a confocal microscope, but also be applied in flow
cytometry to perform bulk measurements.
Thiol (RT) probe is the second generation reversible
reaction-based GSH probe developed by the Wang group. A few key
features of RealThiol: 1) it has a much faster forward and backward
reaction kinetics compared to ThiolQuant Green, which enables real
time monitoring of GSH dynamics in live cells. 2) only micromolar to
Thiol is needed for staining in cell based
experiments, which induces minimal perturbation to GSH level in cells.
3) a high quantum yield coumarin fluorophore was implemented so that
background noise can be minimized 4) equilibrium constant of the
reaction between Real
Thiol and GSH has been fine tuned to respond to
physiologically relevant concentration of GSH. Real
Thiol can be used
to perform measurements of glutathione levels in single cells using a
high resolution confocal microscope, as well as be applied in flow
cytometry to perform bulk measurements in high throughput manner.
PROTEIN BASED GLUTATHIONE PROBES
Another approach, which allows measurement of the glutathione redox
potential at a high spatial and temporal resolution in living cells is
based on redox imaging using the redox-sensitive green fluorescent
protein (roGFP) or redox sensitive yellow fluorescent protein (rxYFP)
GSSG because its very low physiological concentration is difficult to
measure accurately unless the procedure is carefully executed and
monitored and the occurrence of interfering compounds is properly
addressed. GSSG concentration ranges from 10 to 50 μM in all solid
tissues, and from 2 to 5 μM in blood (13–33 nmol per gram Hb).
GSH-to-GSSG ratio ranges from 100 to 700.
OTHER BIOLOGICAL IMPLICATIONS
The sulphur-rich aspect of glutathione results in it forming
relatively strong complexes with lead(II).
Once a tumor has been established, elevated levels of glutathione may
act to protect cancerous cells by conferring resistance to
chemotherapeutic drugs. The antineoplastic mustard drug canfosfamide
was modelled on the structure of glutathione.
Several studies have been completed on the effectiveness of
introducing inhaled glutathione to people with cystic fibrosis with
ALZHEIMER\'S DISEASE (AD)
Whilst extracellular amyloid beta (Aβ) plaques, neurofibrillary
tangles (NFT), inflammation in the form of reactive astrocytes and
microglia , and neuronal loss are all consistent pathological features
of AD, a mechanistic link between these factors is yet to be
clarified. Although the majority of past research has focused on
fibrillar Aβ, soluble oligomeric Aβ species are now considered to be
of major pathological importance in AD. Up-regulation of GSH may be
protective against the oxidative and neurotoxic effects of oligomeric
The content of glutathione in must , the first raw form of wine,
determines the browning , or caramelizing effect, during the
production of white wine by trapping the caffeoyltartaric acid
quinones generated by enzymic oxidation as grape reaction product .
Its concentration in wine can be determined by UPLC-MRM mass
Glutathione plays an important role in preventing oxidative damage to
the skin. In addition to its many recognized biological functions,
glutathione has also been associated with skin lightening ability.
The role of glutathione as a skin whitener was discovered as a side
effect of large doses of glutathione.
Glutathione utilizes different
mechanisms to exert its action as a skin whitening agent at various
levels of melanogenesis . It inhibits melanin synthesis by means of
stopping the neurotransmitter precursor
L-DOPA 's ability to interact
with tyrosinase in the process of melanin production. Glutathione
inhibits the actual production as well as agglutination of melanin by
interrupting the function of L-DOPA. Another study found that
glutathione inhibits melanin formation by direct inactivation of the
enzyme tyrosinase by binding and chelating copper within the enzyme's
active site. Glutathione's antioxidant property allows it to inhibit
melanin synthesis by quenching of free radicals and peroxides that
contribute to tyrosinase activation and melanin formation. Its
antioxidant property also protects the skin from UV radiation and
other environmental as well as internal stressors that generate free
radicals that cause skin damage and hyperpigmentation . In most
mammals, melanin formation consists of eumelanin (brown-black pigment)
and pheomelanin ( yellow-red pigment) as either mixtures or
co-polymers. Increase in glutathione level may induce the pigment
cell to produce pheomelanin instead of eumelanin pigments. A research
by Te-Sheng Chang found lowest levels of reduced glutathione to be
associated with eumelanin type pigmentation, whereas the highest ones
were associated with the pheomelanin. As a result, it is reasonable
to assume that depletion of glutathione would result in eumelanin
formation. Prota observed that decreased glutathione concentration
led to the conversion of
Dopachrome , increasing the
formation of brown-black pigment (eumelanin).
IMPORTANCE OF GAMMA-GLUTAMYLCYSTEINE AS A PRECURSOR FOR GLUTATHIONE
Gamma-glutamylcysteine (GGC) is the immediate precursor to GSH. GGC
supplementation would circumvent feedback inhibitory control of GCL by
the end product GSH. Accordingly, a method of elevating GSH levels
with the notable advantage of bypassing negative feedback inhibition
has been described. Because of this, GGC has been the focus of
therapeutic efforts since Puri and Meister 1983. The first documented
use of GGC in brains appears to be Pileblad and Magnusson, 1992.
Astroglia cells are capable of utilising GGC. Direct delivery of the
GSH precursor GCC to brain has been reported to effectively replenish
levels of GSH in the brain.
Most of the work done on GGC has been preclinical, based on in vivo
animal models, or in vitro brain cultures. In order for the
therapeutic value of GGC elevation against AD to be vindicated, three
empirical hurdles have to be cleared. The first is to demonstrate that
delivery of GGC into the brain can indeed increase GSH. The second is
to demonstrate that the increase in GGC can indeed reduce oxidative
stress in the brain, a condition frequently linked with cognitive
Glutathione synthetase deficiency
* roGFP , a tool to measure the cellular glutathione redox potential
Bacterial glutathione transferase
Thioredoxin , a cysteine-containing small proteins with very
similar functions as reducing agents
Glutaredoxin , an antioxidant protein that uses reduced
glutathione as a cofactor and is reduced nonenzymatically by it
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Glutathione bound to proteins in the PDB
* Risk Factors
* Acetyl-L-carnitine (ALCAR)
* Alpha-lipoic acid (ALA)