Succinate in the citric acid cycle

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. 

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. 

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. 

Since in the citric acid cycle there is no net production of its intermediates, mechanisms must be available for their continual production. In the absence of a supply of oxalacetic acid, acctaic" cannot enter the cycle. Intermediates for the cycle can arise from the carinxylation of pyruvic acid with CO, (e.g., to form malic acid), the addition of CO > to phosphcnnlpyruvic acid to yield oxalacetic acid, the formation of succinic acid from propionic acid plus CO, and the conversion of glutamic acid and aspartic acid to alpha-ketoglutaric acid and oxalacetic acid, respectively. See Fig. 3. 

The citric acid cycle operates in the mitochondria of eukaryotes and in the cytosol of prokaryotes. Succinate dehydrogenase, the only membrane-bound enzyme in the citric acid cycle, is embedded in the inner mitochondrial membrane in eukaryotes and in the plasma membrane in prokaryotes. 

Succinate dehydrogenase catalyzes the so-called trans elimination of two H s. This is the only reaction in the citric acid cycle involving FAD, and succinate dehydrogenase is the only enzyme in the cycle that is membrane-bound. The importance of this will be discussed in Chap. 14. 

There are four major regulatory enzymes in the citric acid cycle. These are citrate synthase (step 1), isocitrate dehydrogenase (step 3), 2-oxoglutarate dehydrogenase (step 4), and succinate dehydrogenase (step 6). 

Figure 6.3. GABA shunt as an alternative to a-ketoglutarate dehydrogenase in the citric acid cycle. 2-Oxoglutarate dehydrogenase, EC 1.2.4.2 glutamate decarboxylase, EC 4.1.1.15 GABA aminotransferase, EC 2.6.1.19 and succinic semialdehyde dehydrogenase, ECl.2.1.16.

Many bacteria and plants are able to subsist on acetate or other compounds that yield acetyl CoA. They make use of a metabolic pathway absent in most other organisms that converts two-carbon acetyl units into four-carbon units (succinate) for energy production and biosyntheses. This reaction sequence, called the glyoxylate cycle, bypasses the two decarboxylation steps of the citric acid cycle. Another key difference is that two molecules of acetyl CoA enter per turn of the glyoxylate cycle, compared with one in the citric acid cycle. 

---