Chapter 1 Cellular ATP

Abstract

Summary ATP is a kinetically stable molecule with a high free energy of hydrolysis/high phosphate transfer potential. This means it can act as a common unit of exchange of energy between a variety of highly exergonic catabolic processes and energy requiring reactions within the aqueous medium of a cell. The chemical nature of the ATP molecule means that it can drive a wide variety of such reactions, including movement of ions and proteins, dehydrations (in macromolecule biosyntheses), activation of small molecules, and imparting a negative charge to sugars and proteins. The relative contributions of these processes to the energy demand of a cell depends on the tissue; muscle expends some 70% of its ATP turnover on movements of actomyosin, brain about 40% of its ATP on Na + transport, and exocrine cells about 50% on biosyntheses. The molecular basis for the coupling of ATP hydrolysis to non-chemical processes (e.g., muscle contraction, ion pumping) is not precisely known. A model is presented in which the transducing enzyme can manipulate the stages in the release of energy from ATP to link binding energy changes to conformational changes. This rationale unifies existing schemes for the function of these enzymes, and also for the functioning of the mitochondrial ATP synthase, which couples transmembrane proton flow to ATP synthesis. In humans, the bulk of ATP synthesis occurs via oxidative phosphorylation in mitochondria, although the fuel oxidized is dependent on tissue. In some tissues (and in rapidly growing tumors), however, considerable amounts of ATP are made by glycolytic conversion of glucose to lactate. This reflects an adaptation of these tissues to specific functions; for example, sustained contraction (and hence restricted O 2 supply) in white muscle or a high requirement for biosynthetic precursors (e.g., in lymphocytes). ATP levels inside cells are maintained very precisely (around 8 mM) under all physiological conditions by increasing the rate of ATP synthesis to match demand. In contrast, rates of ATP synthesis can vary greatly (5–100-fold) with the energy demands of the tissue. Together, these facts indicate that ATP itself cannot regulate its own synthesis. Cytoplasmic (glycolytic) ATP synthesis is regulated internally by AMP, changes in whose concentration amplify the changes in [ATP]; other regulators are Ca 2+ and cAMP, which signal an actual or potential increased work rate by the tissue. Mitochondrial (oxidative) ATP synthesis is regulated by cytoplasmic ADP (entering via the adenine nucleotide translocase) and/or by cytoplasmic Ca 2+ (entering via the Ca 2+ uniport), depending on the tissue. Prolonged ATP depletion leads to cell death, largely due to the development of ionic and osmotic imbalance. Such depletion occurs in a variety of clinical conditions. There may be deficiencies in the enzymes of ATP production (e.g., pyruvate kinase, pyruvate dehydrogenase, mitochondrial dehydrogenases) or conditions which lead to abnormal ATP utilization (e.g., fructose intolerance, malignant hyperpyrexia, ischemia/reperfusion). The resulting symptoms vary considerably, depending on the tissue most susceptible to the defect.