An account of a century of ATP research

The synthesis of adenosine triphosphate (ATP), the universal biological energy currency, by oxidative phosphorylation and photophosphorylation catalyzed by the F_OF₁-ATP synthase is the fundamental means of cellular energy generation in animals, plants, and microorganisms. Since the ocean area and the amount of biomass is very large, the formation of ATP and its utilization by the myriad energy-consuming processes in the cell is the principal net chemical reaction taking place on the surface of the earth. This is indeed a most important reaction. How exactly does it occur? Since the development of the famous colorimetric assay for measurement of inorganic phosphate (Pi) in 1925, followed by the discovery of ATP in 1929, an enormous amount of research has been done to understand these intracellular energy-linked processes. I present an account of the major developments on ATP synthesis and hydrolysis in a century of research, and summarize the current state of knowledge. My account focuses on the fields of bioenergetics, muscle contraction and motility in cell life, and covers key aspects of metabolic disease, mitochondrial apoptosis and cell death in relation to ATP and the ATP synthase, and the permeability transition pore. It includes developments at molecular, cellular, and macroscopic levels—ascending into ecology—thanks to the conservative nature of metabolic pathways, with ATP as the universal intermediate in the coupled reactions of biological energy transduction. New, emerging sub-fields on ATP and the Warburg Effect, purinergic signaling, condensates and the role of ATP as a biological hydrotope are discussed briefly, and applications in aging and precision medicine are foreseen. I have divided the subject matter into the following five eras to cover the vast ground. (i)—the beginning era of the 1920s (Section 2), (ii)—an era of trials and trails of the 1930s–1940s (Sections 3.1–3.5), (iii)—an era of population-based biochemistry and enzymology in the 1950s–1980s (Sections 4.1–4.9), (iv)—a high-tech era of the 1990s–2020s of high-resolution structural and single-molecule studies, but also an interdisciplinary era of systems biology that integrates approaches from physics, chemistry, biology, mathematics, and engineering (Sections 5.1–5.15), (v)—future prospects (Section 6). The article works out new explanations—with quantitative equations or physical criteria developed for the first time—that may help resolve longstanding issues in muscle contraction, bioenergetics, and transport. My tryst with ATP during 35-years of research is also described, and the search for a theory with greater numerical accuracy is emphasized. Errors of previous theories are identified and corrected, and apparent contradictions are resolved. The aim is to explain and correctly interpret the cumulative experimental record, check for consistency of theory with experiment, remove the inconsistencies in previous theories, and arrive at a unified molecular theory of energy coupling, transduction, ATP synthesis, and ATP hydrolysis. To conclude, a number of recommendations for the progress of scientific research in interdisciplinary and multidisciplinary areas have been made.