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Adenosine triphosphate (ATP)

Adenosine triphosphate (ATP)

Fig. 11.3 Synthesis of ATP

ATP is a high-(free) energy molecule, but the free energy of the reactants is even larger, so the standard free energy change of the synthesis reaction is negative. Even with the favorable thermochemistry, the reaction needs to be catalyzed by an enzyme in order to proceed at a rate sufficient for the body's needs.

11.4.2 Hydrolysis and Phosphorylation

A critical equilibrium reaction for transferring free energy to other reactions is the hydrolysis of ATP:

where HP2- stands for the orthophosphate ion ( HPO\ ).AG° for this reaction is +8 kJ/mole and the equilibrium constant is:

At 25oC, K = 25, and at normal body temperature (36oC), K = 23.

In itself, reaction (11.4a) is not important. What is important is its effect when coupled to other reactions, such as the phosphorylation of glucose. In abbreviated notation, Eq (11.2) is:

For which AGo = +14 kJ/mole. Because of the positive standard free energy change, a phosphate group cannot be added to glucose by this reaction alone.

However, in the presence of ATP, reaction (11.4c) is "coupled" to reaction (11.4a), leading to the equilibrium reaction:

This reaction has a standard free energy of +22 kJ/mole, corresponding, at room temperature, to an equilibr glucose is:

an equilibrium constant ofK = 1.4x104. The equilibrium ratio of phosphorylated glucose to bare

At pH = 7, even when 95% of the ATP has been converted to ADP, nearly 99% of the glucose has been phosphorylated.

Mechanistically, reaction (11.4d) proceeds by breaking the O-H bond in the hydroxyl group attached to the No. 6 carbon atom in the ring form of glucose (dotted line in Fig. 11.2) and removing the proton. At the same time, the terminal PO group on the ATP molecule is separated from the rest of the molecule at the dotted line in Fig. 11.3 and becomes attached to the glucose molecule where the proton was removed.

Aside from the favorable thermochemistry, an electric feature of the glucose-ATP reaction is very important in cell metabolism. Glucose enters a cell via a carrier protein. Reaction (11.4d) takes place inside the cell with ATP already there. However, the membrane will not pass G6P2- because of its charge. This species is thus trapped in the cell and available for further decomposition, ultimately leading to pyruvate and energy release.

11.4.3 Regeneration of ATP by oxidative phosphorylation

If ATP is consumed by reaction (11.4d), how then does the cell regenerate it? It does so by a process termed oxidative phosphorylation, a reaction that adds a phosphate ion to ADP:

The equilibrium constant for this reaction yields an ATP/ADP ratio of:

would not normally favor the product side; despite the standard free-energy change of -8 kJ/mole (K = 25), an H+ concentration of 10-7 M and an orthophosphate ion concentration of ~ 10-3 M maintains a very small ATP/ADP ratio. However, the reaction does not occur in a manner amenable to simple thermochemical analysis. Rather, it occurs in a particular component of mammalian cells called the mitochondrion. Figure 11.4 illustrates the complexity of a typical cell, with the mitochondrion just one of many similar bodies, all with different functions. A typical mitochondrian is shaped like a loaf of French bread, with a length of about 7 mm and a diameter of 1 mm.

As shown in Fig. 11.5, this unit is comprised of a central matrix separated from an intermembrane space by an inner membrane. Several enzymes are embedded in the inner membrane. Those on the right labeled I, III and IV pump hydrogen ions against their concentration gradient, from the matrix into the intermembrane space. The mechanism by which protons produced along with the glucose-6-phosphate by reaction (11.4d) are pumped out of the matrix is too complex to describe here, but a description of it is given in Ref. 1. How this proton pump alters the unfavorable equilibrium thermochemistry is explained by the following quasi-thermodynamic model.

The "oxidative" portion of the overall process takes place in or at these enzymes. Oxygen reacts with many nucleotides, the most important of which is NADH2:

The standard free-energy change for this reaction is - 260 kJ/mole.

This reaction (and others like it), uses its large negative AG° to "pump" protons from the matrix through the enzymes in the inner membrane and into the intermembrane space. This process creates a higher H+ concentration in the intermembrane space than in the matrix, thereby setting up both an electric field and a proton driving force across the inner membrane. The combination produces a reservoir of free energy given by:

2 NADH is the acronym for the reduced form of nucotinamide adenine dinucleotide, the structure of which is shown in Fig. 13.16 of Ref. 1

AG = FAf + RT lnf [H ]im I = FAf + 2.3RTA(pH) (11.7)

where F is the Faraday and R is the gas constant. The subscripts IM and MA refer to the intermembrane space and the matrix, respectively. A(pH) is the difference in pH across the membrane, which is estimated to be about 1. The electric potential difference is ~ 0.2 V. As the

Fig. 11.4 Components of a typical cell (fromW. Yang, "Biothermal-fluid Sciences", Hemisphere Publishing (1989))
Fig. 11.5 The mitochondrian component of the cell (from Wikipedia)

protons return to the matrix via the ATP synthase enzyme3 in Fig. 11.4b, these two effects provide an additional ~ 20 kJ/mole to AG° of reaction (11.5), effectively upping the free-energy driving force to -28 kJ/mole. From an equilibrium thermodynamic point of view, this augmented AGo is still insufficient to convert a significant fraction of the ADP to ATP by reaction (11.4e). The equilibrium constant is increased from 25 to ~ 105, which still cannot overcome the low concentrations of the orthophosphate ions and H+.

The process can be better viewed by converting the free-energy changes to work according to Eq (1.20) (reversible work of any process that takes place at constant T and p equals the negative of the free-energy change). Thus the work input in pumping protons from the matrix to the intermembrane space (wH ~ 20 kJ per mole of H+) is available for driving reaction (11.4e) as the protons return to the matrix. The work required for this process is calculated from the nonequilibrium version of Eq (11.5). With typical (measured) concentrations of the species involved in reaction (11.4e), the work necessary to drive the reaction is4:

3 ATP synthase is a very large enzyme consisting of ~ 23,000 atoms and ~3000 amino acids. (see Fig. 5)

4 WATP is negative because it represents work done on the system (the ATP synthase enzyme), not by the system

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