Glutathione and Non-Ribosomal Peptides

While most human peptides originate from ribosomal translation, a distinct class of non-ribosomal peptides (NRPs) is assembled enzymatically.

Glutathione (GSH): The Master Antioxidant

Structure: γ-L-Glutamyl-L-Cysteinyl-Glycine

Unique Features - **γ-peptide bond** — Links Glu γ-carboxyl to Cys amino group - **Non-ribosomal synthesis** — Two-step enzymatic pathway - **Protease resistant** — γ-linkage not recognized by standard peptidases - **High concentration** — 1-10 mM in cells (vs. nM-μM for signaling peptides)

Biosynthesis

• Rate-limiting step
• Produces γ-glutamylcysteine
• Feedback inhibited by GSH

• Adds glycine to complete the tripeptide
• ATP-dependent

Functions 1. **Antioxidant defense** — Reduces reactive oxygen species 2. **Xenobiotic metabolism** — Conjugates toxins for excretion 3. **Amino acid transport** — γ-glutamyl cycle 4. **Protein thiol maintenance** — Prevents oxidative damage 5. **Immune function** — Supports lymphocyte proliferation

The Glutathione Redox Cycle - GSH + ROS → GSSG (oxidized form) - GSSG + NADPH → 2 GSH (reduced by glutathione reductase)

Other Human Non-Ribosomal Peptides

Carnosine (β-Alanyl-L-Histidine) - Synthesized by carnosine synthase - Contains **β-alanine** (non-proteinogenic) - Functions: - pH buffering in muscle - Metal chelation - Antioxidant activity

Anserine (β-Alanyl-1-Methyl-L-Histidine) - Methylated derivative of carnosine - Found in cardiac and skeletal muscle

Differences from Ribosomal Peptides

Significance

• Life evolved multiple strategies for peptide synthesis
• Non-standard bonds can confer protease resistance
• Some essential peptides require enzymatic rather than genetic specification