Reassessment of the role of ATP in vivo

In 1941 Lipmann introduced the term “high energy phosphate bond”. This concept has had profound effects on the development of biochemical thinking and has led to a considerable preoccupation with free energy changes, either actual or standard, associated with metabolic reactions and, in particular, with the hydrolysis of ATP. In this paper we wish to propose the view that the original concept put forward by Lipmann was ill-founded and that its effect is to divert attention from the genuine problem of the mechanism of events in which ATP takes part. We shall show that (a) the hydrolysis of ATP is a forbidden reaction in intermediary metabolism, (b) that the Lipmann concept would be appropriate for a closed system containing energy-linked reactions (of which there are no known examples in biochemistry) and (c), most importantly, that since real organisms are openand not closedsystems even the direction of flow of matter through a particular unit step cannot be predicted from the associated standard free energy change but only from the properties of the whole system making up the steady state. In other words simple thermodynamic parameters are irrelevant in discussing whole organisms: these must be understood in kinetic and mechanistic terms. We shall illustrate these ideas by considering some metabolic processes and, in particular, we shall show that for oxidative phosphorylation the exclusion of simple thermodynamic considerations enormously simplifies the discussion and leads naturally to a plausible mechanism for ATP formation. We shall conclude by considering the factors which may have been important in the selection of ATP for its metabolic role. Although the values of the standard free energies of hydrolysis of phosphate esters are irrelevant in vivo, a critical account is given in the Appendix of the experimental data on which the accepted values are based. Brief accounts of these views have already been published.