Citric acid cycle succinate

Citric acid cycle Succinate thiokinase Phosphorylation at substrate level 2... 

A FIGURE 2-25 Conversion of succinate to fumarate. In this oxidation reaction, which occurs in mitochondria as part of the citric acid cycle, succinate loses two electrons and two protons. These are transferred to FAD, reducing it to FADH2. 

Most fatty acids have an even number of carbon atoms, so none are left over after /3-oxidation. Those fatty acids with an odd number of carbon atoms yield the three-carbon propionyl CoA in the final j3-oxidation. Propionyl CoA is then converted to succinate by a multistep radical pathway, and succinate enters the citric acid cycle (Section 29.7). Note that the three-carbon propionyl group should properly be called propnnoyl, but biochemists generally use the non-systematic name. 

Succinyl-CoA is converted to succinate by the enzyme succinate thiokinase (succinyl-CoA synthetase). This is the only example in the citric acid cycle of substrate-level phosphorylation. Tissues in which glu-coneogenesis occurs (the hver and kidney) contain two isoenzymes of succinate thiokinase, one specific for GDP and the other for ADP. The GTP formed is used for the decarboxylation of oxaloacetate to phos-phoenolpymvate in gluconeogenesis and provides a regulatory hnk between citric acid cycle activity and the withdrawal of oxaloacetate for gluconeogenesis. Nongluconeogenic tissues have only the isoenzyme that uses ADP. 

Figure 16-2. The citric acid cycle the major catabolic pathway for acetyl-CoA in aerobic organisms. Acetyl-CoA, the product of carbohydrate, protein, and lipid catabolism, is taken into the cycle, together with HjO, and oxidized to CO2 with the release of reducing equivalents (2H). Subsequent oxidation of 2H in the respiratory chain leads to coupled phosphorylation of ADP to ATP. For one turn of the cycle, 11 are generated via oxidative phosphorylation and one arises at substrate level from the conversion of succinyl-CoA to succinate.

As a result of oxidations catalyzed by the dehydrogenases of the citric acid cycle, three molecules of NADH and one of FADHj are produced for each molecule of acetyl-CoA catabohzed in one mrn of the cycle. These reducing equivalents are transferred to the respiratory chain (Figure 16-2), where reoxidation of each NADH results in formation of 3 ATP and reoxidation of FADHj in formation of 2 ATP. In addition, 1 ATP (or GTP) is formed by substrate-level phosphorylation catalyzed by succinate thiokinase. 

Four of the B vitamins are essential in the citric acid cycle and therefore in energy-yielding metabolism (1) riboflavin, in the form of flavin adenine dinucleotide (FAD), a cofactor in the a-ketoglutarate dehydrogenase complex and in succinate dehydrogenase (2) niacin, in the form of nicotinamide adenine dinucleotide (NAD),... 

FADH is produced by succinate dehydrogenase in the citric acid cycle and by the a-glycerol phosphate shuttle. Both enzymes are located in the inner membrane and can reoxidize FADHj directly by transferring electrons into the ETC. Once FADH2 has been oxidized, the FAD can be made available once again for use by the enzyme. 

FIGURE 16-7 Reactions of the citric acid cycle. The carbon atoms shaded in pink are those derived from the acetate of acetyl-CoA in the first turn of the cycle these are not the carbons released as CO2 in the first turn. Note that in succinate and fumarate, the two-carbon group derived from acetate can no longer be specifically denoted because succinate and fumarate are symmetric molecules, C-l and C-2 are indistinguishable from C-4 and C-3. The number beside each... 

Conversion of Succinyl-CoA to Succinate Succinyl-CoA, like acetyl-CoA, has a thioester bond with a strongly negative standard free energy of hydrolysis (AG ° = -36 kJ/mol). In the next step of the citric acid cycle, energy released in the breakage of this bond is used to drive the synthesis of a phosphoanhydride bond in either GTP or ATP, with a net AG ° of only -2.9 kJ/mol. Succinate is formed in the process ... 

Although the citric acid cycle directly generates only one ATP per turn (in the conversion of succinyl-CoA to succinate), the four oxidation steps in the cycle provide a large flow of electrons into the respiratory chain via NADH and FADH2 and thus lead to formation of a large number of ATP molecules during oxidative phosphorylation. 

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 ... 

FIGURE 16-22 Relationship between the glyoxylate and citric acid cycles. The reactions of the glyoxylate cycle (in glyoxysomes) proceed simultaneously with, and mesh with, those of the citric acid cycle (in mitochondria), as intermediates pass between these compartments. The conversion of succinate to oxaloacetate is catalyzed by citric acid cycle enzymes. The oxidation of fatty acids to acetyl-CoA is described in Chapter 17 the synthesis of hexoses from oxaloacetate is described in Chapter 20. 

Balance Sheet for the Citric Acid Cycle The citric acid cycle has eight enzymes citrate synthase, aconitase, isocitrate dehydrogenase, a-ketoglutarate dehydrogenase, succinyl-CoA synthetase, succinate dehydrogenase, fumarase, and malate dehydrogenase. 

FIGURE 20-35 Conversion of stored fatty acids to sucrose in germinating seeds. This pathway begins in glyoxysomes. Succinate is produced and exported to mitochondria, where it is converted to oxaloacetate by enzymes of the citric acid cycle. Oxaloacetate enters the cytosol and serves as the starting material for gluconeogenesis and for the synthesis of sucrose, the transport form of carbon in plants. 

The following is the sum of three steps in the citric acid cycle A + B + FAD + H20 — C + FADH2 + NADH Reactant A Reactant B Reactant C A. Succinyl CoA GDP Succinate B. Succinate NAD+ Oxaloacetate C. Fumarate NAD Oxaloacetate D. Succinate NAD Malate E. Fumarate GTP Malate Correct answer = B. Succinate + NAD" + FAD oxaloacetate + NADH + FADH2... 

One of the first persons to study the oxidation of organic compounds by animal tissues was T. Thunberg, who between 1911 and 1920 discovered about 40 organic compounds that could be oxidized by animal tissues. Salts of succinate, fumarate, malate, and citrate were oxidized the fastest. Well aware of Knoop s (3 oxidation theory, Thunberg proposed a cyclic mechanism for oxidation of acetate. Two molecules of this two-carbon compound were supposed to condense (with reduction) to succinate, which was then oxidized as in the citric acid cycle to oxaloacetate. The latter was decarboxylated to pyruvate, which was oxidatively decarboxylated to acetate to complete the cycle. One of the reactions essential for this cycle could not be verified experimentally. It is left to the reader to recognize which one. 

In muscle, 90% of all respiration was inhibited and succinate was shown to accumulate, powerful proof of the importance of the citric acid cycle in the respiration of animal tissues. 

The primary substrate of the citric acid cycle is acetyl-CoA. Despite many references in the biochemical literature to substrates "entering" the cycle as oxaloacetate (or as one of the immediate precursors succinate, fumarate, or malate), these compounds are not consumed by the cycle but are completely regenerated hence the term regenerating substrate, which can be applied to any of these four substances. A prerequisite for the operation of a catalytic cycle is that a regenerating substrate be readily available and that its concentration... 

---