Roots: Activated intermediates: The unexpected may sometimes carry a message

In this Roots essay, Fritz Lipmann reviews the ways in which a number of activated metabolic intermediates were discovered, and where, not infrequently, he himself played a leading role. The concept of ‘squiggle‐P’ (∼ P) to denote the controversially named ‘high‐energy bond’, the discoveries of acetylphosphate, the activation of carboxylic acids and of amino acids, and of acetyl coenzyme A, are reviewed. In addition, carbamoyl phosphate as perhaps the earliest activated phosphate donor to evolve, and active sulfate, in phosphoadenosine phosphosulfate, are discussed, as well as the remarkable earlier discovery by Buchner and Hahn of how to prepare a yeast extract that fermented carbohydrate to ethanol; this discovery is viewed by Lipmann as the opening chapter in the new sciences of biochemistry and molecular biology.