Question

Glutathione (G-SH), one of the most common tripeptides in animals, plants, and bacteria, is a scavenger of oxidizing agents. In reacting with oxidizing agents, glutathione is converted to G-S-S-G. (a) Name the amino acids in this tripeptide. (b) What is unusual about the peptide bond formed by the \(N\)-terminal amino acid? (c) Write a balanced half-reaction for the reaction of two molecules of glutathione to form a disulfide bond. Is glutathione a biological oxidizing agent or a biological reducing agent?(d) Write a balanced equation for reaction of glutathione with molecular oxygen, \(\mathrm{O}_{2}\), to form G-S- S-G and \(\mathrm{H}_{2} \mathrm{O}\). Is molecular oxygen oxidized or reduced in this process?

Short answer

(a) The amino acids in glutathione are: 1. Glutamic acid (Glu) 2. Cysteine (Cys) 3. Glycine (Gly) (b) The unusual peptide bond in glutathione is formed between the carboxyl side chain of glutamic acid and the amino group of cysteine, leading to a gamma (γ) linkage in the tripeptide. (c) Glutathione acts as a biological reducing agent, as its balanced half-reaction is: 2 G-SH ⟶ G-S-S-G + 2H+ + 2e- (d) In the reaction of glutathione with molecular oxygen (O2), oxygen is reduced: 4 G-SH + O2 ⟶ 2 G-S-S-G + 2H2O

Step-by-step solution

(a) Naming the amino acids in glutathione

Glutathione (G-SH) is a tripeptide, meaning it is composed of three amino acids. Its structure is \(\gamma\)-glutamylcysteinylglycine or, in short, Glu-Cys-Gly. Therefore, the amino acids in glutathione are: 1. Glutamic acid (Glu) 2. Cysteine (Cys) 3. Glycine (Gly)

(b) Unusual peptide bond in glutathione

In most peptides, the peptide bond is formed between the amino group (\(\mathrm{NH}_{2}\)) of one amino acid and the carboxyl group (\(\mathrm{COOH}\)) of another amino acid. However, in glutathione, the peptide bond between the N-terminal amino acid (glutamic acid) and the second amino acid (cysteine) is unusual because it is not formed between these functional groups. Instead, the peptide bond is formed between the carboxyl side chain (\(\mathrm{-COOH}\)) of glutamic acid and the amino group (\(\mathrm{-NH}_{2}\)) of cysteine, leading to a gamma (\(\gamma\)) linkage in the tripeptide.

(c) Balanced half-reaction of glutathione

When two molecules of glutathione react to form a disulfide bond, a molecule of G-S-S-G is produced. The balanced half-reaction can be represented as follows: 2 G-SH ⟶ G-S-S-G + 2H+ + 2e- In this reaction, two glutathione molecules are reduced to form G-S-S-G, releasing two protons (H+) and two electrons (e-). Since glutathione loses electrons in this reaction, it acts as a biological reducing agent.

(d) Reaction of glutathione with molecular oxygen

When glutathione reacts with molecular oxygen (O2), G-S-S-G and H2O are produced. To balance the equation, we must ensure that the number of atoms is equal on both sides of the reaction. The balanced equation can be represented as follows: 4 G-SH + O2 ⟶ 2 G-S-S-G + 2H2O In this reaction, glutathione (G-SH) is reduced to G-S-S-G, and molecular oxygen (O2) is reduced to water (H2O). Since oxygen gains electrons in this process, it is reduced.

Key concepts

Tripeptide

Glutathione is known as a tripeptide because it is composed of three amino acids linked together. These amino acids are linked through peptide bonds to form a structure central to its function in biological processes.
This specific sequence includes:**

• Glutamic acid (Glu)
• Cysteine (Cys)
• Glycine (Gly)

Understanding the structure of a tripeptide is crucial because each amino acid contributes to the overall properties and function of the molecule. For glutathione, its structure allows it to effectively act as an antioxidant, protecting cells from damage by neutralizing oxidizing agents.

Biological reducing agent

Glutathione is known as an important biological reducing agent, meaning it has the ability to donate electrons to other molecules. In chemical terms, this helps reduce the oxidation state of other molecules, effectively keeping them stable.
In the body, glutathione plays critical roles such as: **

• Neutralizing harmful free radicals
• Helping maintain the reduced state of other antioxidants
• Participating in DNA synthesis and repair

By donating electrons, glutathione protects cells from oxidative stress, which can damage proteins, lipids, and DNA.

Peptide bond

The peptide bond is a type of covalent bond that joins two amino acids together. Typically, this occurs between the carboxyl group of one amino acid and the amino group of another, releasing a molecule of water.
Glutathione has a unique peptide bond between its N-terminal glutamic acid and cysteine. This particular bond is a gamma linkage instead of the usual alpha linkage. Instead of the terminal carboxyl group, the side chain carboxyl of glutamic acid bonds with cysteine, making its structure distinct from other peptides.

Amino acids

Amino acids are the building blocks of proteins and peptides. For glutathione, the three amino acids—glutamic acid, cysteine, and glycine—combine to form a potent antioxidant.
Each amino acid contributes uniquely:

• Glutamic acid: Provides a gamma linkage and additional stability through its side chain.
• Cysteine: Contains a thiol group, vital for reductive capabilities and link formation like disulfides.
• Glycine: Offers structural flexibility to the peptide chain.

Together, these amino acids make glutathione a powerful agent against cellular damage.

Disulfide bond

A disulfide bond is a strong covalent bond formed between the sulfur atoms of two cysteine residues, which in turn stabilizes protein structures. In glutathione, when two molecules of it join via their cysteine thiol groups, a disulfide bond is formed, resulting in G-S-S-G.
This bond is crucial because it:

• Acts as a switch in redox reactions, toggling between reduced (G-SH) and oxidized (G-S-S-G) forms.
• Allows the recycling of glutathione within cells as a means of managing oxidative stress.
• Plays a role in signaling pathways by modulating protein function.

Through its ability to form and break disulfide bonds, glutathione remains an integral component of cellular defense mechanisms.