FACTORS LIMITING ADENOSINE-TRIPHOSPHATASE FUNCTION DURING HIGH-INTENSITY EXERCISE - THERMODYNAMIC AND REGULATORY CONSIDERATIONS

It is widely accepted that a structural organisation favouring interac tion between functionally-related enzymes is required for the economy and efficiency of metabolic reactions. Many functionary-related enzyme s have been shown to be reversibly bound to cellular structures and to other enzymes at the sites where they are required. Resulting from th is binding, close structural proximity and concentration of enzymes, a microenvironment is generated where the product of one enzyme is the substrate of the other. This reduces the diffusion distance for the su bstrate, saturates binding sites with maximal speed and, as a final ou tcome, increases the efficiency and economy of function behind these m etabolic reactions. Available data indicate that the above-described a ssociation between adenosine triphosphatase (ATPase) and enzymes regen erating ATP has an important role in the regulation of ATPase function . A general consensus exists among published studies that the concentr ation of ATP ([ATP]) is not significantly decreased in fatigued muscle , even in those with severely diminished power output. However, in stu dies with isolated perfused hearts it has been possible to significant ly reduce [ATP] in muscle cells without compromising mechanical activi ty. An explanation for this discrepancy is connected with local ATP re generation in the vicinity of ATPase. Furthermore, when ATP regenerati on is unable to balance ATP consumption a critical drop in the free en ergy of ATP hydrolysis is avoided by down-regulation of ATP consumptio n. The main function of local ATP regeneration is to maintain a low co ncentration of adenosine diphosphate ([ADP]), and the ADP/ATP ratio in the vicinity of the ATP-binding site of ATPase that is a prerequisite for high thermodynamic efficiency of ATP hydrolysis. Close proximity of creatine kinase and glycolytic enzymes to ATPase and high-affinity binding of substrates generate an ATPase microenvironment, where ADP a nd ATP are not in free equilibrium with those adenine nucleotides in t he surrounding medium. In the physiological range of operation for imp ortant cellular ATPases (free energy change of 55 to 60 KJ/mol ATP) on ly a small fraction of energy, available in ATP, can be utilised, prov ided that no ATP regeneration takes place. However, ATP regeneration a llows utilisation of most of the regenerating capacity, before ATP hyd rolysis drops below the critical 55 kJ/mol. The importance of local AT P regeneration increases in parallel with an increase in the rate of A TPase turnover. Furthermore, the time during which cells can maintain high rates of ATP hydrolysis depends on the capacity of mechanisms for local ATP regeneration, provided that ATPase is not inhibited by fact ors other than the reaction products. When this capacity is exhausted and the ADP/ATP ratio starts to increase, a further decrease in the fr ee energy of ATP hydrolysis is avoided by down-regulation of ATP consu mption. Because cellular ATPases, and especially sarcoplasmic reticulu m Ca++-ATPase, require substantial amounts of the free energy availabl e from ATP hydrolysis, this down-regulation of ATP hydrolysis is direc ted to maintain that level of structural organisation (primarily ionic gradients) which is essential for living cells. Consequently, the bio logical significance of this down-regulation is to prevent an increase in entropy and irreversible structural changes.