TCA cycle

To burn the acetyl-CoA made from fat, glucose, or protein in order to make ATP in cooperation with oxidative phosphorylation. 

Pyruvate makes oxaloacetate and malate through the anaplerotic reactions. 

To amino acid degradation through acetyl-CoA and various intermediates of the cycle. 

Acetyl CoA condenses with oxaloacetate, forming citrate. 

Citrate is isomerized to isocitrate by a rearrangement of the molecule. Aconitate serves as an enzyme-bound intermediate. 

Isocitrate is oxidized to a-ketoglutarate in the first oxidative decarboxylation reaction. COz is produced, and the electrons are passed to NAD+ to form NADH + H+. 

Succinyl CoA is cleaved to succinate. Cleavage of the high-energy thioester bond of succinyl CoA provides energy for the substrate-level phosphorylation of GDP to GTP. Since this does not involve the electron transport chain, it is not an oxidative phosphorylation. 

Succinate is oxidized to fumarate. Two hydrogens are removed together with their electrons from succinate and transferred to FAD, forming FADH2. 

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Respiratory, or oxidative, metaboHsm produces more energy than fermentation. Complete oxidation of one mol of glucose to carbon dioxide and water may produce up to 36 mol ATP in the tricarboxyHc acid (TCA) cycle or related oxidative pathways. More substrates can be respired than fermented, including pentoses (eg, by Candida species), ethanol (eg, by Saccharomjces), methanol (eg, by Hansenu/a species), and alkanes (eg, by Saccharomjces lipoljticd). 

Possibly the most serious nutrition problem in the United States is excessive food consumption, and many people have experimented with fad diets in the hope of losing excess weight. One of the most popular of the fad diets has been the high-protein, high-fat (low-carbohydrate) diet. The premise for such diets is tantalizing because the tricarboxylic acid (TCA) cycle (see Chapter 20) is the primary site of fat metabolism, and because glucose is usually needed to replenish intermediates in the TCA cycle, if carbohydrates are restricted in the diet, dietary fat should merely be converted to ketone bodies and excreted. This so-called diet appears to work at first because a low-carbohydrate diet results in an initial water (and weight) loss. This occurs because... 

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,... 

Citrate synthase is the first step in this metabolic pathway, and as stated the reaction has a large negative AG°. As might be expected, it is a highly regulated enzyme. NADH, a product of the TCA cycle, is an allosteric inhibitor of citrate synthase, as is succinyl-CoA, the product of the fifth step in the cycle (and an acetyl-CoA analog). 

Isocitrate Dehydrogenase Links the TCA Cycle and Electron Transport... 

The First Five Steps of the TCA Cycle Produce NADH, CO, GTP (ATP), and Succinate... 

This is a good point to pause in our trip through the TCA cycle and see what has happened. A two-carbon acetyl group has been introduced as acetyl-CoA and linked to oxaloacetate, and two COg molecules have been liberated. The cycle has produced two molecules of NADH and one of GTP or ATP, and has left a molecule of succinate. 

The TCA cycle can now be completed by converting succinate to oxaloacetate. This latter process represents a net oxidation. The TCA cycle breaks it down into (consecutively) an oxidation step, a hydration reaction, and a second oxidation step. The oxidation steps are accompanied by the reduction of an [FAD] and an NAD. The reduced coenzymes, [FADHg] and NADH, subsequently provide reducing power in the electron transport chain. (We see in Chapter 24 that virtually the same chemical strategy is used in /3-oxidation of fatty acids.)... 

The net reaction accomplished by the TCA cycle, as follows, shows two molecules of COg, one ATP, and four reduced coenzymes produced per acetate group oxidized. The cycle is exergonic, with a net AG° for one pass around the cycle of approximately —40 kj/mol. Table 20.1 compares the AG° values for the individual reactions with the overall AG° for the net reaction. 

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 ... 

It can be seen that the carbonyl and methyl carbons of labeled acetyl-CoA have very different fates in the TCA cycle. The carbonyl carbon survives the first turn intact but is completely lost in the second turn. The methyl carbon... 

Until now we have viewed the TCA cycle as a catabolic process because it oxidizes acetate units to COg and converts the liberated energy to ATP and reduced coenzymes. The TCA cycle is, after all, the end point for breakdown of food materials, at least in terms of carbon turnover. However, as shown in Figure 20.22, four-, five-, and six-carbon species produced in the TCA cycle also fuel avariety of biosynthetic processes. a-Ketoglutarate, succinyl-CoA, fumarate, and oxaloacetate are all precursors of important cellular species. (In order to par-... 

FIGURE 20.21 The fate of the carbon atoms of acetate in successive TCA cycles. 

FIGURE 20.22 The TCA cycle provides intermediates for nmnerons biosynthetic processes in the cell. 

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. 

FIGURE 20.24 Phosphoenolpyruvate (PEP) carboxylase, pyrnvate carboxylase, and malic enzyme catalyze anaplerotlc reactions, replenishing TCA cycle Intermediates. 

One of these alternate models, postulated by Gunter Wachtershanser, involves an archaic version of the TCA cycle running in the reverse (reductive) direction. Reversal of the TCA cycle results in assimilation of CO9 and fixation of carbon as shown. For each turn of the reversed cycle, two carbons are fixed in the formation of isocitrate and two more are fixed in the reductive transformation of acetyl-CoA to oxaloacetate. Thus, for every succinate that enters the reversed cycle, two succinates are returned, making the cycle highly antocatalytic. Because TCA cycle intermediates are involved in many biosynthetic pathways (see Section 20.13), a reversed TCA cycle would be a bountiful and broad source of metabolic substrates. 

A reversed, reductive TCA cycle would require energy input to drive it. What might have been the thermodynamic driving force for such a cycle Wachtershanser hypothesizes that the anaerobic reaction of FeS and H9S to form insoluble FeS9 (pyrite, also known as fool s gold) in the prebiotic milieu could have been the driving reaction ... 

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