Biological energy transduction
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Adenosine triphosphate as the currency of energy exchange
When the terminal phosphate group is removed from ATP by hydrolysis, two negatively charged products are formed, ADP3− and the phosphate group HPO42− (reaction [47]).
These products are electrically more stable than the parent molecule and do not readily recombine. The total free energy (G) of the products is much less than that of ATP; hence, energy is liberated (i.e., the reaction is exergonic). The amount of energy liberated under strictly defined conditions is called the standard free energy change (ΔG′). This value for the hydrolysis of ATP is relatively high, at −8 kilocalories per mole. (One kilocalorie is the amount of heat required to raise the temperature of 1,000 grams of water one degree Celsius.) Conversely, the formation of ATP from ADP and inorganic phosphate (Pi) is an energy-requiring (i.e., endergonic) reaction with a standard free energy change of +8 kilocalories per mole.
The hydrolysis of the remaining phosphate-to-phosphate bond of ADP is also accompanied by a liberation of free energy (the standard free energy change is −6.5 kilocalories per mole); AMP hydrolysis liberates less energy (the standard free energy change is −2.2 kilocalories per mole).
The free energy of hydrolysis of a compound thus is a measure of the difference in energy content between the starting substances (reactants) and the final substances (products). ATP does not have the highest standard free energy of hydrolysis of all the naturally occurring phosphates but instead occupies a position at approximately the halfway point in a series of phosphate compounds with a wide range of standard free energies of hydrolysis. Compounds such as 1,3-diphosphoglycerate and phosphoenolpyruvate (PEP), which are above ATP on the scale, have large negative ΔG′ values on hydrolysis and are often called high-energy phosphates. They are said to exhibit a high phosphate group transfer potential because they have a tendency to lose their phosphate groups. Compounds such as glucose 6-phosphate and fructose 6-phosphate, which are below ATP on the scale because they have smaller negative ΔG′ values on hydrolysis, have a tendency to hold on to their phosphate groups and thus act as low-energy phosphate acceptors.
Both ATP and ADP act as intermediate carriers for the transfer of phosphate groups (which are more precisely called phosphoryl groups), and hence of energy, from compounds lying above ATP to those lying beneath it. Thus, in glycolysis, ADP acts as an acceptor of a phosphate group during the synthesis of ATP from PEP (reaction [10]), and ATP functions as a donor of a phosphate group during the formation of fructose 1,6-diphosphate from fructose 6-phosphate (reaction [3]).
The first step in glycolysis, the formation of glucose 6-phosphate (G6P), illustrates how an energetically unfavourable reaction may become feasible under intracellular conditions by coupling it to ATP.
Reaction [48] has a positive ΔG′ value, indicating that the reaction tends to proceed in the reverse direction. It is therefore necessary to use the standard free energy generated by the breaking of the first phosphate bond in ATP (reaction [48a]), which is −7.3 kilocalories per mole, to move reaction [48] in the forward direction. Combining these reactions and their standard free energies gives reaction [48b] and a standard free energy value of −4 kilocalories per mole, indicating that the reaction will proceed in the forward direction. There are many intracellular reactions in which the formation of ADP or AMP from ATP provides energy for otherwise unfavourable biosyntheses. Some cellular reactions use equivalent phosphorylated analogues of ATP—for example, guanosine triphosphate (GTP) for protein synthesis.
The function of ATP as a common intermediate of energy transfer during anabolism is further dealt with below (see The biosynthesis of cell components). In certain specialized cells or tissues, the chemical energy of ATP is used to perform work other than the chemical work of anabolism—for example, mechanical work, such as muscular contraction or the movement of contractile structures called cilia and flagella, which are responsible for the motility of many small organisms. The performance of osmotic work also requires ATP—e.g., the transport of ions or metabolites through membranes against a concentration gradient, a process that is basically responsible for many physiological functions, including nerve conduction, the secretion of hydrochloric acid in the stomach, and the removal of water from the kidneys.
Energy conservation
The amount of ATP in a cell is limited, and it must be replaced continually to maintain repair and growth. This is achieved by using the energy liberated during the oxidative stages of catabolism to synthesize ATP from ADP and phosphate. The synthesis of ATP linked to catabolism occurs by two distinct mechanisms: substrate-level phosphorylation and oxidative, or respiratory-chain, phosphorylation. Oxidative phosphorylation is the major method of energy conservation under aerobic conditions in all nonphotosynthetic cells.
Substrate-level phosphorylation
In substrate-level phosphorylation a phosphoryl group is transferred from an energy-rich donor (e.g., 1,3-diphosphoglycerate) to ADP to yield a molecule of ATP. This type of ATP synthesis (reactions [7], [10], and [43]) does not require molecular oxygen (O2), although it is frequently, but not always, preceded by an oxidation (i.e., dehydrogenation) reaction. Substrate-level phosphorylation is the major method of energy conservation in oxygen-depleted tissues and during fermentative growth of microorganisms.
Oxidative, or respiratory-chain, phosphorylation
In oxidative phosphorylation the oxidation of catabolic intermediates by molecular oxygen occurs via a highly ordered series of substances that act as hydrogen and electron carriers. They constitute the electron transfer system, or respiratory chain. In most animals, plants, and fungi, the electron transfer system is fixed in the membranes of mitochondria; in bacteria (which have no mitochondria) this system is incorporated into the plasma membrane. Sufficient free energy is released to allow the synthesis of ATP by a process described below. First, however, it is necessary to consider the nature of the respiratory chain.
The nature of the respiratory chain
Four types of hydrogen or electron carriers are known to participate in the respiratory chain, in which they serve to transfer two reducing equivalents (2H) from reduced substrate (AH2) to molecular oxygen (reaction [49]); the products are the oxidized substrate (A) and water (H2O).
The carriers are NAD+ and, less frequently, NADP+; the flavoproteins FAD and FMN (flavin mononucleotide); ubiquinone (or coenzyme Q); and several types of cytochromes. Each carrier has an oxidized and reduced form (e.g., FAD and FADH2, respectively), the two forms constituting an oxidation-reduction, or redox, couple. Within the respiratory chain, each redox couple undergoes cyclic oxidation-reduction; i.e., the oxidized component of the couple accepts reducing equivalents from either a substrate or a reduced carrier preceding it in the series and in turn donates these reducing equivalents to the next oxidized carrier in the sequence. Reducing equivalents are thus transferred from substrates to molecular oxygen by a number of sequential redox reactions.
Most oxidizable catabolic intermediates initially undergo a dehydrogenation reaction, during which a dehydrogenase enzyme transfers the equivalent of a hydride ion (H+ + 2e−, with e− representing an electron) to its coenzyme, either NAD+ or NADP+. The reduced NAD+ (or NADP+) thus produced (usually written as NADH + H+ or NADPH + H+) diffuses to the membrane-bound respiratory chain to be oxidized by an enzyme known as NADH dehydrogenase; the enzyme has as its coenzyme FMN. There is no corresponding NADPH dehydrogenase in mammalian mitochondria; instead, the reducing equivalents of NADPH + H+ are transferred to NAD+ in a reaction catalyzed by a transhydrogenase enzyme, with the products being reduced NADH + H+ and NADP+. A few substrates (e.g., acyl coenzyme A and succinate; reactions [22] and [44]) bypass this reaction and instead undergo immediate dehydrogenation by specific membrane-bound dehydrogenase enzymes. During the reaction, the coenzyme FAD accepts two hydrogen atoms and two electrons (2H + 2e−). The reduced flavoproteins (i.e., FMNH2 and FADH2) donate their two hydrogen atoms to the lipid carrier ubiquinone, which is thus reduced.
The fourth type of carrier, the cytochromes, consists of hemoproteins—i.e., proteins with a nonprotein component, or prosthetic group, called heme (or a derivative of heme), which is an iron-containing pigment molecule. The iron atom in the prosthetic group is able to carry one electron and oscillates between the oxidized, or ferric (Fe 3+), and the reduced, or ferrous (Fe 2+), forms. The five cytochromes present in the mammalian respiratory chain, designated cytochromes b, c1, c, a, and a3, act in sequence between ubiquinone and molecular oxygen. The terminal cytochrome of this sequence (a3, also known as cytochrome oxidase) is able to donate electrons to oxygen rather than to another electron carrier; a3 is also the site of action of two substances that inhibit the respiratory chain, potassium cyanide and carbon monoxide. Special Fe-S complexes play a role in the activity of NADH dehydrogenase and succinate dehydrogenase.
In each redox couple, the reduced form has a tendency to lose reducing equivalents (i.e., to act as an electron or hydrogen donor); similarly, the oxidized form has a tendency to gain reducing equivalents (i.e., to act as an electron or hydrogen acceptor). The oxidation-reduction characteristics of each couple can be determined experimentally under well-defined standard conditions. The value thus obtained is the standard oxidation-reduction (redox) potential (Eó). Values for respiratory chain carriers range from Eó = −320 millivolts (one millivolt = 0.001 volt) for NAD+/reduced NAD+ to Eó = +820 millivolts for 1/2O2/H2O; the values for intermediate carriers lie between. Reduced NAD+ is the most electronegative carrier, oxygen the most electropositive acceptor. During respiration, reducing equivalents undergo stepwise transfer from the reduced form of the most electronegative carrier (reduced NAD+) to the oxidized form of the most electropositive couple (oxygen). Each step is accompanied by a decline in standard free energy (ΔG′) proportional to the difference in the standard redox potentials (ΔE0) of the two carriers involved.
Overall oxidation of reduced NAD+ by oxygen (ΔE0 = +1,140 millivolts) is accompanied by the liberation of free energy (ΔG′ = −52.4 kilocalories per mole). In theory, this energy is sufficient to allow the synthesis of six or seven molecules of ATP. In the cell, however, this synthesis of ATP, called oxidative phosphorylation, proceeds with an efficiency of about 46 percent. Thus, only three molecules of ATP are produced per atom of oxygen consumed—this being the so-called P/2e-, P/O, or ADP/O ratio. The energy that is not conserved as ATP is lost as heat. The oxidation of succinate by molecular oxygen (ΔE0 = +790 millivolts), which is accompanied by a smaller liberation of free energy (ΔG′ = −36.5 kilocalories per mole), yields only two molecules of ATP per atom of oxygen consumed (P/O = 2).