Just as commerce is facilitated by the use of a common monetary currency, the commerce of the cell—metabolism—is facilitated by the use of a common energy currency, adenosine triphosphate (ATP). Part of the free energy derived from the oxidation of carbon fuels and from light is transformed into this readily available molecule, which acts as the free-energy donor in most energy-requiring processes such as motion, active transport, or biosynthesis. Indeed, most of catabolism consists of reactions that extract energy from fuels such as carbohydrates and fats and convert it into ATP. Interestingly, the other nucleoside triphosphates are as energy rich as ATP and are in fact sometimes used as free-energy donors. The reason why ATP, and not another nucleoside triphosphate, is the cellular energy currency is lost in evolutionary history.

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ATP is a nucleotide consisting of adenine, a ribose, and a triphosphate unit (Figure 15.4). In considering the role of ATP as an energy carrier, we can focus on its triphosphate moiety. ATP is an energy-rich molecule because its triphosphate unit contains two phosphoanhydride linkages. Phosphoanhydride linkages are formed between two phosphoryl groups accompanied by the loss of a molecule of water. A large amount of free energy is liberated when ATP is hydrolyzed to adenosine diphosphate (ADP) and orthophosphate (P_i) or when ATP is hydrolyzed to adenosine monophosphate (AMP) and pyrophosphate (PP_i):

The precise ΔG°′ for these reactions depends on the ionic strength of the medium and on the concentrations of Mg²⁺ and other metal ions in the medium (problems 27 and 32). Under typical cellular concentrations, the actual ΔG for these hydrolyses is approximately −50 kJ mol⁻¹ (−12 kcal mol⁻¹).

The free energy liberated in the hydrolysis of ATP is harnessed to drive reactions that require an input of free energy, such as muscle contraction. In turn, ATP is formed from ADP and P_i when fuel molecules are oxidized in chemotrophs or when light is trapped by phototrophs. This ATP–ADP cycle is the fundamental mode of energy exchange in biological systems.

An otherwise unfavorable reaction can be made possible by coupling to ATP hydrolysis. Consider an endergonic chemical reaction, a reaction that would not occur without an input of free energy, but yet is required for biosynthetic pathway.

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Suppose that the standard free energy of the conversion of compound A into compound B is + 16.7 kJ mol⁻¹ (+4.0 kcal mol⁻¹):

The equilibrium constant K′_eq of this reaction at 25°C is related to ΔG°′ (in units of kilojoules per mole) by

Thus, the net conversion of A into B cannot take place when the molar ratio of B to A is equal to or greater than 1.15 × 10⁻³. However, A can be converted into B under these conditions if the reaction is coupled to the hydrolysis of ATP. Under standard conditions, the ΔG°′ of hydrolysis is approximately −30.5 kJ mol⁻¹ (−7.3 kcal mol⁻¹). The new overall reaction is

Its free-energy change of −13.8 kJ mol⁻¹ (−3.3 kcal mol⁻¹) is the sum of the value of ΔG°′ for the conversion of A into B [+16.7 kJ mol⁻¹ (+4.0 kcal mol⁻¹)] and the value of ΔG°′ for the hydrolysis of ATP [−30.5 kJ mol⁻¹ (−7.3 kcal mol⁻¹)]. At pH 7, the equilibrium constant of this coupled reaction is

At equilibrium, the ratio of [B] to [A] is given by

which means that the hydrolysis of ATP enables compound A to be converted into compound B until the [B]/[A] ratio reaches a value of 2.67 × 10². This equilibrium ratio is strikingly different from the value of 1.15 × 10⁻³ for the reaction A → B in the absence of ATP hydrolysis. In other words, coupling the hydrolysis of ATP with the conversion of A into B under standard conditions has changed the equilibrium ratio of B to A by a factor of about 10⁵. If we were to use the ΔG° of hydrolysis of ATP under cellular conditions [−50.2 kJ mol⁻¹ (−12 kcal mol⁻¹)] in our calculations instead of ΔG°′, the change in the equilibrium ratio would be even more dramatic, of the order of 10⁸ (problem 31).

We see here the thermodynamic essence of ATP’s action as an energy-coupling agent. In the cell, the hydrolysis of an ATP molecule in a coupled reaction changes the equilibrium ratio of products to reactants by a very large factor. Thus, a thermodynamically unfavorable reaction sequence can be converted into a favorable one by coupling it to the hydrolysis of ATP molecules in a new reaction.

Note that A and B in the preceding coupled reaction may be interpreted very generally, not only as different metabolites. For example, A and B may represent activated and unactivated conformations of a protein that is activated by phosphorylation with ATP. Through such changes in protein conformation, muscle proteins convert the chemical energy of ATP into the mechanical energy of muscle contraction. Alternatively, A and B may refer to the concentrations of an ion or molecule on the outside and inside of a cell, as in the active transport of a nutrient.

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What makes ATP an efficient energy currency? To answer this question, we need a means of comparing the tendency of various organic compounds bearing a phosphoryl group to transfer the phosphoryl group to an acceptor molecule. A common means of comparison is to determine the amount of energy released when the phosphorylated compound transfers the phosphoryl group to water under standard conditions. The energy released is called the standard free energy of hydrolysis. Let us compare the standard free energy of hydrolysis of ATP with that of a phosphate ester, such as glycerol 3-phosphate:

The magnitude of ΔG°′ for the hydrolysis of glycerol 3-phosphate is much smaller than that of ATP, which means that the tendency of ATP to transfer its terminal phosphoryl group to water is stronger than that of glycerol 3-phosphate. In other words, ATP has a larger phosphoryl-transfer potential (phosphoryl-group-transfer potential) than does glycerol 3-phosphate.

The high phosphoryl-transfer potential of ATP can be explained by features of the ATP structure. Because ΔG°′ depends on the difference in free energies of the products and reactants, we need to examine the structures of both ATP and its hydrolysis products, ADP and P_i, to understand the basis of high phosphoryl-transfer potential. Four factors differentiate the stability of the reactants and products: electrostatic repulsion, resonance stabilization, an increase in entropy, and stabilization due to hydration.

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ATP is often called a high-energy phosphate compound, and its phosphoanhydride bonds are referred to as high-energy bonds. Indeed, a “squiggle” (~P) is often used to indicate such a bond. Nonetheless, there is nothing special about the bonds themselves. They are high-energy bonds in the sense that much free energy is released when they are hydrolyzed, for the reasons listed above.

The standard free energies of hydrolysis provide a convenient means of comparing the phosphoryl-transfer potential of phosphorylated compounds. Such comparisons reveal that ATP is not the only compound with a high phosphoryl-transfer potential. In fact, some compounds in biological systems have a higher phosphoryl-transfer potential than that of ATP. These compounds include phosphoenolpyruvate (PEP), 1,3-bisphosphoglycerate (1,3-BPG), and creatine phosphate (Figure 15.7). Thus, PEP can transfer its phosphoryl group to ADP to form ATP. Indeed, this transfer is one of the ways in which ATP is generated in the breakdown of sugars (Chapter 16). Of significance is that ATP has a phosphoryl-transfer potential that is intermediate among the biologically important phosphorylated molecules (Table 15.1). This intermediate position enables ATP to function efficiently as a carrier of phosphoryl groups.

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We have seen in Chapter 13 and in this chapter the prominence of phosphoryl group transfer from ATP to acceptor molecules. How is it that phosphate came to play such a prominent role in biology? Phosphate and its esters have several characteristics that render it useful for biochemical systems. First, phosphate esters have the important property of being thermodynamically unstable while being kinetically stable. Phosphate esters are thus molecules whose energy release can be manipulated by enzymes. Second, the stability of phosphate esters is due to the negative charges that make them resistant to hydrolysis in the absence of enzymes. This accounts for the presence of phosphate in the backbone of DNA. Third, because phosphate esters are so kinetically stable, they make ideal regulatory molecules, added to proteins by kinases and removed only by phosphatases. As we will see many times, phosphates are also frequently added to metabolites that might otherwise diffuse through the cell membrane.

No other ions have the chemical characteristics of phosphate. Citrate is not sufficiently charged to prevent hydrolysis. Arsenate forms esters that are unstable and susceptible to spontaneous hydrolysis. Indeed, arsenate is poisonous to cells because it can replace phosphate in reactions required for ATP synthesis, generating unstable compounds and preventing ATP synthesis. Silicate is more abundant than phosphate, but silicate salts are virtually insoluble, and in fact, are used for biomineralization. Only phosphate has the chemical properties to meet the needs of living systems.