Glutathione

Glutathione is a tripeptide of glutamic acid, cysteine and glycine, and it is present in almost every cell at concentrations that put most other small molecules in the shade — often several millimolar, which is high for something with a specific job. It is not a supplement the body happens to use; it is a core component of cellular chemistry.

Its function depends on the middle residue. Cysteine carries a sulphur atom with a reactive hydrogen attached, and that sulphur is what does the work: it gives up an electron to neutralise reactive molecules, and two glutathione molecules then bond to one another. The cell regenerates them with an enzyme, and the ratio between the reduced and oxidised forms is one of the most direct measures available of a cell's chemical state.

Its structure is also unusual in a way that matters. The link between the first two residues is not the ordinary peptide bond found in proteins; it runs from the side chain instead. That single difference means the standard enzymes that break peptides down cannot touch it, which is why a three-residue molecule survives inside a cell at all.

• Redox balance as a readout: The ratio of reduced to oxidised glutathione is a standard measure of oxidative state in a cell. Much of what is known about oxidative stress is measured through this one ratio.

• Conjugation chemistry: Beyond neutralising radicals, it is attached to foreign compounds by a family of enzymes to make them water-soluble and removable. This is one of the body's main routes for clearing xenobiotics.

• An unusual bond: The gamma linkage between its first two residues makes it resistant to ordinary peptide-cutting enzymes, and is a neat example of how a small structural change determines whether a molecule survives.

• The delivery problem: Taken by mouth it is largely broken down before absorption, and cells generally make their own. How to raise intracellular concentrations is an unresolved practical question.

Using oxygen to generate energy inevitably produces reactive by-products — molecules with unpaired electrons that will strip an electron from whatever they meet, damaging proteins, membranes and DNA. This is not a malfunction; it is a cost of aerobic metabolism, and every cell needs continuous defences against it.

Glutathione is the main one. Its cysteine sulphur donates an electron to a reactive molecule, neutralising it, and in doing so becomes reactive itself — but mildly, and in a way the cell is equipped to handle. Two spent glutathione molecules join together, and an enzyme then separates and restores them. It is a buffer that is continually consumed and continually regenerated.

The second role is disposal. A family of enzymes attaches glutathione to foreign compounds, and the attachment tags the compound as waste and makes it water-soluble enough to be excreted. This is a major pathway for clearing drugs and toxins, and it means glutathione is spent by that work as well as by radical neutralisation. A cell short of it is short for both jobs at once.

The biochemistry is thoroughly established. Glutathione’s structure, its redox cycle, the enzymes that regenerate it and the conjugation pathway are textbook material, reproduced and refined over more than half a century.

Most work on supplying it concerns correcting a deficiency rather than adding to sufficiency, and oral absorption is poor because it is broken down in the gut. It holds no medicines approval for cosmetic use in the UK or EU and is supplied for laboratory research only. Its research value is as the reference point for cellular redox state: the ratio of its reduced to oxidised forms is the standard measure of oxidative balance in a cell.

NAD+ is the closest comparison in this catalogue: another small molecule central to cellular chemistry, also declining with age, and facing the same delivery question about whether supplying it from outside raises it inside cells.

SS-31 approaches oxidative damage from the other end — reducing the production of reactive molecules at their mitochondrial source rather than neutralising them once made.