Phosphorylase and the origin of reversible protein phosphorylation

This article presents a historical account of the discovery of reversible protein phosphorylation. The process was uncovered in the mid-1950s in a study designed to elucidate the complex hormonal regulation of skeletal muscle glycogen phosphorylase. This Enzyme was originally thought to be regulated by AMP now known to serve as an allosteric effector. By contrast, hormonal regulation was found to result from a phosphorylation of the protein triggered by Ca(2+) and ATP which activate phosphorylase kinase; the reverse reaction is catalyzed by a phosphorylase Phosphatase. Although that reaction is extremely simple, it came nevertheless as a complete surprise because essentially nothing was known at that time about the structure and function of phosphoproteins. This study led to the establishment of the first hormonal cascade of successive enzymatic reactions, kinases acting on kinases, initiated by cAMP discovered by Earl Sutherland. It also showed how two different physiological processes (carbohydrate metabolism and muscle contraction) could be regulated in concert. The regulation of phosphorylase was so straightforward that it was thought to represent the prototype for these kinds of interconversions. We know today that it was almost the absolute exception.