Glutathione (GSH) vs SS-31 (Elamipretide)

Glutathione (GSH)

Glutathione is a tripeptide of glutamate, cysteine and glycine in which glutamate is linked through its side-chain (gamma) carboxyl group. It is made inside cells by two ATP-dependent enzymes, glutamate–cysteine ligase and glutathione synthetase, and is one of the most abundant small thiols in animal cells. It occurs in a reduced form (GSH) and an oxidised disulfide form (GSSG), and the ratio between them is widely used as a measure of cellular redox state. Its biochemistry inside the cell is well mapped. Studies that supply glutathione from outside, in animals or people, are harder to interpret because extracellular glutathione is readily broken down, and human findings in that area are inconsistent.

SS-31 (Elamipretide)

SS-31, also named elamipretide, is a synthetic tetrapeptide of alternating aromatic and basic residues that concentrates in mitochondria. Its sequence is D-Arg-Dmt-Lys-Phe-NH2, where Dmt is 2′,6′-dimethyltyrosine; the N-terminal D-amino acid slows enzymatic breakdown, and the peptide carries a net charge of +3 at neutral pH. The SS prefix refers to Szeto and Schiller, who described a series of related peptides that grew out of opioid peptide research, although SS-31 is reported to have no opioid activity. Most mechanistic work uses isolated mitochondria, cultured cells and rodent ischaemia models. It has also been tested in human clinical trials, chiefly in inherited mitochondrial disorders, and those data are smaller and less consistent than the preclinical literature.

How Glutathione (GSH) acts

The reactive part of glutathione is the thiol of its cysteine residue. Glutathione peroxidases use it to reduce hydrogen peroxide and lipid hydroperoxides, in the process oxidising two molecules of GSH to GSSG; glutathione reductase then regenerates GSH using NADPH. Glutathione S-transferases attach it to electrophilic compounds, the first step in a conjugation pathway that handles many drugs and foreign chemicals. It also forms mixed disulfides with cysteine residues in proteins, a modification studied as a form of redox signalling. Because the gamma-glutamyl bond resists most peptidases, breakdown begins with gamma-glutamyl transpeptidase on the outer surface of cells.

How SS-31 (Elamipretide) acts

SS-31 crosses cell membranes despite its positive charge and has been reported to accumulate at the inner mitochondrial membrane. The favoured explanation is binding to cardiolipin, a phospholipid largely confined to that membrane, through electrostatic and hydrophobic contacts. Biophysical studies suggest this binding changes membrane surface charge and the way cytochrome c associates with cardiolipin, including cytochrome c's peroxidase activity. In isolated mitochondria and cell models, its effects on cristae structure, electron transport and reactive oxygen species have been examined. Early papers described it as a direct antioxidant via its dimethyltyrosine; later work puts more weight on cardiolipin.

The records side by side

• Type: Glutathione (GSH), Tripeptide; SS-31 (Elamipretide), Aromatic-cationic tetrapeptide — mitochondria-targeted
• Length: Glutathione (GSH), 3 amino acids; SS-31 (Elamipretide), 4 amino acids
• Molecular weight: Glutathione (GSH), 307.33 g/mol; SS-31 (Elamipretide), 639.8 g/mol
• Molecular formula: Glutathione (GSH), C10H17N3O6S; SS-31 (Elamipretide), C32H49N9O5

Reading a comparison

A comparison places two records side by side; it does not merge them. Each description above is drawn from that compound's own record, and the two were not necessarily characterised by the same methods, at the same time, or to the same level of detail. Before comparing any attribute, it is worth establishing that both records describe the substance you think they describe — names are not identifiers, and two entries sharing a name can differ in salt form, stereochemistry or the convention used to state a mass. Where a figure carries no method beside it, the comparison is between two reported numbers rather than between two measurements.