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Krebs Cycle

Krebs Cycle


The Krebs cycle is a series of enzymatic reactions that catalyzes the aerobic metabolism of fuel molecules to carbon dioxide and water, thereby generating energy for the production of adenosine triphosphate (ATP) molecules. The Krebs cycle is so named because much of its elucidation was the work of the British biochemist Hans Krebs. Many types of fuel molecules can be drawn into and utilized by the cycle, including acetyl coenzyme A (acetyl CoA), derived from glycolysis or fatty acid oxidation . Some amino acids are metabolized via the enzymatic reactions of the Krebs cycle. In eukaryotic cells , all but one of the enzymes catalyzing the reactions of the Krebs cycle are found in the mitochondrial matrixes.

The sequence of events known as the Krebs cycle is indeed a cycle; oxaloacetate is both the first reactant and the final product of the metabolic pathway (creating a loop). Because the Krebs cycle is responsible for the ultimate oxidation of metabolic intermediates produced during the metabolism of fats, proteins, and carbohydrates, it is the central mechanism for metabolism in the cell. In the first reaction of the cycle, acetyl CoA condenses with oxaloacetate to form citric acid. Acetyl CoA utilized in this way by the cycle has been produced either via the oxidation of fatty acids, the breakdown of certain amino acids, or the oxidative decarboxylation of pyruvate (a product of glycolysis). The citric acid produced by the condensation of acetyl CoA and oxaloacetate is a tricarboxylic acid containing three carboxylate groups. (Hence, the Krebs cycle is also referred to as the citric acid cycle or tricarboxylic acid cycle.)

After citrate has been formed, the cycle machinery continues through seven distinct enzyme-catalyzed reactions that produce, in order, isocitrate, α -ketoglutarate, succinyl coenzyme A, succinate, fumarate, malate, and

oxaloacetate. The freshly produced oxaloacetate, in turn, reacts with yet another molecule of acetyl CoA, and the cycle begins again. Each turn of the Krebs cycle produces two molecules of carbon dioxide, one guanosine triphosphate molecule (GTP), and enough electrons to generate three molecules of NADH and one molecule of FADH2.

The Krebs cycle is present in virtually all eukaryotic cells that contain mitochondria, but functions only as part of aerobic metabolism (when oxygen is available). This oxygen requirement is owing to the close relationship between the mitochondrial electron transport chain and the Krebs cycle. In the Krebs cycle, four oxidationreduction reactions occur. A high energy phosphate bond in the form of GTP is also generated. (This high energy phosphate bond is later transferred to adenosine diphosphate [ADP] to form adenosine triphosphate [ATP].) As the enzymes of the Krebs cycle oxidize fuel molecules to carbon dioxide, the coenzymes NAD+, FAD, and coenzyme Q (also known as ubiquinone) are reduced. In order for the cycle to continue, these reduced coenzymes must become reoxidized by transferring their electrons to oxygen, thus producing water. Therefore, the final acceptor of the electrons produced by the oxidation of fuel molecules as part of the Krebs cycle is oxygen. In the absence of oxygen, the Krebs cycle is inhibited.

The citric acid cycle is an amphibolic pathway, meaning that it can be used for both the synthesis and degradation of biomolecules. Besides acetyl CoA (generated from glucose , fatty acids, or ketogenic amino acids), other biomolecules are metabolized by the cycle. Several amino acids are degraded to become what are intermediates of the cycle. Likewise, odd-chain fatty acids are metabolized to form succinyl coenzyme A, another intermediate of the cycle. Krebs cycle intermediates are also used by many organisms for the synthesis of other important biomolecules. Some organisms use the Krebs cycle intermediates α -ketoglutarate and oxaloacetate in the synthesis of several amino acids. Succinyl coenzyme A is utilized in the synthesis of porphyrin rings, used in heme manufacture and chlorophyll biosynthesis . Oxaloacetate and malate are utilized in the synthesis of glucose, in a process known as gluconeogenesis.

see also Glycolysis; Krebs, Hans Adolf.

Robert Noiva

Bibliography

Berg, Jeremy M.; Tymoczko, John L.; and Stryer, Lubert (2002). Biochemistry, 5th edition. New York: W. H. Freeman.

Voet, Donald; Voet, Judith G.; and Pratt, Charlotte W. (2002). Fundamentals of Biochemistry, updated edition. New York: Wiley.

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Krebs Cycle

Krebs Cycle

When glucose is converted to pyruvate during glycolysis , two adenosine triphosphates (ATPs ) are formed, but most of the energy in the original glucose remains in pyruvate. In most aerobic cells, the pyruvate formed by glycolysis is further degraded in a pathway called the Krebs cycle (also called the tricarboxylic acid cycle or citric acid cycle). In the Krebs cycle, the carbon of pyruvate is fully oxidized to carbon dioxide in a series of oxidationreduction reactions. During these reactions, much of the energy in the original pyruvate is carried as high-energy electrons by the electron shuttles NADH and FADH2. These electrons will ultimately be passed to the electron transport chain, where their energy will be used to synthesize ATP by oxidative phosphorylation . Much more ATP is made by the Krebs cycle and oxidative phosphorylation than by glycolysis alone.

In eukaryotic cells , pyruvate is transported to the mitochondrial matrix , where the Krebs cycle takes place. Before entering the Krebs cycle, the three-carbon pyruvate is oxidized to a two-carbon acetate molecule and carbon dioxide, producing one molecule of NADH. The acetate joins to a molecule of coenzyme A to form acetyl coenzyme A, which carries the acetyl group to the Krebs cycle. The acetate enters the cycle by combining with OAA (oxaloacetic acid) to form citric acid. At this point, two of the original three carbon atoms in pyruvate have been incorporated into citric acid and one has been oxidized to carbon dioxide, and one molecule of NADH has been produced.

As the reactions of the Krebs cycle continue, the two acetyl carbons are successively oxidized to carbon dioxide, forming two molecules of NADH and one of FADH2, which will provide electrons to the electron transport chain to form ATP. In addition, one guanosine triphosphate (GTP) is formed directly by substrate-level phosphorylation , or transfer of a phosphate directly from the reacting molecules. (The GTP eventually transfers its phosphate to form ATP.) The final unoxidized product of the entire cycle is OAA, which can accept another acetyl group to start the cycle again.

The Krebs cycle occupies a central position in cellular metabolism . It can break down the pyruvate produced in glycolysis, but these two pathways do not form an isolated system in cells. Both are linked to other processes in many ways. Acetyl coenzyme A is produced by other means, notably by fatty-acid oxidation, and the Krebs cycle will oxidize this acetyl coenzyme A as readily as that produced from pyruvate.

Similarly, other substances are fed into the Krebs cycle at this and other points, either to be consumed as fuel or to be transformed for other cellular needs. For example, amino acids can be consumed by entering the Krebs cycle at several points. Conversely, several amino acids can be synthesized from intermediates of the Krebs cycle. Thus the Krebs cycle can serve either to degrade amino acids, releasing energy in the process, or to supply precursor molecules for amino acid synthesis. Which of these activities prevails depends on the needs of the cell at any particular time.

see also Glycolysis and Fermentation; Metabolism, Cellular; Mitochondrion; Oxidative Phosphorylation

David W. Tapley

Bibliography

Bodner, G. M. "The Tricarboxylic Acid (TCA), Citric Acid or Krebs Cycle." Journal of Chemical Education 63 (1986): 673677.

Hinkle, P. C., and R. E. McCarty. "How Cells Make ATP." Scientific American 238 (March 1978).

Racker, E. "The Membrane of the Mitochondrion." Scientific American 218 (February 1968).

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Krebs Cycle

Krebs cycle

The Krebs cycle is a set of biochemical reactions that occur in the mitochondria. The Krebs cycle is the final common pathway for the oxidation of food molecules such as sugars and fatty acids. It is also the source of intermediates in biosynthetic pathways, providing carbon skeletons for the synthesis of amino acids, nucleotides, and other key molecules in the cell. The Krebs cycle is also known as the citric acid cycle, and the tricarboxylic acid cycle. The Krebs cycle is a cycle because, during its course, it regenerates one of its key reactants.

To enter the Krebs cycle, a food molecule must first be broken into two-carbon fragments known as acetyl groups, which are then joined to the carrier molecule coenzyme A (the A stands for acetylation). Coenzyme A is composed of the RNA nucleotide adenine diphosphate, linked to a pantothenate, linked to a mercaptoethylamine unit, with a terminal S-H.Dehydration of this linkage with the OH of an acetate group produces acetyl CoA. This reaction is catalyzed by pyruvate dehydrogenase complex, a large multienzyme complex.

The acetyl CoA linkage is weak, and it is easily and irreversibly hydrolyzed when Acetyl CoA reacts with the four-carbon compound oxaloacetate. Oxaloacetate plus the acetyl group form the six-carbon citric acid, or citrate. (Citric acid contains three carboxylic acid groups, hence the alternate names for the Krebs cycle.)

Following this initiating reaction, the citric acid undergoes a series of transformations. These result in the formation of three molecules of the high-energy hydrogen carrier NADH (nicotinamide adenine dinucleotide), 1 molecule of another hydrogen carrier FADH2 (flavin adenine dinucleotide), 1 molecule of high-energy GTP (guanine triphosphate), and 2 molecules of carbon dioxide, a waste product. The oxaloacetate is regenerated, and the cycle is ready to begin again. NADH and FADH2 are used in the final stages of cellular respiration to generate large amounts of ATP.

As a central metabolic pathway in the cell, the rate of the Krebs cycle must be tightly controlled to prevent too much, or too little, formation of products. This regulation occurs through inhibition or activation of several of the enzymes involved. Most notably, the activity of pyruvate dehydrogenase is inhibited by its products, acetyl CoA and NADH, as well as by GTP. This enzyme can also be inhibited by enzymatic addition of a phosphate group, which occurs more readily when ATP levels are high. Each of these actions serves to slow down the Krebs cycle when energy levels are high in the cell. It is important to note that the Krebs cycle is also halted when the cell is low on oxygen, even though no oxygen is consumed in it. Oxygen is needed further along in cell respiration though, to regenerate NAD+ and FAD. Without these, the cycle cannot continue, and pyruvic acid is converted in the cytosol to lactic acid by the fermentation pathway.

The Krebs cycle is also a source for precursors for biosynthesis of a number of cell molecules. For instance, the synthetic pathway for amino acids can begin with either oxaloacetate or alpha-ketoglutarate, while the production of porphyrins, used in hemoglobin and other proteins, begins with succinyl CoA. Molecules withdrawn from the cycle for biosynthesis must be replenished. Oxaloacetate, for instance, can be formed from pyruvate, carbon dioxide, and water, with the use of one ATP molecule.

See also Mitochondria and cellular energy

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Krebs cycle

Krebs cycle, series of chemical reactions carried out in the living cell; in most higher animals, including humans, it is essential for the oxidative metabolism of glucose and other simple sugars. The breakdown of glucose to carbon dioxide and water is a complex set of chemical interconversions called carbohydrate catabolism, and the Krebs cycle is the second of three major stages in the process, occurring between glycolysis and oxidative phosphorylation. This cycle, also known as the citric acid cycle, was named in recognition of the German chemist Hans Krebs, whose research into the cellular utilization of glucose contributed greatly to the modern understanding of this aspect of metabolism. The name citric acid cycle is derived from the first product generated by the sequence of conversions, i.e., citric acid. The reactions are seen to comprise a cycle inasmuch as citric acid is both the first product and the final reactant, being regenerated at the conclusion of one complete set of chemical rearrangements. Citric acid is a so-called tricarboxylic acid, containing three carboxyl groups (COOH). Hence the Krebs cycle is sometimes referred to as the tricarboxylic acid (TCA) cycle. The Krebs cycle begins with the condensation of one molecule of a compound called oxaloacetic acid and one molecule of acetyl CoA (a derivative of coenzyme A; see coenzyme). The acetyl portion of acetyl CoA is derived from pyruvic acid, which is produced by the degradation of glucose in glycolysis. After condensation, the oxaloacetic acid and acetyl CoA react to produce citric acid, which serves as a substrate for seven distinct enzyme-catalyzed reactions that occur in sequence and proceed with the formation of seven intermediate compounds, including succinic acid, fumaric acid, and malic acid. Malic acid is converted to oxaloacetic acid, which, in turn, reacts with yet another molecule of acetyl CoA, thus producing citric acid, and the cycle begins again. Each turn of the citric acid cycle produces, simultaneously, two molecules of carbon dioxide and eight atoms of hydrogen as byproducts. The carbon dioxide generated is an ultimate end product of glucose breakdown and is removed from the cell by the blood. The hydrogen atoms are donated as hydride ions to the system of electron transport molecules, which allow for oxidative phosphorylation. In most higher plants, in certain microorganisms, such as the bacterium Escherichia coli, and in the algae, the citric acid cycle is modified to a form called the glyoxylate cycle, so named because of the prominent intermediate, glyoxylic acid.

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Krebs cycle

Krebs cycle (citric acid cycle; tricarboxylic acid cycle; TCA cycle) A cyclical series of biochemical reactions that is fundamental to the metabolism of aerobic organisms, i.e. animals, plants, and many microorganisms (see illustration). The enzymes of the Krebs cycle are located in the mitochondria and are in close association with the components of the electron transport chain. The two-carbon acetyl coenzyme A (acetyl CoA) reacts with the four-carbon oxaloacetate to form the six-carbon citrate. In a series of seven reactions, this is reconverted to oxaloacetate and produces two molecules of carbon dioxide. Most importantly, the cycle generates one molecule of guanosine triphosphate (GTP – equivalent to 1 ATP) and reduces three molecules of the coenzyme NAD to NADH and one molecule of the coenzyme FAD to FADH2. NADH and FADH2 are then oxidized by the electron transport chain to generate three and two molecules of ATP respectively (depending on the values of their respective P/O ratios). This gives a net yield of 12 molecules of ATP per molecule of acetyl CoA.

Acetyl CoA can be derived from carbohydrates (via glycolysis), fats, or certain amino acids. (Other amino acids may enter the cycle at different stages.) Thus the Krebs cycle is the central ‘crossroads’ in the complex system of metabolic pathways and is involved not only in degradation and energy production but also in the synthesis of biomolecules. It is named after its principal discoverer, Hans Krebs.

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Krebs Cycle

KREBS CYCLE

The Krebs cycle is a series of biochemical changes that occur during the metabolism of nutrients, facilitating the storage of energy for further use. It is named after Hans Adolph Krebs (19001981), the biochemist who identified it. The alternative, and more descriptive, name is the tricarboxylic, or citric acid, cycle. The fundamental process involves oxidizing acetate molecules to carbon dioxide (CO2) and water with transfer of the metabolic energy to "high energy" bonds for later use by the body. In the process, acetate is attached biochemically to a dicarboxylic acid to produce citric acidsthe tricarboxylic acid from which the cycle derives its name. The citric acid then goes through a number of biochemical steps to oxidize the two carbons from acetate, and to regenerate the dicarboxylic acid to which the acetate was originally attached.

George A. Bray

(see also: Energy; Nutrition )

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Krebs cycle

Krebs cycle (citric acid or tricarboxylic acid cycle) Biochemical pathway by which most eukaryote organisms, including animals and plants, obtain much of their energy by oxidizing foodstuffs. Occurring in the mitochondria of cells, the Krebs cycle comprises a number of complex chemical reactions, many of which release energy, in association with a process called the electron transport system, as adenosine triphosphate (ATP) becomes adenosine diphosphate (ADP). ATP provides chemical energy for metabolic reactions. The Krebs cycle is an essential part of the process of cell respiration and metabolism. It is named after British biochemist Sir Hans Krebs. See also mitochondrion

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Krebs cycle

Krebs cycle (citric acid cycle) (krebz) n. a complex cycle of enzyme-catalysed reactions, occurring within the cells of all living animals, in which acetate is broken down to produce energy in the form of ATP and carbon dioxide. The cycle is the final step in the oxidation of carbohydrates, fats, and proteins. [ Sir H. A. Krebs (1900–81), German-born biochemist]

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Krebs cycle

Krebs' cycle Or citric acid cycle, a central pathway for the metabolism of fats, carbohydrates, and amino acids.

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Krebs cycle

Krebs cycle

Resources

The Krebs cycle, also called the citric acid cycle and tricarboxylic acid cycle, is the common pathway by which organic fuel molecules of the cell are oxidized during cellular respiration. These fuel molecules, glucose, fatty acids, and amino acids, are broken down and fed into the Krebs cycle, becoming oxidized to acetyl coenzyme A (acetyl CoA) before entering the cycle. The Krebs cycle is part of the aerobic degradative process in eukaryotes known as cellular respiration, which is a process that generates adenosine triphosphate (ATP) by oxidizing energy-rich fuel molecules.

The Krebs cycle, first postulated in 1937 by Hans Krebs, is an efficient way for cells to produce energy during the degradation of energy-rich molecules. Electrons removed from intermediate metabolic products during the Krebs cycle are used to reduce coenzyme molecules nicotinamide adenine dinucleotide [NAD+] and flavin mononucleotide [FAD]) to NADH and FADH2, respectively. These coenzymes are subsequently oxidized in the electron transport chain, where a series of enzymes transfers the electrons of NADH and FADH2 to oxygen, which is the final electron acceptor of cellular respiration in all eukaryotes.

The importance of the Krebs cycle lies in both the efficiency with which it captures energy released from nutrient molecules and stores it in a usable form, and in the raw materials it provides for the biosynthesis of certain amino acids and of purines and pyrimidines. Pyrimidines are the nucleotide bases of deoxyribonu-cleic acid (DNA).

In the absence of oxygen, when anaerobic respiration occurs, such as in fermentation, glucose is degraded to lactate and lactic acid, and only a small fraction of the available energy of the original glucose molecule is released. Much more energy is released if glucose is fully degraded by the Krebs cycle, where it is completely oxidized to CO2 and H2O.

Before glucose, fatty acids, and most amino acids can be oxidized to CO2 and H2O in the Krebs cycle, they must first be broken down to acetyl CoA. In glycolysis, the 6-carbon glucose is connected to two 3-carbon pyruvate molecules, and then to the 2-carbon acetyl-CoA. In eukaryotic cells, the enzymes that are reponsible for this breakdown are located in the mitochondria, while in procaryotes they are in the cytoplasm.

The two hydrogenatoms removed from the pyruvate molecule yield NADH, which subsequently gives up its electrons to the electron transport chain to form ATP and water.

The breakdown of pyruvate irreversibly funnels the products of glycolysis into the Krebs cycle. Thus, the transformation of pyruvate to acetyl-CoA is the link between the metabolic reactions of glycolysis and the Krebs cycle.

The enzymatic steps of glycolysis and the subsequent synthesis of acetyl-CoA involve a linear sequence, whereas the oxidation of acetyl-CoA in the Krebs cycle is a cyclic sequence of reactions in which the starting substrate is subsequently regenerated with each turn of the cycle.

The carbon atom of the methyl group of acetyl-CoA is very resistant to chemical oxidation, and under ordinary circumstances, the reaction would require very harsh conditions, incompatible with the cellular environment, to oxidize the carbon atoms of acetyl-CoA to CO2. However, this problem is overcome in the first step of the Krebs cycle when the acetic acid of acetyl-CoA is combined with oxaloacetate to yield citrate, which is much more susceptible than the acetyl group to the dehydrogenation and decarboxylation reactions needed to remove electrons for reduction of NAD+ and FAD+.

Each turn of the Krebs cycle therefore begins when one of the two acetyl-CoA molecules derived from the original 6-carbon glucose molecule yields its acetyl group to the 4-carbon compound oxaloacetate to form the 6-carbon tricarboxylic acid (citrate) molecule. This reaction is catalyzed by the enzyme citrate synthetase. In step two of the Krebs cycle, citrate is isomerized to isocitrate by means of a dehydration reaction that yields cis -aconitate, followed by a hydration reaction that replaces the H+ and OH- to form isocitrate. The enzyme aconitase catalyzes both steps, since the intermediate is cis -aconitate.

Following the formation of isocitrate there are four oxidation-reduction reactions, the first of which, the oxidative decarboxylation of isocitrate, is catalyzed by isocitrate dehydrogenase.

The oxidation of isocitrate is coupled with the reduction of NADþ to NADH and the production of CO2. The intermediate product in this oxidative decarboxylation reaction is oxalosuccinate, whose formation is coupled with the production of NADH + H+. While still bound to the enzyme, oxalosuccinate loses CO2 to produce alpha-ketoglutarate.

The next step is the oxidative decarboxylation of succinyl CoA from alpha-ketoglutarate. This reaction is catalyzed by the alpha-ketoglutarate dehydrogenase complex of three enzymes, and is similar to the conversion of pyruvate to acetyl CoA, and, like that reaction, includes the cofactors NADþ and CoA. Likewise, NADþ is reduced to NADH and CO2 is formed.

Succinyl CoA carries an energy-rich bond in the form of the thioester CoA. The enzyme succinyl CoA synthetase catalyzes the cleavage of this bond, a reaction that is coupled to the phosphorylation of guano-sine diphosphate (GDP) to produce guanosine triphosphate (GTP). The phosphoryl group in GTP is then transferred to adenosine diphosphate (ADP) to form ATP, in a reaction catalyzed by the enzyme nucleoside diphosphokinase.

This reaction, which is the only one in the Krebs cycle that directly yields a high-energy phosphate bond, is an example of substrate-level phosphorylation. In contrast, oxidative phosphorylation forms ATP in a reaction that is coupled to oxidation of NADH and FADH2 by O2 on the electron transport chain.

The final stages of the Krebs cycle include reactions of 4-carbon compounds. Succinate is first oxidized to fumarate by succinate dehydrogenase, a reaction coupled to the reduction of FAD to FADH2. The enzyme fumarate hydratase (fumarase) catalyzes the subsequent hydration of fumarate to L-malate. Finally, L-malate is dehydrogenated to oxaloacetate, which is catalyzed by the NAD-linked enzyme L-malate dehydrogenase. The reaction also yields NADH and H+.

Oxaloacetate made from this reaction is then removed by the citrate synthase reaction to produce citrate, which begins the Krebs cycle anew. This continuous removal of oxaloacetate keeps the concentration of this metabolite very low in the cell. The equilibrium of this reversible reaction is thus driven to the right, ensuring that citrate will continue to be made and the Krebs cycle will continue to turn.

Each turn of the Krebs cycle represents the degradation of two 3-carbon pyruvate molecules derived either from the 6-carbon glucose molecule or from the degradation of amino acids or fatty acids. During each turn, a 2-carbon acetyl group combines with oxaloacetate and two carbon atoms are removed during the cycle as CO2. Oxaloacetate is regenerated at the end of the cycle, while four pairs of hydrogen atoms are removed from four of the Krebs cycle intermediate metabolites by enzymatic dehydrogenation. Three pairs are used to reduce three molecules of NADþ to NADH and one pair to reduce the FAD of succinate dehydrogenase to FADH2.

The four pairs of electrons captured by the coen-zymes are released during the oxidation of these molecules in the electron transport chain. These electrons pass down the chain and are used to reduce two molecules of O2 to form four molecules of H2O. The byproduct of this sequential oxidation-reduction of electron carriers in the chain is the production of a large number of ATP molecules. In addition, one molecule of ATP is formed by the Krebs cycle from ADP and phosphate by means of the GTP yielded by substrate level phosphorylation during the succinyl-CoA synthetase reaction.

The Krebs cycle is regulated by several different metabolic steps. When there is an ample supply of ATP, acetyl-CoA, and the Krebs cycle intermediates to meet the cells energy needs, the ATP activates. This enzyme uses the ATP to phosphorylate the pyruvate dehydrogenase into an inactive form, pyruvate dehydrogenase phosphate. When the level of ATP declines, the enzyme loses its phosphate group and is reactivated. This reactivation also occurs when there is an increase in the concentration of Ca2+.

The pyruvate dehydrogenase complex is also directly inhibited by ATP, acetyl-CoA, and NADH, the products of the pyruvate dehydrogenase reaction.

In the Krebs cycle itself the initial reaction, where acetyl-CoA is combined with oxaloacetate to yield citrate and CoA, is catalyzed by citrate synthase, and is controlled by the concentration of acetyl-CoA, which in turn is controlled by the pyruvate dehydrogenase complex. This initial reaction is also controlled by the concentrations of oxaloacetate and of succinyl-CoA.

Another rate-cautioning step in the Krebs cycle is the oxidation of isocitrate to alpha-ketoglutarate and CO2. This step is regulated by the stimulation of the NAD-linked enzyme isocitrate dehydrogenase by ADP, and by the inhibition of this enzyme by NADH and NADPH.

The rates of glycolysis and of the Krebs cycle are integrated so that the amount of glucose degraded produces the quantity of pyruvate needed to supply the Krebs cycle. Moreover, citrate, the product of the first step in the Krebs cycle, is an important inhibitor of an early step of glycolysis, which slows glycolysis and reduces the rate at which pyruvate is made into acetyl-CoA for use by the Krebs cycle.

In addition to its energy-generating function, the Krebs cycle serves as the first stage in a number of biosynthetic pathways for which it supplies the precursors. For example, certain intermediates of the Krebs cycle, especially alpha-ketoglutarate, succinate, and oxaloacetate can be removed from the cycle and used as precursors of amino acids.

Resources

BOOKS

Alberts, Bruce, Dennis Bray, and Julian Lewis, et al. Molecular Biology of the Cell. 2nd ed. New York: Garland Publishers, 1989.

Lehninger, Albert L. Principles of Biochemistry. New York: Worth Publishers, 1982.

OTHER

Florida State University. The Krebs Cycle <http://wine1.sb.fsu.edu/krebs/krebs.htm>(accessed

December 2, 2006).

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Krebs Cycle

Krebs cycle

The citric acid cycle (also called the tricarboxylic acid cycle) is the common pathway by which organic fuel molecules of the cell are oxidized during cellular respiration. These fuel molecules, glucose, fatty acids , and amino acids, are broken down and fed into the Krebs cycle, becoming oxidized to acetyl coenzyme A (acetyl CoA) before entering the cycle. The Krebs cycle is part of the aerobic degradative process in eukaryotes known as cellular respiration, which is a process that generates adenosine triphosphate (ATP) by oxidizing energy-rich fuel molecules.

The Krebs cycle was first postulated in 1937 by Hans Krebs, and represents an efficient way for cells to produce energy during the degradation of energy-rich molecules. The electrons removed from intermediate metabolic products during the Krebs cycle are used to reduce coenzyme molecules nicotinamide adenine dinucleotide [NAD+] and flavin mononucleotide [FAD]) to NADH and FADH2, respectively. These coenzymes are subsequently oxidized in the electron transport chain, where a series of enzymes transfers the electrons of NADH and FADH2 to oxygen , which is the final electron acceptor of cellular respiration in all eukaryotes.

The importance of the Krebs cycle lies in both the efficiency with which it captures energy released from nutrient molecules and stores it in a usable form, and in the raw materials it provides for the biosynthesis of certain amino acids and of purines and pyrimidines. Pyrimidines are the nucleotide bases of deoxyribonucleic acid (DNA) .

In the absence of oxygen, when anaerobic respiration occurs, such as in fermentation , glucose is degraded to lactate and lactic acid , and only a small fraction of the available energy of the original glucose molecule is released. Much more energy is released if glucose is fully degraded by the Krebs cycle, where it is completely oxidized to CO2 and H2O.

Before glucose, fatty acids, and most amino acids can be oxidized to CO2 and H2O in the Krebs cycle, they must first be broken down to acetyl CoA. In glycolysis , the 6-carbon glucose is connected to two 3-carbon pyruvate molecules, and then to the 2-carbon acetyl-CoA. In eukaryotic cells, the enzymes that are reponsible for this breakdown are located in the mitochondria, while in procaryotes they are in the cytoplasm.

The two hydrogen atoms removed from the pyruvate molecule yield NADH which subsequently gives up its electrons to the electron transport chain to form ATP and water .

The breakdown of pyruvate irreversibly funnels the products of glycolysis into the Krebs cycle. Thus, the transformation of pyruvate to acetyl-CoA is the link between the metabolic reactions of glycolysis and the Krebs cycle.

The enzymatic steps of glycolysis and the subsequent synthesis of acetyl-CoA involve a linear sequence, whereas the oxidation of acetyl-CoA in the Krebs cycle is a cyclic sequence of reactions in which the starting substrate is subsequently regenerated with each turn of the cycle.

The carbon atom of the methyl group of acetyl-CoA is very resistant to chemical oxidation, and under ordinary circumstances, the reaction would require very harsh conditions, incompatible with the cellular environment, to oxidize the carbon atoms of acetyl-CoA to CO2. However, this problem is overcome in the first step of the Krebs cycle when the acetic acid of acetyl-CoA is combined with oxaloacetate to yield citrate, which is much more susceptible than the acetyl group to the dehydrogenation and decarboxylation reactions needed to remove electrons for reduction of NAD+ and FAD+.

Each turn of the Krebs cycle therefore begins when one of the two acetyl-CoA molecules derived from the original 6-carbon glucose molecule yields its acetyl group to the 4-carbon compound oxaloacetate to form the 6-carbon tricarboxylic acid (citrate) molecule. This reaction is catalyzed by the enzyme citrate synthetase. In step two of the Krebs cycle, citrate is isomerized to isocitrate by means of a dehydration reaction that yields cis-aconitate, followed by a hydration reaction that replaces the H+ and OH- to form isocitrate. The enzyme aconitase catalyzes both steps, since the intermediate is cis-aconitate.

Following the formation of isocitrate there are four oxidation-reduction reactions, the first of which, the oxidative decarboxylation of isocitrate, is catalyzed by isocitrate dehydrogenase.

The oxidation of isocitrate is coupled with the reduction of NAD+ to NADH and the production of CO2. The intermediate product in this oxidative decarboxylation reaction is oxalosuccinate, whose formation is coupled with the production of NADH + H+. While still bound to the enzyme, oxalosuccinate loses CO2 to produce alpha-ketoglutarate.

The next step is the oxidative decarboxylation of succinyl CoA from alpha-ketoglutarate. This reaction is catalyzed by the alpha-ketoglutarate dehydrogenase complex of three enzymes, and is similar to the conversion of pyruvate to acetyl CoA, and, like that reaction, includes the cofactors NAD+ and CoA. Likewise, NAD+ is reduced to NADH and CO2 is formed.

Succinyl CoA carries an energy-rich bond in the form of the thioester CoA. The enzyme succinyl CoA synthetase catalyzes the cleavage of this bond, a reaction that is coupled to the phosphorylation of guanosine diphosphate (GDP) to produce guanosine triphosphate (GTP). The phosphoryl group in GTP is then transferred to adenosine diphosphate (ADP) to form ATP, in a reaction catalyzed by the enzyme nucleoside diphosphokinase.

This reaction, which is the only one in the Krebs cycle that directly yields a high-energy phosphate bond, is an example of substrate-level phosphorylation. In contrast, oxidative phosphorylation forms ATP in a reaction that is coupled to oxidation of NADH and FADH2 by O2 on the electron transport chain.

The final stages of the Krebs cycle include reactions of 4-carbon compounds. Succinate is first oxidized to fumarate by succinate dehydrogenase, a reaction coupled to the reduction of FAD to FADH2. The enzyme fumarate hydratase (fumarase) catalyzes the subsequent hydration of fumarate to L-malate. Finally, L-malate is dehydrogenated to oxaloacetate, which is catalyzed by the NAD-linked enzyme L-malate dehydrogenase. The reaction also yields NADH and H+.

Oxaloacetate made from this reaction is then removed by the citrate synthase reaction to produce citrate, which begins the Krebs cycle anew. This continuous removal of oxaloacetate keeps the concentration of this metabolite very low in the cell. The equilibrium of this reversible reaction is thus driven to the right, ensuring that citrate will continue to be made and the Krebs cycle will continue to turn.

Each turn of the Krebs cycle represents the degradation of two 3-carbon pyruvate molecules derived either from the 6-carbon glucose molecule or from the degradation of amino acids or fatty acids. During each turn, a 2-carbon acetyl group combines with oxaloacetate and two carbon atoms are removed during the cycle as CO2. Oxaloacetate is regenerated at the end of the cycle, while four pairs of hydrogen atoms are removed from four of the Krebs cycle intermediate metabolites by enzymatic dehydrogenation. Three pairs are used to reduce three molecules of NAD+ to NADH and one pair to reduce the FAD of succinate dehydrogenase to FADH2.

The four pairs of electrons captured by the coenzymes are released during the oxidation of these molecules in the electron transport chain. These electrons pass down the chain and are used to reduce two molecules of O2 to form four molecules of H2O. The byproduct of this sequential oxidation-reduction of electron carriers in the chain is the production of a large number of ATP molecules. In addition, one molecule of ATP is formed by the Krebs cycle from ADP and phosphate by means of the GTP yielded by substrate level phosphorylation during the succinyl-CoA synthetase reaction.

The Krebs cycle is regulated by several different metabolic steps. When there is an ample supply of ATP, acetyl-CoA, and the Krebs cycle intermediates to meet the cell's energy needs, the ATP activates. This enzyme uses the ATP to phosphorylate the pyruvate dehydrogenase into an inactive form, pyruvate dehydrogenase phosphate. When the level of ATP declines, the enzyme loses its phosphate group and is reactivated. This reactivation also occurs when there is an increase in the concentration of Ca2+.

The pyruvate dehydrogenase complex is also directly inhibited by ATP, acetyl-CoA, and NADH, the products of the pyruvate dehydrogenase reaction.

In the Krebs cycle itself the initial reaction, where acetyl-CoA is combined with oxaloacetate to yield citrate and CoA, is catalyzed by citrate synthase, and is controlled by the concentration of acetyl-CoA, which in turn is controlled by the pyruvate dehydrogenase complex. This initial reaction is also controlled by the concentrations of oxaloacetate and of succinyl-CoA.

Another rate-cautioning step in the Krebs cycle is the oxidation of isocitrate to alpha-ketoglutarate and CO2. This step is regulated by the stimulation of the NAD-linked enzyme isocitrate dehydrogenase by ADP, and by the inhibition of this enzyme by NADH and NADPH.

The rates of glycolysis and of the Krebs cycle are integrated so that the amount of glucose degraded produces the quantity of pyruvate needed to supply the Krebs cycle. Moreover, citrate, the product of the first step in the Krebs cycle, is an important inhibitor of an early step of glycolysis, which slows glycolysis and reduces the rate at which pyruvate is made into acetyl-CoA for use by the Krebs cycle.

In addition to its energy-generating function, the Krebs cycle serves as the first stage in a number of biosynthetic pathways for which it supplies the precursors. For example, certain intermediates of the Krebs cycle, especially alpha-ketoglutarate, succinate, and oxaloacetate can be removed from the cycle and used as precursors of amino acids.


Resources

books

Alberts, Bruce, Dennis Bray, and Julian Lewis, et al. MolecularBiology of The Cell. 2nd ed. New York: Garland Publishers, 1989.

Lehninger, Albert L. Principles of Biochemistry. New York: Worth Publishers, 1982.

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