Glutathione

GLUTATHIONE
1
1.Introducion
• Glutathione (γ-glutamylcysteinylglycine,
GSH) is a sulfhydryl (-SH) antioxidant,
antitoxin, and enzyme cofactor.
• Glutathione can be found in animals,
plants, and microorganisms.
• It is found mainly in the cell cytosol and
other aqueous phases of the living system
• It one of the most highly concentrated
intracellular antioxidants.
2
Introducion (continue)
3
• Reduced or oxidized form (GSH GSSG)
• In the healthy cell GSSG, the oxidized
(electron-poor) form, rarely exceeds 10
percent of total cell glutathione.
• Studies have led to the free radical theory
of human diseases and to the
advancement of nutritional therapies to
improve GSH status under various
pathological conditions.
4
• The adequate provision of sulfur-
containing amino acids as well as
glutamate or glutamine and glycine (or
serine) is critical for the maximization of
GSH synthesis.
5
2.Glutathion synthesis
• The first step of GSH synthesis is rate-
limiting and catalyzed by glutamate-
cysteine ligase (GCL) formerly referred to
as -glutamylcysteine synthetase (GCS).
This enzyme absolutely require either Mg++ or Mn++.
• GCL, heterodimer made up of the heavy
sub unit (73 kDa) has the catalytic activity
(GCLC), and is the site of GSH feed back
inhibition
• The light (30 kDa) or modifier (GCLM) sub
unit, alter, or regulate the activity of the
holoenzyme
6
Glutamate cysteine ligase (GCL)
L-glutamate + L-cysteine + ATP

-L-glutamyl-L-cysteine + ADP + Pi
GCL is regultate physiologically by :
• Feed back competitive inhibition by
GSH
• The availability of its precurser,
L-cysteine.
7
The availability of its precurser,
L-cysteine.
• The cysteine content of the diet liver
Cysteine transport
Cystine transport
Methionine transport
Transsulfuration pathway
8
Transsulfuration pathway
• Ability for the liver cell to convert methionine to
cysteine is important since the liver is the major
site of methionine catabolism and the major
storage organ for GSH
• It is absent or insignificant in other GSH-
synthesizing systems
• Markedly impaired or absent in the fetus and
newborn infant, cirrhotic patients, and patients
with homocystinemia
• the Km of hepatic methionine
adenosyltransferase for ATP is high (2 mM)
• hypoxic depletion of ATP is more likely to affect
GSH synthesis from methionine than cysteine 9
Activity of GCL will be influenced by :
• Oxidative stress, insulin and many others

increase GCL transcription or activity in
variety of cells
• Dietary protein deficiency,dexamethasone,
and GCL phosphorylation decrease GCS
transcription or activity
• NO production
↑ NO production loss of GSH
↓ NO production prevent GSH
depletion 10
Glutathione synthase (GS)
-L-glutamyl-L-cysteine + glycine + ATP
GSH + ADP + Pi
• The regions of the active site that bind glycine
and the cysteinyl moiety of γ-glutamylcysteine
are highly specific
• It’s activity is modified ADP
• GSH synthase is not subject to feedback
inhibition by GSH
• GSH synthase deficiency
γ-glutamylcysteine is converted to
5-oxoproline 11
Biosynthesis of glutathione
GSH synthase
Glutamate-cysteine ligase (GCL) (GS)
-Glu-Cys-Gly
disulfide S
bond S
-Glu-Cys-Gly
12
Glutathione distribution
• Glutathione synthesis in the body occure mainly in liver
• About 80 percent of the GSH synthesized in the liver is
exported from the hepatocytes
• Most of this is utilized by the kidneys
• GSH, to supply cysteine as needed
• Circulating GSH is safe; it reacts only slowly with
Oxygen, is less susceptible to auto-oxidative degradation
than is cysteine
• Soluble in the plasma
• GSH comes in with the diet (150 mg daily by rough
estimate)
• Hormones and other vasoactive substances increase
GSH efflux into the bile
13
Strategies for Repleting Cellular Glutathione
• Oral dosing with GSH
An oral bolus of 15 mg/kg to the human
to raise plasma GSH two-to five-fold
The intestinal lumen absorb GSH via non-energy-
requiring, carrier-mediated diffusion, and later export
it into the blood
(lung alveolar cells, vessel endothelial cells, retinal
pigmented epithelial cells, and cells of the kidney's
proximal tubule;
it seems also to cross the blood-brain barrier;
while brain endothelial and nerve cells, red blood
cells, lymphocytes - appear incapable of absorbing
GSH as the intact tripeptide )
14
15
16
L-methionine
• Is an essential amino acid
• It must first be converted to cysteine
• This convertion is inactive in neonates and
in certain adults, such as patients with liver
disease
• The "activated" methionine metabolite
known as SAM (S-adenosyl methionine) is
effective in raising red cell GSH and
hepatic GSH when given orally at 1600 mg
per day
17
L-methionine
• L-methionine intake is 13 mg per kg or
about 0.75 gram daily for adults
• During methionine supplementation, intake
B6 and folic acid should also be included
• Excessive methionine intake, together with
inadequate intake of folic acid, vitamin B6,
and vitamin B12, can increase the
conversion of methionine to homocysteine
• Homocysteine is a potentially harmful
blood fat that has been linked to
atherosclerosis
18
L-cysteine
• Cysteine is probably unsafe for routine
oral administration
• In the blood it readily auto-oxidizes to
potentially toxic degradation products
• The auto-oxidation
Hydroxyl radical
• The cystine produced from cysteine
oxidation is taken up into the kidney, and
requires energy and enzymatic
intervention to be converted to cysteine
19
N-acetyl cysteine (NAC)
• NAC is a cysteine precursor; it is well absorbed by the

intestine
• Metabolized by the liver, cysteine is one of metabolite
• It seems not to raise GSH levels if they are already
within the normal range
• It can raise abnormally low GSH levels back to normal
• This is the basis for its use as an antidote to
acetaminophen's liver toxicity
• Used in Europe for many years as a mucolytic agent
• 600 mg was beneficial and innocuous while 1200 mg
and 1800 mg per day caused significant adverse effects
20
Alpha lipoic acid
• Alpha lipoic acid (ALA) is available as
supplement
• It is a natural antioxidants and could
increase intracellular glutathione through
it reducing power
21
Selenium
• Is a co-factor for the enzyme glutathione
peroxidase
• Studies suggest they may play a role in
decreasing the risk of certain condition in which
glutathione are depleted
• Too much selenium can cause toxic effects
including gastrointestinal upset, brittle nails, hair
lost and mild nerve damage
• Upper estimated requirement of 90 μg Se/d
• Lower estimated requirement of 39 μg Se/d
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What is glutathione and what are its main functions?

How is glutathione synthesized in the body?

GLUTATHIONE

L-glutamate + L-cysteine + ATP

• Oxidative stress, insulin and many others

• NAC is a cysteine precursor; it is well absorbed by the

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