Citric acid cycle steps

The first step in the citric acid cycle (step a, Fig. 

In the next three steps in the citric acid cycle (Steps 6 through 8), the four-carbon succinate ion is converted to oxaloacetate ion to complete the cycle. 

Considering the citric acid cycle steps between a-ketoglutarate and malate, how many high-energy phosphate bonds, or net ATP molecules, can be generated ... 

The next steps of glucose catabolism are called the citric acid cycle. The pyruvic acid formed in glycolysis is transported into the mitochondria, which arc subcellular organelles with double (inner and outer) membranes. They are referred to as the powerhous-... 

The citric acid cycle, a nine-step process, also diverts chemical energy to the production of ATP and the reduction of NAD and FAD. In each step of the citric acid cycle (also known as the Krebs cycle) a glucose metabolite is oxidized while one of the carrier molecules, NAD or FAD, is reduced. Enzymes, nature s chemical catalysts, do a remarkable job of coupling the oxidation and reduction reactions so that energy is transferred with great efficiency. 

Problem 5.9 Predict the products of the following polar reaction, a step in the citric acid cycle for food metabolism, by interpreting the flow of elections indicated by Uie curved arrows ... 

Acid-catalyzed hydration of isolated double bonds is also uncommon in biological pathways. More frequently, biological hydrations require that the double bond be adjacent to a carbonyl group for reaction to proceed. Fumarate, for instance, is hydrated to give malate as one step in the citric acid cycle of food metabolism. Note that the requirement for an adjacent carbonyl group in the addition of water is the same as that we saw in Section 7.1 for the elimination of water. We ll see the reason for the requirement in Section 19.13, but might note for now that the reaction is not an electrophilic addition but instead occurs... 

In contrast to laboratory reactions, enzyme-catalyzed reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to (Z)-aconitate (usually called ris-aconitate) to give isocitrate. 

A large number of biological reactions involve prochiral compounds. One of the steps in the citric acid cycle by which food is metabolized, for instance, is... 

The dehydration of citrate to yield c/s-aconitate, a step jn the citric acid cycle, involves the pro-R "arm" of citrate rather than the pio-S arm. Which of the following two products is formed ... 

The first step in the citric acid cycle is reaction of oxaloacetate with acetyl CoA to give citrate. Propose a mechanism, using acid or base catalysis as needed. 

Enzymes work by bringing reactant molecules together, holding them, in the orientation necessary for reaction, and providing any necessary acidic or basic sites to catalyze specific steps. As an example, let s look at citrate synthase, an enzyme that catalyzes the aldol-like addition of acetyl CoA to oxaloacetate to give citrate. The reaction is the first step in the citric acid cycle, in which acetyl groups produced by degradation of food molecules are metabolized to yield C02 and H20. We ll look at the details of the citric acid cycle in Section 29.7. 

The conversion occurs through a multistep sequence of reactions catalyzed by a complex of enzymes and cofactors called the pyruvate dehydrogenase complex. The process occurs in three stages, each catalyzed by one of the enzymes in the complex, as outlined in Figure 29.11 on page 1152. Acetyl CoA, the ultimate product, then acts as fuel for the final stage of catabolism, the citric acid cycle. All the steps have laboratory analogies. 

The initial stages of catabolism result in the conversion of both fats and carbohydrates into acetyl groups that are bonded through a thioester link to coenzyme A. Acetyl CoA then enters the next stage of catabolism—the citric acid cycle, also called the tricarboxylic acid (TCA) cycle, or Krebs tycle, after Hans Krebs, who unraveled its complexities in 1937. The overall result of the cycle is the conversion of an acetyl group into two molecules of C02 plus reduced coenzymes by the eight-step sequence of reactions shown in Figure 29.12. 

As its name implies, the citric acid cycle is a closed loop of reactions in which the product of the hnal step (oxaloacetate) is a reactant in the first step. The intermediates are constantly regenerated and flow continuously through the cycle, which operates as long as the oxidizing coenzymes NAD+ and FAD are available. To meet this condition, the reduced coenzymes NADH and FADH2 must be reoxidized via the electron-transport chain, which in turn relies on oxygen as the ultimate electron acceptor. Thus, the cycle is dependent on the availability of oxygen and on the operation of the electron-transport chain. 

Figure 29.12 MECHANISM The citric acid cycle is an eight-step series of reactions that results in the conversion of an acetyl group into two molecules of C02 plus reduced coenzymes. Individual steps are explained in the text.

Step 1 of Figure 29.12 Addition to Oxaloacetate Acetyl CoA enters the citric acid cycle in step 1 by nucleophilic addition to the oxaloacetate carbonyl group, to give (S)-citryl CoA. The addition is an aldol reaction and is catalyzed by citrate synthase, as discussed in Section 26.11. (S)-Citryl CoA is then hydrolyzed to citrate by a typical nucleophilic acyl substitution reaction, catalyzed by the same citrate synthase enzyme. 

Steps 7-8 of Figure 29.12 Hydration and Oxidation The final two steps in the citric acid cycle are the conjugate nucleophilic addition of water to fumarate to yield (S)-malate (L-malate) and the oxidation of (S)-malate by NAD+ to give oxaloacetate. The addition is cataiyzed by fumarase and is mechanistically similar to the addition of water to ris-aconitate in step 2. The reaction occurs through an enolate-ion intermediate, which is protonated on the side opposite the OH, leading to a net anti addition. 

The final step is the oxidation of (S)-malate by NAD+ to give oxaloacetate, a reaction catalyzed by malate dehydrogenase. The citric acid cycle has now returned to its starting point, ready to revolve again. The overall result of the cycle is... 

Problem 29.11 Write mechanisms for step 2 of the citric acid cycle, the dehj dration of citrate and the addition of water to aconitate. 

Problem 29.12 ls the pro-R or pro-5 hydrogen removed from citrate during the dehydration in step 2 of the citric acid cycle Does the elimination reaction occur with syn or anti geometry ... 

Step 2 of Figure 29.13 Decarboxylation and Phosphorylation Decarboxylation of oxaloacetate, a jB-keto acid, occurs by the typical retro-aldol mechanism like that in step 3 in the citric acid cycle (Figure 29.12), and phosphorylation of the resultant pyruvate enolate ion by GTP occurs concurrently to give phosphoenol-pyruvate. The reaction is catalyzed by phosphoenolpyruvate carboxykinase. 

Write a mechanism for the conversion of a--ketoglutarate to succinyl CoA in step 4 of the citric acid cycle (Figure 29.12). 

The citric acid cycle One is generated directly in the cycle at the succinyl thiokinase step (Figure... 

Citrate is isomerized to isocitrate by the enzyme aconitase (aconitate hydratase) the reaction occurs in two steps dehydration to r-aconitate, some of which remains bound to the enzyme and rehydration to isocitrate. Although citrate is a symmetric molecule, aconitase reacts with citrate asymmetrically, so that the two carbon atoms that are lost in subsequent reactions of the cycle are not those that were added from acetyl-CoA. This asymmetric behavior is due to channeling— transfer of the product of citrate synthase directly onto the active site of aconitase without entering free solution. This provides integration of citric acid cycle activity and the provision of citrate in the cytosol as a source of acetyl-CoA for fatty acid synthesis. The poison fluo-roacetate is toxic because fluoroacetyl-CoA condenses with oxaloacetate to form fluorocitrate, which inhibits aconitase, causing citrate to accumulate. 

Ketogenesis is regulated at three cmcial steps (1) control of free fatty acid mobihzation from adipose tissue (2) the activity of carnitine palmitoyltransferase-1 in hver, which determines the proportion of the fatty acid flux that is oxidized rather than esteri-fied and (3) partition of acetyl-CoA between the pathway of ketogenesis and the citric acid cycle. 

The criteria for gene displacement in this study were strict. The reactions catalyzed were required to have the same EC (Enzyme Commission) number, which implies that the same cofactors had to be involved. In the example of reactions involved in the citric acid cycle given previously, when only the carbohydrate substrate and product of the reaction were the same, we could identify gene displacements at 6 of the 11 steps included in the analysis. Only two of those (malate dehydrogenase and fumarase) met the criteria in Galperin et al. (1998). 

Q ttflif Identify the steps in the citric acid cycle that fit the following descriptions. 

Q ttfiM In the citric acid cycle, every step that is an oxidation reaction also produces energy, until the most oxidized form of carbon leaves the cycle as carbon dioxide. Which steps in the cycle produce energy ... 

Pyridoxal phosphate is a required coenzyme for many enzyme-catalyzed reactions. Most of these reactions are associated with the metabolism of amino acids, including the decarboxylation reactions involved in the synthesis of the neurotransmitters dopamine and serotonin. In addition, pyridoxal phosphate is required for a key step in the synthesis of porphyrins, including the heme group that is an essential player in the transport of molecular oxygen by hemoglobin. Finally, pyridoxal phosphate-dependent reactions link amino acid metabolism to the citric acid cycle (chapter 16). 

We should recognize that the citric acid cycle is catalytic. Specifically, the molecule that is required to condense with acetyl-SCoA in the first step of the cycle is regenerated in the last step. In principle therefore, the cycle is capable of consuming acetyl-SCoA and producing carbon dioxide endlessly as it turns. Here is a schematic... 

The tricarboxylic acid cycle (TCA cycle, also known as the citric acid cycle or Krebs cycle) is a cyclic metabolic pathway in the mitochondrial matrix (see p. 210). in eight steps, it oxidizes acetyl residues (CH3-CO-) to carbon dioxide (CO2). The reducing equivalents obtained in this process are transferred to NAD"" or ubiquinone, and from there to the respiratory chain (see p. 140). Additional metabolic functions of the cycle are discussed on p. 138. 

The toxicity of fluoroacetic acid and of its derivatives has played an historical decisive role at the conceptual level. Indeed, it demonstrates that a fluorinated analogue of a natural substrate could have an activity profile that is far different from that of the nonfluorinated parent compound. The toxicity of fluoroacetic acid is due to its ability to block the citric acid cycle (Krebs cycle), which is an essential process of the respiratory chain. The fluoroacetate is transformed in vivo into 2-fluorocitrate by the citrate synthase. It is generally admitted that aconitase (the enzyme that performs the following step of the Krebs cycle) is inhibited by 2-fluorocitrate the formation of aconitate through elimination of the water molecule is a priori impossible from this substrate analogue (Figure 7.1). 

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