Glutathione (GSH)

Chemical Identity

Property	Value
Systematic Name	(2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid
Molecular Formula	C₁₀H₁₇N₃O₆S
Molecular Weight	307.32 Da
CAS Number	70-18-8
PubChem CID	124886
SMILES	C(CC(=O)N)C(C(=O)NCC(=O)O)N
Isoelectric Point	5.93
Charge at pH 7.4	−1

Structure

Glutathione is a tripeptide composed of three amino acids:

1. L-Glutamic acid (Glu) — linked via γ-carboxyl group (not α-carboxyl)
2. L-Cysteine (Cys) — central residue with thiol group
3. Glycine (Gly) — C-terminal residue

The γ-linkage between glutamate and cysteine is critical — it renders glutathione resistant to most intracellular peptidases, which typically cleave α-peptide bonds.

Biosynthesis

Glutathione synthesis occurs in two ATP-dependent steps:

1. γ-Glutamylcysteine synthetase (GCL): Glutamate + Cysteine → γ-Glutamylcysteine
2. Glutathione synthetase: γ-Glutamylcysteine + Glycine → Glutathione

Redox Chemistry

The thiol group of cysteine (pKₐ = 8.56) is the functional center:

$$\text{GSH} \rightleftharpoons \text{GS}^- + \text{H}^+$$

The GSH/GSSG ratio is a key indicator of cellular redox state:

• Healthy cells: GSH/GSSG ≈ 100:1
• Oxidative stress: GSH/GSSG < 10:1

Biological Functions

1. Antioxidant defense: Direct ROS scavenging and cofactor for glutathione peroxidase
2. Xenobiotic metabolism: Cofactor for glutathione S-transferases (Phase II detoxification)
3. Nitric oxide signaling: S-nitrosoglutathione (GSNO) as NO carrier
4. Protein function: Glutathionylation protects cysteine residues from oxidation
5. Amino acid transport: γ-Glutamyl cycle for cysteine uptake

Clinical Significance

• Deficiency: Associated with hemolytic anemia, neurodegeneration, immunodeficiency
• Supplementation: N-acetylcysteine (NAC) as glutathione precursor
• Measuring: Ellman’s reagent (DTNB), monochlorobimane fluorescence, HPLC