ATP is able to act as a donor of high-energy phosphate to form those compounds below it in Table 11–1. Likewise, with the necessary enzymes, ADP can accept high-energy phosphate to form ATP from those compounds above ATP in the table. In effect, an ATP/ADP cycle connects those processes that generate ~Ⓟ to those processes that utilize ~Ⓟ (Figure 11–7), continuously consuming and regenerating ATP. This occurs at a very rapid rate since the total ATP/ADP pool is extremely small and sufficient to maintain an active tissue for only a few seconds.
Role of ATP/ADP cycle in transfer of high-energy phosphate.
There are three major sources of ~Ⓟ taking part in energy conservation or energy capture:
Oxidative phosphorylation is the greatest quantitative source of ~Ⓟ in aerobic organisms. ATP is generated in the mitochondrial matrix as O2 is reduced to H2O by electrons passing down the respiratory chain (see Chapter 13).
Glycolysis. A net formation of two ~Ⓟ results from the formation of lactate from one molecule of glucose, generated in two reactions catalyzed by phosphoglycerate kinase and pyruvate kinase, respectively (see Figure 17–2).
The citric acid cycle. One ~Ⓟ is generated directly in the cycle at the succinate thiokinase step (see Figure 16–3).
Phosphagens act as storage forms of high-energy phosphate and include creatine phosphate, which occurs in vertebrate skeletal muscle, heart, spermatozoa, and brain, and arginine phosphate, which occurs in invertebrate muscle. When ATP is rapidly being utilized as a source of energy for muscular contraction, phosphagens permit its concentrations to be maintained, but when the ATP/ADP ratio is high, their concentration can increase to act as a store of high-energy phosphate (Figure 11–8).
Transfer of high-energy phosphate between ATP and creatine.
When ATP acts as a phosphate donor to form compounds of lower free energy of hydrolysis (Table 11–1), the phosphate group is invariably converted to one of low energy. For example, the phosphorylation of glycerol to form glycerol-3-phosphate:
ATP Allows the Coupling of Thermodynamically Unfavorable Reactions to Favorable Ones
Endergonic reactions cannot proceed without an input of free energy. For example, the phosphorylation of glucose to glucose-6-phosphate, the first reaction of glycolysis (see Figure 17–2):
is highly endergonic and cannot proceed under physiologic conditions. Thus, in order to take place, the reaction must be coupled with another—more exergonic—reaction such as the hydrolysis of the terminal phosphate of ATP.
When (1) and (2) are coupled in a reaction catalyzed by hexokinase, phosphorylation of glucose readily proceeds in a highly exergonic reaction that under physiologic conditions is irreversible. Many “activation” reactions follow this pattern.
Adenylate Kinase (Myokinase) Interconverts Adenine Nucleotides
This enzyme is present in most cells. It catalyzes the following reaction:
Adenylate kinase is important for the maintenance of energy homeostasis in cells because it allows:
High-energy phosphate in ADP to be used in the synthesis of ATP.
The AMP formed as a consequence of activating reactions involving ATP to rephosphorylated to ADP.
AMP to increase in concentration when ATP becomes depleted so that it is able to act as a metabolic (allosteric) signal to increase the rate of catabolic reactions, which in turn lead to the generation of more ATP (see Chapter 14).
When ATP Forms AMP, Inorganic Pyrophosphate (PPi) Is Produced
ATP can also be hydrolyzed directly to AMP, with the release of PPi (Table 11–1). This occurs, for example, in the activation of long-chain fatty acids (see Chapter 22).
This reaction is accompanied by loss of free energy as heat, which ensures that the activation reaction will go to the right, and is further aided by the hydrolytic splitting of PPi, catalyzed by inorganic pyrophosphatase, a reaction that itself has a large ΔG0′ of -19.2 kJ/mol. Note that activations via the pyrophosphate pathway result in the loss of two ~ rather than one, as occurs when ADP and Pi are formed.
A combination of the above reactions makes it possible for phosphate to be recycled and the adenine nucleotides to interchange (Figure 11–9).
Phosphate cycles and interchange of adenine nucleotides.
Other Nucleoside Triphosphates Participate in the Transfer of High-Energy Phosphate
By means of the nucleoside diphosphate (NDP) kinases, UTP, GTP, and CTP can be synthesized from their diphosphates, for example, UDP reacts with ATP to form UTP.
All of these triphosphates take part in phosphorylations in the cell. Similarly, specific nucleoside monophosphate (NMP) kinases catalyze the formation of nucleoside diphosphates from the corresponding monophosphates.
Thus, adenylate kinase is a specialized NMP kinase.