Blog
The Tripeptide Inside Every Cell: Frederick Gowland Hopkins and the Discovery of Glutathione
The most abundant small peptide in your cells is not a hormone or a drug. It is glutathione, three amino acids long, present at millimolar concentrations, and it keeps the chemistry of the cell in balance. Its discovery was quiet, and its first structure was wrong.
Key takeaways
- Frederick Gowland Hopkins, working in Cambridge, described the substance in 1921.
- He first thought it was a dipeptide of glutamic acid and cysteine.
- In 1929 the correct tripeptide structure, gamma-glutamyl-cysteinyl-glycine, was established.
- The glutamate is joined through its side chain, an unusual bond that protects it from many enzymes.
- The cysteine thiol group makes glutathione a major cellular reducing agent.
A substance that took up oxygen
Hopkins was a pioneer of biochemistry who later shared a Nobel Prize in 1929 for work on vitamins. In 1921, he extracted a substance from yeast, muscle and liver that readily reacted with oxygen and seemed to act as a carrier in cell respiration. He called it glutathione, from glutamic acid and thiol, a sulfur-containing group. The behavior depended on a free sulfur group, the same group found in cysteine.
Getting the structure right
Hopkins initially proposed that glutathione was made of two amino acids. Eight years later, work from several groups, including Hopkins himself, showed there was a third, glycine. Even more interesting was how the first two were joined. The glutamic acid is linked through the carboxyl group on its side chain, not the one that normally forms peptide bonds. This gamma linkage makes glutathione resistant to the ordinary enzymes that chew peptides.
What it does
The cysteine in the middle carries a thiol group that can give up a hydrogen and be oxidized. Two oxidized molecules join to form a disulfide-linked pair, called GSSG, and enzymes restore the reduced form. In this way, glutathione helps neutralize reactive oxygen species, keeps proteins in their proper state and takes part in detoxification. The same thiol chemistry is why cysteine-containing peptides are tricky to store, a subject in our cysteine post.
Lessons from a first guess that was wrong
The glutathione story is an example of how structure determination can change a story. Hopkins’s initial idea was reasonable and still incorrect. The mistake was corrected not by argument but by better chemistry, such as the methods developed to measure amino acid content in amino acid analysis.
Lab angles
- Thiol-containing peptides should be stored to avoid oxidation.
- Free thiols can be measured with Ellman’s test, covered in our Ellman’s reagent post.
- Reducing agents in buffers change what you see by HPLC, as in detection wavelength choices.
- Disulfide pairing is critical for peptides like conotoxins.
The bottom line
Glutathione shows that a tiny peptide can be a pillar of cell chemistry. Its discovery also shows that structure matters even for three amino acids. For more short-peptide stories, read the GHK story.
Related reading
Explore Lucid Aminos
- Shop all research compounds
- Read the lab reports (COA)
- Monthly Research Panel
- Frequently asked questions
- Partner program
- About Lucid Aminos
- Contact us
For laboratory research use only. Not for human or veterinary use, and not intended to diagnose, treat, cure or prevent any condition. This article is educational and is not medical advice.