TCA cycle pyruvate

In the early 1940s, before the discovery of 14C and when acetyl-coenzyme A was unknown, two research groups used the stable isotope 13C and mass spectrometers to study carbon flow in the TCA cycle. Pyruvate and 13C02 were added to pigeon liver preparations to form carboxy-labeled oxaloacetate. Malonate was added to stop the TCA cycle at succinate. The expected result was that half of the 13C would be found in succinate and the other half in C02 (fig. 13.10). 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Figure 19-1 a Normal and ischemic myocardial metabolism of glucose. A total production of 36 moles of ATP results from the aerobic catabolism of 1 mole of glucose and use of NADH and FADH. in the oxidative phosphorylation process in mitochondria. When oxygen is not available, NADH and FADH levels rise and shut off the tricarboxylic acid (TCA) cycle. Pyruvate is converted to lactate. Only 2 moles of ATP are formed from anaerobic catabolism of 1 mole of glucose. (Adapted from Giuliani, E. R., ei al. Cardiology Fundamentals and Practice, 2nd ed. By permission of the Mayo Foundation, Rochester, MN.)... 

Fig. 3-10 The biochemical pathway of the tricarboxylic acid cycle (TCA cycle). Pyruvate, generated from glycolysis (Fig. 3-8), enters the cycle as acetyl-CoA (acetyl-coenzyme A), and is then degraded through a series of reactions to a 4-carbon compound, oxaloacetate. The energy resulting from the reactions is stored as ATP, which is produced through electron transport and oxidative phosphorylation (see Fig. 3-11).

Entry of 2-carbon units is carried out by pyruvate dehydrogenase and citrate synthase in the first phase of the TCA cycle. Pyruvate from glycolysis or other pathways enters the TCA cycle through the action... 

The TCA Cycle—A Brief Summary The Bridging Step Oxidadve Decarboxylation of Pyruvate Entry into the Cycle The Citrate Syntha.se Reaction The Lsomerizadon of Citrate by Aconita.se... 

FIGURE 20.1 Pyruvate produced hi glycolysis is oxidized in the tricarboxylic acid (TCA) cycle. Electrons liberated in this oxidation flow through the electron transport chain and drive the synthesis of ATP in oxidative phosphorylation. In eukaryotic cells, this overall process occurs in mitochondria. 

Pyruvate produced by glycolysis is a significant source of acetyl-CoA for the TCA cycle. Because, in eukaryotic ceils, glycolysis occurs in the cytoplasm, whereas the TCA cycle reactions and ail subsequent steps of aerobic metabolism take place in the mitochondria, pyruvate must first enter the mitochondria to enter the TCA cycle. The oxidative decarboxylation of pyruvate to acetyl-CoA,... 

Glucose metabolized via glycolysis produces two molecules of pyruvate and thus two molecules of acetyl-CoA, which can enter the TCA cycle. Combining glycolysis and the TCA cycle gives the net reaction shown ... 

In a sort of reciprocal arrangement, the cell also feeds many intermediates back into the TCA cycle from other reactions. Since such reactions replenish the TCA cycle intermediates, Hans Kornberg proposed that they be called anaplerotie reactions (literally, the filling up reactions). Thus, PEP carboxylase and pyruvate carboxylase synthesize oxaloacetate from pyruvate (Figure 20.24). 

Pyruvate carboxylase is the most important of the anaplerotie reactions. It exists in the mitochondria of animal cells but not in plants, and it provides a direct link between glycolysis and the TCA cycle. The enzyme is tetrameric and contains covalently bound biotin and an Mg site on each subunit. (It is examined in greater detail in our discussion of gluconeogenesis in Chapter 23.) Pyruvate carboxylase has an absolute allosteric requirement for acetyl-CoA. Thus, when acetyl-CoA levels exceed the oxaloacetate supply, allosteric activation of pyruvate carboxylase by acetyl-CoA raises oxaloacetate levels, so that the excess acetyl-CoA can enter the TCA cycle. 

The catabolism of amino acids provides pyruvate, acetyl-CoA, oxaloacetate, fumarate, a-ketoglutarate, and succinate, ail of which may be oxidized by the TCA cycle. In this way, proteins may serve as excellent sources of nutrient energy, as seen in Chapter 26. 

COMPARTMENTALIZED PYRUVATE CARBOXYLASE DEPENDS ON METABOLITE CONVERSION AND TRANSPORT The second interesting feature of pyruvate carboxylase is that it is found only in the matrix of the mitochondria. By contrast, the next enzyme in the gluconeogenic pathway, PEP carboxykinase, may be localized in the cytosol or in the mitochondria or both. For example, rabbit liver PEP carboxykinase is predominantly mitochondrial, whereas the rat liver enzyme is strictly cytosolic. In human liver, PEP carboxykinase is found both in the cytosol and in the mitochondria. Pyruvate is transported into the mitochondrial matrix, where it can be converted to acetyl-CoA (for use in the TCA cycle) and then to citrate (for fatty acid synthesis see Figure 25.1). /Uternatively, it may be converted directly to 0/ A by pyruvate carboxylase and used in glu-... 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

BOTH NADPH AND ATP ARE NEEDED BY THE CELL, BUT RmOSE-5-P IS NOT Under some conditions, both NADPH and ATP must be provided in the cell. This can be accomplished in a series of reactions similar to case 3, if the fructose-6-P and glyceraldehyde-3-P produced in this way proceed through glycolysis to produce ATP and pyruvate, which itself can yield even more ATP by continuing on to the TCA cycle (Figure 23.40). The net reaction for this alternative is... 

Succinyl-CoA derived from propionyl-CoA can enter the TCA cycle. Oxidation of succinate to oxaloacetate provides a substrate for glucose synthesis. Thus, although the acetate units produced in /3-oxidation cannot be utilized in glu-coneogenesis by animals, the occasional propionate produced from oxidation of odd-carbon fatty acids can be used for sugar synthesis. Alternatively, succinate introduced to the TCA cycle from odd-carbon fatty acid oxidation may be oxidized to COg. However, all of the 4-carbon intermediates in the TCA cycle are regenerated in the cycle and thus should be viewed as catalytic species. Net consumption of succinyl-CoA thus does not occur directly in the TCA cycle. Rather, the succinyl-CoA generated from /3-oxidation of odd-carbon fatty acids must be converted to pyruvate and then to acetyl-CoA (which is completely oxidized in the TCA cycle). To follow this latter route, succinyl-CoA entering the TCA cycle must be first converted to malate in the usual way, and then transported from the mitochondrial matrix to the cytosol, where it is oxida-... 

Acceptable answers to part 1) indude amino adds and fatty adds or specific examples of each, such as glycine or stearic add respectively. The obvious answer for part 2) is the central metabolite pyruvate, though all of the adds of the TCA cycle would be appropriate. Answers to part 3) include the prindpal add of the hexose monophosphate... 

In the reaction that bridges glycolysis and the TCA cycle, for each pyruvate degraded to acetyl CoA, one CO2 is released and a further NAD+ is reduced to NADH + H+. 

Figure 5.3 Major control points of glycolysis and the TCA cycle. Enzymes I, hexokinase II, phosphofructokinase III, pyruvate kinase IV, pyruvate dehydrogenase V, citrate synthase VI, aconitase VII, isocitrate dehydrogenase VIII, a-oxoglutarate dehydrogenase.

Draw your own version of the reactions from pyruvate onwards to incorporate your understanding of the TCA cycle in A. niger during dtric add formation. 

The metabolic pathway for bacterial sugar fermentation proceeds through the Embden-Meyerhof-Paranas (EMP) pathway. The pathway involves many catalysed enzyme reactions which start with glucose, a six-carbon carbohydrate, and end with two moles of three carbon intermediates, pyruvate. The end pyruvate may go to lactate or be converted to acetyl CoA for the tricarboxylic acid (TCA) cycle. The fermentation pathways from pyruvate and the resulting end products are shown in Figures 9.7 and 9.8. 

Aerobic living features metabolize sugars and fatty acids to carbon dioxide. Accordingly, there are some kinds of decarboxylation reactions. TPP-mediated decarboxylation of pyruvic acid to acetaldehyde is one of the most important steps of the metabolism of sugar compounds (Fig. 1). When the intermediate reacts with lipoic acid instead of a proton, pyruvic acid is converted to acetylcoenzyme A, which is introduced to TCA cycle (Fig. 2). 

Mitochondria from body wall muscle and probably the pharynx lack a functional TCA cycle and their novel anaerobic pathways rely on reduced organic acids as terminal electron acceptors, instead of oxygen (Saz, 1971 Ma et al, 1993 Duran et al, 1998). Malate and pyruvate are oxidized intramitochondrially by malic enzyme and the pyruvate dehydrogenase complex, respectively, and excess reducing power in the form of NADH drives Complex II and [3-oxidation in the direction opposite to that observed in aerobic organelles (Kita, 1992 Duran et al, 1993 Ma et al,... 

This chapter focuses on the developmental regulation of the pyruvate dehydrogenase complex (PDC). The PDC plays diverse and pivotal roles in the entry of glycolytically generated carbon into the TCA cycle in aerobic stages and the metabolism of mitochondrially generated pyruvate in anaerobic stages (Fig. 14.1). 

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