SN5 SHORT NOTE 5M ★ High-yield

Describe the structure, synthesis and functions of glutathione.

Biochemistry · 1st Professional — Pre-Clinical

Structure

Glutathione (GSH) = a tripeptide of glutamate, cysteine and glycine — γ-glutamyl-cysteinyl-glycine.

The glutamate is joined by an unusual γ-peptide bond, which makes it resistant to ordinary peptidases
The –SH group of cysteine is the functional part
The most abundant intracellular thiol, at about 5 mmol/L
Exists as reduced GSH and oxidised GSSG; the normal GSH:GSSG ratio exceeds 100:1

Synthesis and Regeneration

Glutamate + cysteine → γ-glutamylcysteine (ATP) → + Glycine → glutathione (ATP) → Used as reductant → GSSG → Glutathione reductase — needs NADPH from the HMP shunt → Back to 2 GSH

The HMP shunt is therefore essential to glutathione function — the link that explains G6PD deficiency

Functions

Antioxidant — glutathione peroxidase (a selenium enzyme) destroys H2O2 and lipid peroxides
Keeps protein –SH groups reduced, including haemoglobin and enzymes
Detoxification — glutathione S-transferase conjugates drugs, carcinogens and heavy metals; the basis of mercapturic acid formation
Amino acid transport — the γ-glutamyl cycle (Meister cycle), using GGT
Maintains RBC membrane integrity — prevents haemolysis
Coenzyme for some enzymes; store and transport form of cysteine
Regenerates vitamins C and E from their oxidised forms

Clinical Correlations

Condition	Mechanism
G6PD deficiency	↓ NADPH → GSH cannot be regenerated → oxidative haemolysis with Heinz bodies after oxidant drugs, fava beans or infection
Paracetamol poisoning	NAPQI depletes hepatic glutathione → hepatocyte necrosis
Selenium deficiency	Glutathione peroxidase fails → oxidative damage (Keshan disease)
Cataract	↓ Lens glutathione → protein cross-linking
Cancer chemoresistance	Tumour cells over-express glutathione S-transferase and inactivate the drug

Paracetamol Poisoning — the Key Example

Paracetamol, normal dose → 95% conjugated safely → Overdose → conjugation saturated → Cytochrome P450 makes NAPQI (toxic) → Normally detoxified by glutathione → Glutathione stores exhausted → NAPQI binds hepatocyte proteins → necrosis

N-acetylcysteine is the antidote — it supplies cysteine and replenishes glutathione. Most effective within 8–10 hours
Risk is greater in alcoholics and the malnourished, who have induced P450 and depleted glutathione

Applied Aspects

Gamma-glutamyl transferase (GGT), an enzyme of the γ-glutamyl cycle, is the most sensitive marker of alcohol intake
Oral glutathione supplements are of doubtful value — it is hydrolysed in the gut; supplying cysteine is the effective route
Newborns have low glutathione and are more vulnerable to oxidative injury

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