Ophthalmic acid is a glutathione regulating tripeptide

Since its discovery in 1958 in the lens of cows, ophthalmic acid (OPH) has stood in the shadow of its anti‐oxidant analog: glutathione (GSH). Lacking the thiol group that gives GSH many of its important properties, ophthalmic acid's function has remained elusive, and it has been widely presumed to be an accidental product of the same enzymes. In this review, we compile evidence demonstrating that OPH is a ubiquitous metabolite found in bacteria, plants, fungi, and animals, produced through several layers of metabolic regulation. We discuss the limitations of the oft‐repeated suggestions that aberrations in OPH levels should solely indicate GSH deficiency or oxidative stress. Finally, we discuss the available literature and suggest OPH's role in metabolism as a GSH‐regulating tripeptide; controlling both cellular and organelle influx and efflux of GSH, as well as modulating GSH‐dependent reactions and signaling. Ultimately, we hope that this review reinvigorates and directs more research into this versatile metabolite. Contrary to previous beliefs, ophthalmic acid is not just a byproduct of glutathione biosynthesis or a marker of oxidative stress. Instead, it is an evolutionarily conserved and ubiquitous metabolite, and its biosynthesis is regulated and metabolically costly. It has a function as a glutathione‐regulating tripeptide, capable of inhibiting and stimulating glutathione utilization and transport, which we discuss here.