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Home , Adenosine triphosphate, Citric acid cycle, Lipogenesis, Lysine

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Citric acid cycle

Contributed by: Gerhard W. E. Plaut Publication year: 2014

In aerobic cells from animal and certain other species, the major pathway for the complete oxidation of acetyl (the of acetic acid with coenzyme A); also known as the Krebs cycle or tricarboxylic acid cycle. Reduced electron carriers generated in the cycle are reoxidized by via the electron transport system; is formed, and the liberated is conserved by the of diphosphate (ADP) to (ATP). Reactions of the cycle also function in metabolic processes other than energy generation. The role of the cycle in mammalian tissues will be emphasized in this article. See also: ADENOSINE TRIPHOSPHATE (ATP); COENZYME; .

Reactions

The first step in the cycle involves the condensation of the acetyl portion of acetyl coenzyme A (CoA) with the four- compound oxaloacetate to form citrate, a tricarboxylate containing six (see illustration). A shift of the hydroxyl group of citrate to an adjacent carbon results in the formation of D-threo-isocitrate, which in α turn is oxidized to the five-carbon compound -ketoglutarate and (CO,2). In a second oxidative reaction, α-ketoglutarate, in the presence of CoA, is converted to succinyl CoA and another of CO,2. In the subsequent formation of the four-carbon compound succinate and CoA, the energy in the thioester bond of succinyl CoA is conserved by the formation of triphosphate (GTP) from (GDP) and inorganic . Fumarate is formed from succinate by the removal of two of hydrogen, and the unsaturated compound is then hydrated to L-malate. The dehydrogenation of malate forms oxaloacetate, the starting four-carbon compound of the metabolic cycle. Thus, beginning with the two-carbon , one completion of the cycle results in the formation of two of carbon dioxide. The obligatory role of the intact cycle for the complete oxidation of acetyl CoA has been demonstrated by inhibiting required for specific reactions (for example, inhibition of succinate by the analog malonate) or by altering the regeneration or depletion of an intermediate of the cycle.

Electron transport and oxidative phosphorylation

The oxidation of acetyl CoA to CO,2 in the cycle occurs without direct reaction with molecular oxygen. The oxidations occur at dehydrogenation reactions in which hydrogen atoms and electrons are transferred from intermediates of the cycle to the electron carriers dinucleotide (NAD,+) and flavin adenine dinucleotide (FAD). The NAD-specific dehydrogenase reactions are [reaction (1)], α-ketoglutarate dehydrogenase (2), and (3). FAD is the coenzyme for succinate AccessScience from McGraw-Hill Education Page 2 of 6 www.accessscience.com

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dehydrogenase, (4).

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Image of Chem Equation(1) 1

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The electrons from NADH and FADH,2 are transferred to molecular oxygen via a series of electron transport carriers, with regeneration of NAD,+ and FAD. The energy liberated in the is partially conserved by the formation of ATP from ADP and inorganic phosphate, by a process called oxidative phosphorylation. The energy generated as oxygen accepts electrons from the reduced coenzymes generated in one turn of the cycle results in the maximal formation of 11 molecules of ATP. Because GTP obtained by phosphorylation of GDP at the succinyl CoA to succinate step of the cycle is readily converted to ATP by diphosphokinase, as in reaction (5),

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the yield is 12 molecules of ATP per molecule of acetyl CoA metabolized. See also: NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD).

The electron transport and oxidative phosphorylation systems and the enzymes required for the cycle are located in the mitochondria of cells. These mitochondrial systems are the major source of ATP for energy-consuming reactions in most tissues. The does not occur in all cells. For example, mature human red blood cells do not contain mitochondria and the cycle is absent. In these cells, ATP is formed by the anaerobic conversion of to lactate (anaerobic ). See also: MITOCHONDRIA; PHOSPHATE . AccessScience from McGraw-Hill Education Page 4 of 6 www.accessscience.com

Regulation

A major rate-limiting step of the citric acid cycle in aerobic mammalian tissues (for example, heart) is at NAD-specific isocitrate dehydrogenase [reaction (1)]. The activity of the enzyme is dependent on the of the substrate ( isocitrate): it is activated by ADP, (Ca,2+), and citrate, and it is inhibited by NADH and reduced nicotinamide adenine dinucleotide phosphate (NADPH). Differences in energy demand affect the rate of citric acid flux and of modulators of NAD-dependent isocitrate dehydrogenase. At rest, the flux through the cycle is slowed, the cellular concentration of the isocitrate dehydrogenase inhibitor NADH is raised; and the activator ADP is lowered; the opposite occurs during high energy demand. The rate of cycle oxidation in mitochondria increases with decreased NADPH concentration; increased mitochondrial free Ca,2+ enhances cycle flux.

Formation of acetyl CoA and intermediates

Acetyl CoA is formed from , , and the carbon skeleton of amino acids. The origin of a precursor and the extent of its utilization depend on the metabolic capability of a specific and on the physiological state of the organism. For example, most mammalian tissues have the capacity to convert glucose to pyruvate in a reaction called glycolysis. Pyruvate is then taken up from cellular by mitochondria and oxidatively decarboxylated to acetyl CoA and carbon dioxide by , as in reaction (6).

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Acetyl CoA is also the end product of oxidation in mitochondria. However, the fatty acid oxidation pathway occurs in fewer tissues than does glycolysis or the citric acid cycle. For example, nervous tissue utilizes the complete oxidation of glucose but not of fatty acids to maintain energy needs. In prolonged starvation, the level of blood glucose declines to a concentration inadequate to support the optimal energy needs of brain, whereas the level of blood bodies (formed from fatty acids in liver) rises. In this case, the oxidation of (acetoacetate and 3-hydroxybutyrate) via acetyl CoA supplements the diminished oxidation of glucose to fulfill the energy requirements of the brain.

The amino acids follow varied pathways for forming compounds that can enter the citric acid cycle. For example, the paths of degradation of and lead directly to formation of acetyl CoA; only part of the carbons of aromatic amino acids and of are converted to acetyl CoA. Pyruvate, formed by of AccessScience from McGraw-Hill Education Page 5 of 6 www.accessscience.com

with the citric acid cycle intermediate α-ketoglutarate [reaction (7)],

Image of Chem(7) Equation 7

can be oxidatively decarboxylated to acetyl CoA by pyruvate dehydrogenase [reaction (6)] or carboxylated to the cycle intermediate oxaloacetate by [reaction (8)].

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Oxaloacetate can also be formed by aspartate aminotransferase [reaction (9)].

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Portions of the carbon skeletons of , isoleucine, , and are converted to methylmalonyl CoA, which rearranges to the citric acid cycle intermediate succinyl CoA. See also: AMINO ACIDS.

Role in and

In addition to the cycle’s role in yielding catabolic energy, portions of it can supply intermediates for synthetic processes, such as the synthesis of the fatty acid moiety of from glucose (lipogenesis), and formation of glucose from the carbon skeletons of certain amino acids, lactate, or (gluconeogenesis).

Lipogenesis. When dietary intake exceeds the energy needs of the body, the excess calories are deposited as body . Under these conditions in humans, the synthesis of fatty acids from glucose occurs mainly in the liver. It is favored by metabolic changes resulting principally from a rise in blood : (1) The rate of pyruvate formation increases because of the rise in tissue glucose and enhancement of glycolysis. (2) Increases in enzyme activities catalyzing the conversion of pyruvate to acetyl CoA at pyruvate dehydrogenase [reaction (6)] and to oxaloacetate at pyruvate carboxylase [reaction (8)] raise the concentrations of both of these substrates for citrate synthesis. When this occurs at a rate exceeding that of the citric acid cycle, the citrate concentration rises and citrate exits from the mitochondria to the cytosol. (3) In the cytosol, citrate is cleaved to oxaloacetate and acetyl CoA in a reaction requiring CoA and ATP. The acetyl CoA is converted to palmitate and other long-chain fatty acids in a series of condensation steps requiring CO,2, ATP as energy source, and NADPH as reductant. See also: METABOLISM. AccessScience from McGraw-Hill Education Page 6 of 6 www.accessscience.com

Gluconeogenesis. Dietary deprivation of an adult human for more than 2–3 days results in the depletion of liver glycogen stores supporting blood glucose, and the oxidation of fatty acids derived from body depots becomes the principal body energy source. However, certain tissues, such as brain and red and white blood cells, remain partially or wholly dependent on glucose as the energy source. In the starved state, where blood insulin decreases and increases, increased mobilization of amino acids from occurs, and carbons from some of these amino acids become available for glucose synthesis. The interactions of degradation pathways of individual amino acids in various tissues result in markedly increased blood alanine, an important substrate for gluconeogenesis.

Some of the steps in the conversion of alanine to glucose are as follows: (1) Alanine is taken up from the bloodstream by the liver and converted to pyruvate by transamination [reaction (7)]. (2) The further metabolism of pyruvate in liver mitochondria is affected by the increase in the rate of fatty acid oxidation in the starved state, which raises the levels of acetyl CoA and NADH. Since NADH inhibits pyruvate dehydrogenase [reaction (6)], and acetyl CoA activates pyruvate carboxylase [reaction (8)], the conversion of pyruvate to oxaloacetate rather than acetyl CoA is favored. The increased NADH displaces the malate dehydrogenase reaction [reaction (3)] from oxaloacetate toward malate. Malate is transported from the mitochondria to the cytosol, where it is reoxidized by NAD,+ to oxaloacetate by cytosolic malate dehydrogenase. (3) Oxaloacetate is converted to phosphoenolpyruvate (PEP) by the PEP-carboxykinase reaction [reaction (10)].

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Phosphoenolpyruvate is an intermediate of both gluconeogenesis and glycolysis. In the starved state, the levels of modulators, , and so forth activate certain rate-limiting steps favoring the formation of glucose from PEP, and also inhibit key enzyme activities facilitating glycolysis. The net effect of these opposing trends is to funnel the flux of carbons from amino acids toward glucose synthesis. See also: BIOLOGICAL OXIDATION; METABOLISM; (BIOLOGY); GLUCOSE; GLYCOGEN; METABOLISM. Gerhard W. E. Plaut

Additional Readings

M. K. Campbell and S. O. Farrell, , 7th ed., Brooks∕Cole, Belmont, CA, 2012

R. H. Garrett and C. M. Grisham, Biochemistry, 4th ed., Brooks∕Cole, Belmont, CA, 2010

S. R. Rolfes, P. Kathryn, and E. Whitney, Understanding Normal and Clinical , Wadsworth∕Cengage Learning, Belmont, CA, 2009