Intermediates of the Citric Acid Cycle

The biosynthetic pathway to glucose described above allows the net synthesis of glucose not only from pyruvate but also from the four-, five-, and six-carbon intermediates of the citric acid cycle (Chapter 16). Citrate,... 

As intermediates of the citric acid cycle are removed to serve as biosynthetic precursors, they are replenished by anaplerotic reactions (Fig. 16-15 Table 16-2). Under normal circumstances, the reactions by which cycle intermediates are siphoned off into other pathways and those by which they are replenished are in dynamic balance, so that the concentrations of the citric acid cycle intermediates remain almost constant. 

Intermediates of the citric acid cycle are drawn off as precursors in many biosynthetic pathways. Shown in red are four anaplerotic reactions that replenish depleted cycle intermediates (see Table 16-2). 

Besides acetyl-CoA, any compound that gives rise to a four- or five-carbon intermediate of the citric acid cycle—for example, the breakdown products of many amino acids—can be... 

In plants, certain invertebrates, and some microorganisms (including E. coli and yeast) acetate can serve both as an energy-rich fuel and as a source of phosphoenolpyruvate for carbohydrate synthesis. In these organisms, enzymes of the glyoxylate cycle catalyze the net conversion of acetate to succinate or other four-carbon intermediates of the citric acid cycle ... 

Some bacteria, including E. coli, have the full complement of enzymes for the glyoxylate and citric acid cycles in the cytosol and can therefore grow on acetate as their sole source of carbon and energy. The phosphoprotein phosphatase that activates isocitrate dehydrogenase is stimulated by intermediates of the citric acid cycle and glycolysis and by indicators of reduced cellular energy supply (Fig. 16-23). The same metabolites inhibit the protein kinase activity of the bifunctional polypeptide. Thus, the accumulation of intermediates of... 

In extraliepatic tissues, d-/3-hydroxybutyrate is oxidized to acetoacetate by o-/3-hydroxybutyrate dehydrogenase (Fig. 17-19). The acetoacetate is activated to its coenzyme A ester by transfer of CoA from suc-cinyl-CoA, an intermediate of the citric acid cycle (see Fig. 16-7), in a reaction catalyzed by P-ketoacyl-CoA transferase. The acetoacetyl-CoA is then cleaved by thiolase to yield two acetyl-CoAs, which enter the citric acid cycle. Thus the ketone bodies are used as fuels. 

The production and export of ketone bodies by the liver allow continued oxidation of fatty acids with only minimal oxidation of acetyl-CoA When intermediates of the citric acid cycle are being siphoned off for glucose... 

The carbon skeletons of methionine, isoleucine, threonine, and valine are degraded by pathways that yield suc-cinyl-CoA (Fig. 18-27), an intermediate of the citric acid cycle. Methionine donates its methyl group to one of several possible acceptors through S-adenosytmethionine,... 

Phosphofructokinase-1 is also inhibited by citrate, the first intermediate of the citric acid cycle. When the cycle is idling, citrate accumulates within mitochondria, then spills into the cytosol. When the concentrations of both ATP and citrate rise, they produce a concerted allosteric inhibition of phosphofructokinase-1 that is greater than the sum of their individual effects, slowing glycolysis. 

In bacteria and plants, glutamate is produced from glutamine in a reaction catalyzed by glutamate synthase. a-Ketoglutarate, an intermediate of the citric acid cycle, undergoes reductive amination with glutamine as nitrogen donor ... 

Fig. 1.2 Intermediates of the citric acid cycle showing the relationship between glutamate and aspartate. Pyruvate dehydrogenase complex (1) citrate synthase (2) aconitase (3) isocitrate dehydrogenase (4) a-ketoglutarate dehydrogenase (5) succinyl-CoA synthetase (6) fumarate (7) fumarase dehydratase (8) malate dehydrogenase (9) and aspartate aminotransferase (10)...

Answer Oxygen consumption is a measure of the activity of the first two stages of cellular respiration glycolysis and the citric acid cycle. Initial nutrients being oxidized are carbohydrates and lipids. Because several intermediates of the citric acid cycle can be siphoned off into biosynthetic pathways, the cycle may slow down for lack of oxaloacetate in the citrate synthase reaction, and acetyl-CoA will accumulate. Addition of oxaloacetate or malate (converted to oxaloacetate by malate dehydrogenase) will stimulate the cycle and allow it to use the accumulated acetyl-CoA. This stimulates respiration. Oxaloacetate is regenerated in the cycle, so addition of oxaloacetate (or malate) stimulates the oxidation of a much larger amount of acetyl-CoA. 

Answer Succinyl-CoA is an intermediate of the citric acid cycle—the first four-carbon intermediate, formed in the a-ketoglutarate dehydrogenase reaction. Its accumulation signals reduced flux through the cycle, and thus the need for reduced entry of acetyl-CoA into the cycle. 

The intermediate in this reaction, cis-aconitate, is bound to aconitase and is not usually classed as a discrete intermediate of the citric acid cycle. 

Apart from the production of NADH and FADH2, which are the high-energy fuels of electron transport, the citric acid cycle has two other major functions. Several of its intermediate compounds are used to synthesize other cell constituents. This, the provision of molecules for other metabolic or biosynthetic pathways, is the anabolic function of the cycle (Table 12.1). Alternatively, certain other processes occurring within the cell may produce intermediates of the citric acid cycle. These compounds enter the reactions of the cycle, and their degradation involves the catabolic role of the cycle. These two major capabilities classify the citric acid cycle as an amphibolic pathway (Greek amphi meaning both sides ). 

If intermediates of the citric acid cycle enter the cycle via other reactions in the cell, are they oxidized If one molecule of 2-oxoglutarate, for example, were to enter the cycle, its metabolism through one turn of the cycle would be ... 

The cycle oxidizes acetyl-CoA, and to perform this task, it must convert acetyl-CoA to citrate. For this to be achieved, oxaloacetate must be available. If the removal of intermediates results in a decrease in the amount of oxaloacetate for this purpose, acetyl-CoA cannot be removed and will accumulate. This will inhibit the pyruvate dehydrogenase complex and activate pyruvate carboxylase, leading to the conversion of pyruvate to oxaloacetate. This product is now available to condense with the acetyl-CoA to produce citrate, which will restore the status quo. Reactions like that of pyruvate carboxylase that provide molecules for the replacement of intermediates of the citric acid cycle are known as anaplerotic reactions (Greek, meaning to fill up ana = up + plerotikos from pleroun = to make full ). 

By which reactions is pyruvate converted to succinate without depleting any of the intermediates of the citric acid cycle ... 

Amino Acids Are Made from Intermediates of the Citric Acid Cycle and Other Major Pathways... 

A third fate of pyruvate is its carboxylation to oxaloacetate inside mitochondria, the first step in gluconeogenesis. This reaction and the subsequent conversion of oxaloacetate into phosphoenolpyruvate bypass an irreversible step of glycolysis and hence enable glucose to be synthesized from pyruvate. The carboxylation of pyruvate is also important for replenishing intermediates of the citric acid cycle. Acetyl CoA activates pyruvate carboxylase, enhancing the synthesis of oxaloacetate, when the citric acid cycle is slowed by a paucity of this intermediate. 

Amino acids in excess of those needed for biosynthesis can neither be stored, in contrast with fatty acids and glucose, nor excreted. Rather, surplus amino acids are used as metabolic fuel. The a-amino group is removed, am/ the resulting carbon skeleton is converted into a major metabolic intermediate. Most of the amino groups harvested from surplus amino acids are converted into urea through the urea cycle, whereas their carbon skeletons are transformed into acetyl Co A, acetoacetyl C oA, pyruvate, or one of the intermediates of the citric acid cycle. The principal fate of the carbon skeletons is conversion into glucose and glycogen. 

The answer is c. (Murray, pp 627-661. Scriver, pp 3897-3964. Sack, pp 121-138. Wilson, pp 287-320.) Certain amino acids and lipids are dietary necessities because humans cannot synthesize them. The energy usually obtained from carbohydrates can be obtained from lipids and the conversion of some amino acids to intermediates of the citric acid cycle. These alternative substrates can thus provide fuel for oxidation and energy plus reducing equivalents for biosynthesis. Iodine is important for thyroid hormone synthesis, while calcium is essential for muscle contraction and bone metabolism. 

The answer is e. (Murray, pp 505-626. Scriver, pp 4029-4240. Sack, pp 121-138. Wilson, pp 287-320.) All the compounds listed are intermediates of the citric acid cycle. However, only fumarate is an intermediate of both the citric acid and urea cycles. It and arginine are produced from argininosuccinate. Once produced by the urea cycle, fumarate enters the citric acid cycle and is converted to malate and then oxidized to oxaloacetate. Depending upon the organism s needs, oxaloacetate can either enter gluconeogenesis or react with acetyl CoA to form citrate. 

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