Description

Glutathione – Advanced Biochemical Mechanism & Pathway Profile

(γ-L-Glutamyl-L-Cysteinyl-Glycine; Major Cellular Thiol Antioxidant)

Glutathione (GSH) is a tripeptide and the primary intracellular thiol redox buffer, existing in reduced (GSH) and oxidized (GSSG) states. It participates in antioxidant defense, detoxification, thiol–disulfide exchange, and gene-regulatory redox signaling.

✅ 1. Core Enzymatic System

Glutathione Peroxidase (GPx)

• Catalyzes reduction of hydrogen peroxide and lipid hydroperoxides

• GSH → GSSG

• Selenium-dependent isoforms (GPX1–GPX4)

Glutathione Reductase (GR)

• Regenerates GSH from GSSG

• Uses NADPH from pentose phosphate pathway (G6PD/6PGD)

Glutathione S-Transferases (GSTs)

• Conjugate GSH to electrophilic xenobiotics

• Phase II detoxification system

γ-Glutamyl Cycle / Synthesis Enzymes

• Glutamate-cysteine ligase (GCL / GCLC / GCLM)

• Glutathione synthetase (GSS)

✅ 2. Antioxidant & Redox Signaling Pathways

Nrf2/Keap1 Pathway (Master antioxidant response)

GSH regulates cytosolic redox state, affecting oxidation of Keap1 cysteines → release of Nrf2, which translocates to the nucleus.

Nrf2-regulated antioxidant genes:

• SOD1, CAT, GPX4, GCLC, NQO1, HMOX1

• Phase II detoxification genes (GSTs, UGTs, MRPs)

NF-κB Redox Regulation

• High GSSG or low GSH/GSSG ratio promotes IκB kinase activation

• GSH buffering can modulate NF-κB-dependent cytokine genes:

  • TNF-α, IL-6, IL-1β, COX-2

✅ 3. Mitochondrial Pathways

Mitochondrial GSH regulates:

• Complex I and III ROS leakage

• Cardiolipin peroxidation

• Cytochrome-c release

• Caspase activation cascade

Experimental models show protection of mitochondrial membrane potential by maintaining redox balance.

✅ 4. Detoxification, Conjugation & Transport

Phase II Metabolism

GST-mediated conjugation → glutathione-conjugates (GS-R) exported by MRP2/ABCC2 transporters.

Glutathione Peroxidase-4 (GPX4) & Ferroptosis

• GSH required for GPX4 activity

• Limits phospholipid hydroperoxides

• Prevents ferroptotic signaling in cell models

Key gene markers:

• GPX4, SLC7A11 (xCT transporter), GCLC, ACSL4

✅ 5. Protein S-Glutathionylation

GSH modifies protein cysteine residues, altering:

• Enzyme activity

• Ion transport

• Signal transduction

Reversed by glutaredoxin (GRX1/2) enzymes.

✅ 6. Summary of Core Enzymes & Pathways

✅ Key Genes Commonly Monitored in Research

• GCLC, GCLM (rate-limiting synthesis)

• GPX1–GPX4 (antioxidant enzymes)

• HMOX1, NQO1 (Nrf2 targets)

• SLC7A11 (cystine/glutamate transporter)

• MRP2/ABCC2 (export of GSH conjugates)

• TNF-α, IL-6, COX-2 (NF-κB-responsive cytokines)

Research-Only Classification

Glutathione is provided solely for in-vitro laboratory research and is not approved for human or animal consumption, injection, ingestion, or diagnostic or therapeutic purposes.