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Berg JM, Tymoczko JL, Stryer L. Biochemistry. 5th edition. New York: W H Freeman; 2002.

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Biochemistry. 5th edition.

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Section 17.1The Citric Acid Cycle Oxidizes Two-Carbon Units

Acetyl CoA is the fuel for the citric acid cycle. This important molecule is formed from the breakdown of glycogen (the storage form of glucose), fats, and many amino acids. Indeed, as we will see in Chapter 22, fats contain strings of reduced two-carbon units that are first oxidized to acetyl CoA and then completely oxidized to CO2 by the citric acid cycle.

17.1.1. The Formation of Acetyl Coenzyme A from Pyruvate

The formation of acetyl CoA from carbohydrates is less direct than from fat. Recall that carbohydrates, most notably glucose, are processed by glycolysis into pyruvate (Chapter 16). Under anaerobic conditions, the pyruvate is converted into lactic acid or ethanol, depending on the organism. Under aerobic conditions, the pyruvate is transported into mitochondria in exchange for OH- by the pyruvate carrier, an antiporter (Section 13.4). In the mitochondrial matrix, pyruvate is oxidatively decarboxylated by the pyruvate dehydrogenase complex to form acetyl CoA.

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This irreversible reaction is the link between glycolysis and the citric acid cycle. (Figure 17.4) Note that, in the preparation of the glucose derivative pyruvate for the citric acid cycle, an oxidative decarboxylation takes place and high-transfer-potential electrons in the form of NADH are captured. Thus, the pyruvate dehydrogenase reaction has many of the key features of the reactions of the citric acid cycle itself.

Figure 17.4. The Link between Glycolysis and the Citric Acid Cycle.

Figure 17.4

The Link between Glycolysis and the Citric Acid Cycle. Pyruvate produced by glycolysis is converted into acetyl CoA, the fuel of the citric acid cycle.

The pyruvate dehydrogenase complex is a large, highly integrated complex of three kinds of enzymes (Table 17.1). Pyruvate dehydrogenase is a member of a family of homologous complexes that includes the citric acid cycle enzyme α-ketoglutarate dehydrogenase (Section 17.1.6), a branched-chain α-ketoacid dehydrogenase, and acetoin dehydrogenase, found in certain prokaryotes. These complexes are giant, with molecular masses ranging from 4 to 10 million daltons (Figure 17.5). As we will see, their elaborate structures allow groups to travel from one active site to another, connected by tethers to the core of the structure. The mechanism of the pyruvate dehydrogenase reaction is wonderfully complex, more so than is suggested by its relatively simple stoichiometry. The reaction requires the participation of the three enzymes of the pyruvate dehydrogenase complex, each composed of several polypeptide chains, and five coenzymes: thiamine pyrophosphate (TPP), lipoic acid, and FAD serve as catalytic cofactors, and CoA and NAD+ are stoichiometric cofactors.

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Table 17.1. Pyruvate dehydrogenase complex of E. coli.

Table 17.1

Pyruvate dehydrogenase complex of E. coli.

Figure 17.5. Electron Micrograph of the Pyruvate Dehydrogenase Complex From E. coli.

Figure 17.5

Electron Micrograph of the Pyruvate Dehydrogenase Complex From E. coli. [Courtesy of Dr. Lester Reed.]

At least two additional enzymes regulate the activity of the complex.

The conversion of pyruvate into acetyl CoA consists of three steps: decarboxylation, oxidation, and transfer of the resultant acetyl group to CoA.

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These steps must be coupled to preserve the free energy derived from the decarboxylation step to drive the formation of NADH and acetyl CoA. First, pyruvate combines with TPP and is then decarboxylated (Figure 17.6). This reaction is catalyzed by the pyruvate dehydrogenase component (E1) of the multienzyme complex. A key feature of TPP, the prosthetic group of the pyruvate dehydrogenase component, is that the carbon atom between the nitrogen and sulfur atoms in the thiazole ring is much more acidic than most =CH- groups, with a pKa value near 10. This center ionizes to form a carbanion, which readily adds to the carbonyl group of pyruvate.

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Figure 17.6. Mechanism of the Decarboxylation Reaction of E1 , THe Pyruvate Dehydrogenase Component of the Pyruvate Dehydrogenese Complex.

Figure 17.6

Mechanism of the Decarboxylation Reaction of E1 , THe Pyruvate Dehydrogenase Component of the Pyruvate Dehydrogenese Complex.

This addition is followed by the decarboxylation of pyruvate. The positively charged ring of TPP acts as an electron sink that stabilizes the negative charge that is transferred to the ring as part of the decarboxylation. Protonation yields hydroxyethyl-TPP.

Second, the hydroxyethyl group attached to TPP is oxidized to form an acetyl group and concomitantly transferred to lipoamide, a derivative of lipoic acid that is linked to the side chain of a lysine residue by an amide linkage.

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The oxidant in this reaction is the disulfide group of lipoamide, which is reduced to its disulfhydryl form. This reaction, also catalyzed by the pyruvate dehydrogenase component E1, yields acetyllipoamide.

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Third, the acetyl group is transferred from acetyllipoamide to CoA to form acetyl CoA.

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Dihydrolipoyl transacetylase (E2) catalyzes this reaction. The energy-rich thioester bond is preserved as the acetyl group is transferred to CoA. Recall that CoA serves as a carrier of many activated acyl groups, of which acetyl is the simplest (Section 14.3.1). Acetyl CoA, the fuel for the citric acid cycle, has now been generated from pyruvate.

The pyruvate dehydrogenase complex cannot complete another catalytic cycle until the dihydrolipoamide is oxidized to lipoamide. In a fourth step, the oxidized form of lipoamide is regenerated by dihydrolipoyl dehydrogenase (E3). Two electrons are transferred to an FAD prosthetic group of the enzyme and then to NAD+.

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This electron transfer to FAD is unusual, because the common role for FAD is to receive electrons from NADH. The electron transfer potential of FAD is altered by its association with the enzyme and enables it to transfer electrons to NAD+. Proteins tightly associated with FAD or flavin mononucleotide (FMN) are called flavoproteins.

17.1.2. Flexible Linkages Allow Lipoamide to Move Between Different Active Sites

Although the structure of an intact member of the pyruvate dehydrogenase complex family has not yet been determined in atomic detail, the structures of all of the component enzymes are now known, albeit from different complexes and species. Thus, it is now possible to construct an atomic model of the complex to understand its activity (Figure 17.7).

Figure 17.7. Schematic Representation of the Pyruvate Dehydrogenase Complex.

Figure 17.7

Schematic Representation of the Pyruvate Dehydrogenase Complex. The transacetylase core (E2) is shown in red, the pyruvate dehydrogenase component (E1) in yellow, and the dihydrolipoyl dehydrogenase (E3) in green.

The core of the complex is formed by E2. Acetyltransferase consists of eight catalytic trimers assembled to form a hollow cube. Each of the three subunits forming a trimer has three major domains (Figure 17.8). At the amino terminus is a small domain that contains a bound lipoamide cofactor attached to a lysine residue. This domain is homologous to biotin-binding domains such as that of pyruvate carboxylase (see Figure 16.26). The lipoamide domain is followed by a small domain that interacts with E3 within the complex. A larger transacetylase domain completes an E2 subunit. E1 is an α2 β2 tetramer, and E3 is a αβ dimer. Twenty-four copies of E1 and 12 copies of E3 surround the E2 core. How do the three distinct active sites work in concert (Figure 17.9)?

Figure 17.8. Structure of the Transacetylase (E2) core.

Figure 17.8

Structure of the Transacetylase (E2) core. Each red ball represents a trimer of three E2 subunits. Each subunit consists of three domains: a lipoamide-binding domain, a small domain for interaction with E3, and a large transacetylase catalytic domain. (more...)

Figure 17.9. Reactions of the Pyruvate Dehydrogenase Complex.

Figure 17.9

Reactions of the Pyruvate Dehydrogenase Complex. At the top (center), the enzyme (represented by a yellow, a blue, and two red spheres) is unmodified and ready for a catalytic cycle. (1) Pyruvate is decarboxylated to form the hydroxyethyl TPP. (2) The (more...)


Pyruvate is decarboxylated at the active site of E1, forming the substituted TPP intermediate, and CO2 leaves as the first product. This active site lies within the E1 complex, connected to the enzyme surface by a 20-Å-long hydrophobic channel.


E2 inserts the lipoyl-lysine arm of the lipoamide domain into the channel in E1.


E1 catalyzes the transfer of the acetyl group to the lipoamide. The acetylated lipoyl-lysine arm then leaves E1 and enters the E2 cube through 30 Å windows on the sides of the cube to visit the active site of E2, located deep in the cube at the subunit interface.


The acetyl moiety is then transferred to CoA, and the second product, acetyl CoA, leaves the cube. The reduced lipoyl-lysine arm then swings to the active site of the E3 flavoprotein.


At the E3 active site, the lipoamide acid is oxidized by coenzyme FAD.


The final product, NADH, is produced with the reoxidation of FADH2, and the reactivated lipoamide is ready to begin another reaction cycle.

The structural integration of three kinds of enzymes makes the coordinated catalysis of a complex reaction possible. The proximity of one enzyme to another increases the overall reaction rate and minimizes side reactions. All the intermediates in the oxidative decarboxylation of pyruvate are tightly bound to the complex and are readily transferred because of the ability of the lipoyl-lysine arm of E2 to call on each active site in turn.

17.1.3. Citrate Synthase Forms Citrate from Oxaloacetate and Acetyl Coenzyme A

The citric acid cycle begins with the condensation of a four-carbon unit, oxaloacetate, and a two-carbon unit, the acetyl group of acetyl CoA. Oxaloacetate reacts with acetyl CoA and H2O to yield citrate and CoA.

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This reaction, which is an aldol condensation followed by a hydrolysis, is catalyzed by citrate synthase. Oxaloacetate first condenses with acetyl CoA to form citryl CoA, which is then hydrolyzed to citrate and CoA. The hydrolysis of citryl CoA, a high-energy thioester intermediate, drives the overall reaction far in the direction of the synthesis of citrate. In essence, the hydrolysis of the thioester powers the synthesis of a new molecule from two precursors. Because this reaction initiates the cycle, it is very important that side reactions be minimized. Let us briefly consider the how citrate synthase prevents wasteful processes such as the hydrolysis of acetyl CoA.


An enzyme catalyzing a synthetic reaction in which two units are joined without the direct participation of ATP (or another nucleoside triphosphate).

Mammalian citrate synthase is a dimer of identical 49-kd subunits. Each active site is located in a cleft between the large and small domains of a subunit, adjacent to the subunit interface. The results of x-ray crystallographic studies of citrate synthase and its complexes with several substrates and inhibitors revealed that the enzyme undergoes large conformational changes in the course of catalysis. Citrate synthase exhibits sequential, ordered kinetics: oxaloacetate binds first, followed by acetyl CoA. The reason for the ordered binding is that oxaloacetate induces a major structural rearrangement leading to the creation of a binding site for acetyl CoA. The open form of the enzyme observed in the absence of ligands is converted into a closed form by the binding of oxaloacetate (Figure 17.10). In each subunit, the small domain rotates 19 degrees relative to the large domain. Movements as large as 15 Å are produced by the rotation of α helices elicited by quite small shifts of side chains around bound oxaloacetate. This conformational transition is reminiscent of the cleft closure in hexokinase induced by the binding of glucose (Section 16.1.1).

Figure 17.10. Conformational Changes in Citrate Synthase on Binding Oxaloacetate.

Figure 17.10

Conformational Changes in Citrate Synthase on Binding Oxaloacetate. Image mouse.jpg The small domain of each subunit of the homodimer is shown in yellow; the large domain is shown in blue. (Left) Open form of enzyme alone. (Right) Closed form of the liganded enzyme. (more...)

Citrate synthase catalyzes the condensation reaction by bringing the substrates into close proximity, orienting them, and polarizing certain bonds. Two histidine residues and an aspartate residue are important players (Figure 17.11). One of the histidine residues (His 274) donates a proton to the carbonyl oxygen of acetyl CoA to promote the removal of a methyl proton by Asp 375. Oxaloacetate is activated by the transfer of a proton from His 320 to its carbonyl carbon atom. The concomitant attack of the enol of acetyl CoA on the carbonyl carbon of oxaloacetate results in the formation of a carbon-carbon bond. The newly formed citryl CoA induces additional structural changes in the enzyme. The active site becomes completely enclosed. His 274 participates again as a proton donor to hydrolyze the thioester. Coenzyme A leaves the enzyme, followed by citrate, and the enzyme returns to the initial open conformation.

Figure 17.11. Mechanism of Synthesis of Citryl CoA by Citrate Synthase.

Figure 17.11

Mechanism of Synthesis of Citryl CoA by Citrate Synthase. The condensation of oxaloacetate and acetyl CoA proceeds through an enol intermediate. The subsequent hydrolysis of citryl CoA yields citrate and CoA.

We can now understand how the wasteful hydrolysis of acetyl CoA is prevented. Citrate synthase is well suited to hydrolyze citryl CoA but not acetyl CoA. How is this discrimination accomplished? First, acetyl CoA does not bind to the enzyme until oxaloacetate is bound and ready for condensation. Second, the catalytic residues crucial for hydrolysis of the thioester linkage are not appropriately positioned until citryl CoA is formed. As with hexokinase (Section 16.1.1) and triose phosphate isomerase (Section 16.1.4), induced fit prevents an undesirable side reaction.

17.1.4. Citrate Is Isomerized into Isocitrate

The tertiary hydroxyl group is not properly located in the citrate molecule for the oxidative decarboxylations that follow. Thus, citrate is isomerized into isocitrate to enable the six-carbon unit to undergo oxidative decarboxylation. The isomerization of citrate is accomplished by a dehydration step followed by a hydration step. The result is an interchange of a hydrogen atom and a hydroxyl group. The enzyme catalyzing both steps is called aconitase because cis-aconitate is an intermediate.

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Aconitase is an iron-sulfur protein, or nonheme iron protein. It contains four iron atoms that are not incorporated as part of a heme group. The four iron atoms are complexed to four inorganic sulfides and three cysteine sulfur atoms, leaving one iron atom available to bind citrate and then isocitrate through their carboxylate and hydroxyl groups (Figure 17.12). This iron center, in conjunction with other groups on the enzyme, facilitates the dehydration and rehydration reactions. We will consider the role of these iron-sulfur clusters in the electron-transfer reactions of oxidative phosphorylation subsequently (Section 18.3.1).

Figure 17.12. Binding of Citrate to the Iron-Sulfur Complex of Aconitase.

Figure 17.12

Binding of Citrate to the Iron-Sulfur Complex of Aconitase. A 4Fe-4S iron-sulfur cluster is a component of the active site of aconitase. One of the iron atoms of the cluster binds to the carboxylate and hydroxyl groups of citrate.

Image tree.jpg The iron-sulfur cluster in aconitase is somewhat unstable, so one or more iron atoms dissociate under conditions of low iron availability in the cell. Remarkably, this sensitivity to iron level was exploited in the evolution of a mechanism for regulating gene expression in response to iron levels, as will be discussed in Chapter 31.

17.1.5. Isocitrate Is Oxidized and Decarboxylated to α-Ketoglutarate

We come now to the first of four oxidation-reduction reactions in the citric acid cycle. The oxidative decarboxylation of isocitrate is catalyzed by isocitrate dehydrogenase.

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The intermediate in this reaction is oxalosuccinate, an unstable β-ketoacid. While bound to the enzyme, it loses CO2 to form α-ketoglutarate.

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The rate of formation of α-ketoglutarate is important in determining the overall rate of the cycle, as will be discussed in Section 17.2.2. This oxidation generates the first high-transfer-potential electron carrier NADH in the cycle.

17.1.6. Succinyl Coenzyme A Is Formed by the Oxidative Decarboxylation of α-Ketoglutarate

The conversion of isocitrate into α-ketoglutarate is followed by a second oxidative decarboxylation reaction, the formation of succinyl CoA from α-ketoglutarate.

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Image tree.jpg The oxidative decarboxylation of α-ketoglutarate closely resembles that of pyruvate, also an α-ketoacid.

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Both reactions include the decarboxylation of an α-ketoacid and the subsequent formation of a high-transfer-potential thioester linkage with CoA. The complex that catalyzes the oxidative decarboxylation of α-ketoglutarate is homologous to the pyruvate dehydrogenase complex, and the reaction mechanism is entirely analogous. The α-ketoglutarate dehydrogenase component (E2) and transsuccinylase (E1) are different from but homologous to the corresponding enzymes in the pyruvate dehydrogenase complex, whereas the dihydrolipoyl dehydrogenase components (E3) of the two complexes are identical.

17.1.7. A High Phosphoryl-Transfer Potential Compound Is Generated from Succinyl Coenzyme A

Succinyl CoA is an energy-rich thioester compound. The ΔG°′ for the hydrolysis of succinyl CoA is about -8 kcal mol-1 (-33.5 kJ mol-1), which is comparable to that of ATP (-7.3 kcal mol-1, or -30.5 kJ mol-1). In the ci-trate synthase reaction, the cleavage of the thioester bond powers the synthesis of the six-carbon citrate from the four-carbon oxaloacetate and the two-carbon fragment. The cleavage of the thioester bond of succinyl CoA is coupled to the phosphorylation of a purine nucleoside diphosphate, usually GDP. This reaction is catalyzed by succinyl CoA synthetase (succinate thiokinase). This enzyme is an α2β2 heterodimer; the functional unit is one αβ pair. The mechanism is a clear example of energy transformations: energy inherent in the thioester molecule is transformed into phosphoryl-group transfer potential (Figure 17.13). The first step is the displacement of coenzyme A by orthophosphate, which generates another energy-rich compound, succinyl phosphate. A histidine residue of the α subunit removes the phosphoryl group with the concomitant generation of succinate and phosphohistidine. The phosphohistidine residue then swings over to a bound nucleoside diphosphate and the phosphoryl group is transferred to form the nucleoside triphosphate. The participation of high-energy compounds in all the steps is attested to by the fact that the reaction is readily reversible: Δ′ = -0.8 kcal mol-1 (-3.4 kJ mol-1). This is the only step in the citric acid cycle that directly yields a compound with high phosphoryl transfer potential through a substrate-level phosphorylation. Some mammalian succinyl CoA synthetases are specific for GDP and others for ADP. The E. coli enzyme uses either GDP or ADP as the phosphoryl-group acceptor. We have already seen that GTP is an important component of signal-transduction systems (Chapter 15). Alternatively, its γ-phosphoryl group can be readily transferred to ADP to form ATP, in a reaction catalyzed by nucleoside diphosphokinase.

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Figure 17.13. Reaction Mechanism of Succinyl CoA Synthetase.

Figure 17.13

Reaction Mechanism of Succinyl CoA Synthetase. The formation of GTP at the expense of succinyl CoA is an example of substrate-level phosphorylation. The reaction proceeds through a phosphorylated enzyme intermediate.

Image tree.jpg The mechanism of succinyl CoA synthetase reveals that a phosphoryl group is transferred first to succinyl CoA bound in the α subunit and then to a nucleoside diphosphate bound in the β subunit. Examination of the three-dimensional structure of succinyl CoA synthetase shows that each subunit comprises two domains (Figure 17.14). The carboxyl-terminal domains of the two subunits are similar to one another, whereas the amino-terminal domains have different structures, each characteristic of its role in the mechanism. The amino-terminal domain of the α subunit forms a Rossmann fold (Section 16.1.10), which binds the ADP component of succinyl CoA, whereas the amino-terminal domain of the β subunit is an ATP-grasp domain, a nucleotide-activating domain found in many enzymes, especially those catalyzing purine biosynthesis (Section 16.3.2 and Chapter 25). Succinyl CoA synthetase has evolved by adopting these domains and harnessing them to allow the capture of the energy associated with succinyl CoA cleavage to drive the generation of a nucleoside triphosphate.

Figure 17.14. Structure of Succinyl CoA Synthetase.

Figure 17.14

Structure of Succinyl CoA Synthetase. Image mouse.jpg The enzyme is composed of two subunits. The α subunit contains a Rossmann fold that binds the ADP component of CoA, and the β subunit contains a nucleotide-activating region called the ATP-grasp domain. (more...)

17.1.8. Oxaloacetate Is Regenerated by the Oxidation of Succinate

Reactions of four-carbon compounds constitute the final stage of the citric acid cycle: the regeneration of oxaloacetate.

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The reactions constitute a metabolic motif that we will see again in fatty acid synthesis and degradation as well as in the degradation of some amino acids (see Figure 14.17). A methylene group (CH2) is converted into a carbonyl group (C = O) in three steps: an oxidation, a hydration, and a second oxidation reaction. Not only is oxaloacetate thereby regenerated for another round of the cycle, but also more energy is extracted in the form of FADH2 and NADH.

Succinate is oxidized to fumarate by succinate dehydrogenase. The hydrogen acceptor is FAD rather than NAD+, which is used in the other three oxidation reactions in the cycle. In succinate dehydrogenase, the isoalloxazine ring of FAD is covalently attached to a histidine side chain of the enzyme (denoted E-FAD).

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FAD is the hydrogen acceptor in this reaction because the free-energy change is insufficient to reduce NAD+. FAD is nearly always the electron acceptor in oxidations that remove two hydrogen atoms from a substrate.

Succinate dehydrogenase, like aconitase, is an iron-sulfur protein. Indeed, succinate dehydrogenase contains three different kinds of iron-sulfur clusters, 2Fe-2S (two iron atoms bonded to two inorganic sulfides), 3Fe-4S, and 4Fe-4S. Succinate dehydrogenase—which consists of two subunits, one 70 kd and the other 27 kd—differs from other enzymes in the citric acid cycle in being embedded in the inner mitochondrial membrane. In fact, succinate dehydrogenase is directly associated with the electron-transport chain, the link between the citric acid cycle and ATP formation. FADH2 produced by the oxidation of succinate does not dissociate from the enzyme, in contrast with NADH produced in other oxidation-reduction reactions. Rather, two electrons are transferred from FADH2 directly to iron-sulfur clusters of the enzyme. The ultimate acceptor of these electrons is molecular oxygen, as we shall see in Chapter 18.

The next step is the hydration of fumarate to form l-malate. Fumarase catalyzes a stereospecific trans addition of a hydrogen atom and a hydroxyl group. The hydroxyl group adds to only one side of the double bond of fumarate; hence, only the l isomer of malate is formed.

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Finally, malate is oxidized to form oxaloacetate. This reaction is catalyzed by malate dehydrogenase, and NAD+ is again the hydrogen acceptor.

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Note that the standard free energy for this reaction, unlike that for the other steps in the citric acid cycle, is significantly positive. The oxidation of malate is driven by the utilization of the products—oxaloacetate by citrate synthase and NADH by the electron-transport chain.

17.1.9. Stoichiometry of the Citric Acid Cycle

The net reaction of the citric acid cycle is:

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Let us recapitulate the reactions that give this stoichiometry (Figure 17.15 and Table 17.2):

Figure 17.15. The Citric Acid Cycle.

Figure 17.15

The Citric Acid Cycle.

Table 17.2. Citric acid cycle.

Table 17.2

Citric acid cycle.


Two carbon atoms enter the cycle in the condensation of an acetyl unit (from acetyl CoA) with oxaloacetate. Two carbon atoms leave the cycle in the form of CO2 in the successive decarboxylations catalyzed by isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. Interestingly, the results of isotope-labeling studies revealed that the two carbon atoms that enter each cycle are not the ones that leave.


Four pairs of hydrogen atoms leave the cycle in four oxidation reactions. Two molecules of NAD+ are reduced in the oxidative decarboxylations of isocitrate and α-ketoglutarate, one molecule of FAD is reduced in the oxidation of succinate, and one molecule of NAD+ is reduced in the oxidation of malate.


One compound with high phosphoryl transfer potential, usually GTP, is generated from the cleavage of the thioester linkage in succinyl CoA.


Two molecules of water are consumed: one in the synthesis of citrate by the hydrolysis of citryl CoA and the other in the hydration of fumarate.

Recall also that NADH is generated in the formation of acetyl CoA from pyruvate by the pyruvate dehydrogenase reaction.

The efficiency of the citric acid cycle may be enhanced by the arrangement of the constituent enzymes. Evidence is accumulating that the enzymes are physically associated with one another to facilitate substrate channeling between active sites. The word metabolon has been suggested as the name for such multienzyme complexes.

As will be discussed in Chapter 18, the electron-transport chain oxidizes the NADH and FADH2 formed in the citric acid cycle. The transfer of electrons from these carriers to O2, the ultimate electron acceptor, leads to the generation of a proton gradient across the inner mitochondrial membrane. This proton-motive force then powers the generation of ATP; the net stoichiometry is about 2.5 ATP per NADH, and 1.5 ATP per FADH2. Consequently, 9 high-transfer-potential phosphoryl groups are generated when the electron-transport chain oxidizes 3 molecules of NADH and 1 molecule of FADH2, and 1 high-transfer-potential phosphoryl group per acetyl unit is directly formed in the citric acid cycle. Thus, 1 acetate unit generates approximately 10 molecules of ATP. In dramatic contrast, only 2 molecules of ATP are generated per molecule of glucose (which generates 2 molecules of acetyl CoA) by anaerobic glycolysis.

Recall that molecular oxygen does not participate directly in the citric acid cycle. However, the cycle operates only under aerobic conditions because NAD+ and FAD can be regenerated in the mitochondrion only by the transfer of electrons to molecular oxygen. Glycolysis has both an aerobic and an anaerobic mode, whereas the citric acid cycle is strictly aerobic. Glycolysis can proceed under anaerobic conditions because NAD+ is regenerated in the conversion of pyruvate into lactate.

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Copyright © 2002, W. H. Freeman and Company.
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