2-Oxoglutarate in the citric acid cycle

As mentioned in Section 4, glyoxylate can be converted to oxaloacetate by condensation with acetyl-CoA (Fig. 17-16) and the oxaloacetate can be decarboxylated to pyruvate. This sequence of reactions resembles that of the conversion of oxaloacetate to 2-oxoglutarate in the citric acid cycle (Fig. 17-4). Doth... 

A compound that is especially easy to observe is glutamate. This amino acid, most of which is found in the cytoplasm, is nevertheless in relatively rapid equilibrium with 2-oxoglutarate of the citric acid cycle in the mitochondria. The accompanying scheme shows where isotopic carbon from certain compounds will be located when it first enters the citric acid cycle and traces some of the labels into glutamate. For example, uniformly enriched fatty acids will introduce label into the two atoms of the pro-S arm of citrate and into 4- and 5-positions of glutamate whereas [2- C]acetate will introduce label only into the C4 position as marked by in the scheme. In the NMR spectrum a singlet resonance at 32.4 ppm will be observed. However, as successive turns of the citric acid cycle occur the isotope will appear in increasing amounts in the adjacent... 

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). 

The third control step in the citric acid cycle is catalyzed by 2-oxoglutarate dehydrogenase. This multienzyme complex is subject to product inhibition by both NADH and succinyl-CoA. Yet again,... 

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.

O-Ketoglutaric Acid. 2-Oxopentanedioic acid 2-oxoglutaric acid 2-oxo-l,5-pentanedioic acid. CsH40 mol wt 146.10. C 41.10%, H 4.14%, O 54.76%. HOOC. CH.CHjCOCOOH. Plays an important role in amino add metabolism (transamination) see Severo Ochoa, "Enzymic Mechanisms in the Citric Acid Cycle in Advances fn Enzy-mology 15, 183-270 (1954). Prepn Friedman, Kosower, Org. Syn. cell. vol. Ill, 510 (1955) Bottorff. Moore, ibid. Coll. vol. V, 687 (1973). Microbial synthesis using a strain of Pseudomonas Lockwood et al. U.S. pat. 2,443,919 (1948) Berger, Witt, U.S. pat. 2,841,616 (1958). 

L-Malic and citric acids are the major organic acids of fruits (Table 18.13). Malic acid is predominant in pomme and stone fruits, while citric acid is most abundant in berries, citrus and tropical fruits. (2R 3R)-Tartaric acid occurs only in grapes. Many other acids, including the acids in the citric acid cycle, occur only in low amounts. Examples are cis-aconitic, succinic, pyruvic, citramalic, fumaric, glyceric, glycolic, glyoxylic, isocitric, lactic, oxalacetic, oxalic and 2-oxoglutaric acids. In fruit juices, the ratio of citric acid to isocitric acid (examples in Table 18.14) serves as an indicator of dilution with an aqueous solution of citric acid. 

In thiamine deficiency, therefore, the formation from pyruvate of acetyl-coenzyme A, which is normally followed by the oxidation of the 2-C acetyl fragment to CO2 and H2O via the citric acid cycle is blocked, and the pyruvate formed by glycolysis consequently accumulates. In addition in its role in the oxidative decarboxylation of pyruvate, thiamine pyrophosphate is also needed as a co-enzyme in the similar decarboxylation of the closely related a-oxoglutarate, one of the intermediaries in the citric acid cycle. 

Fig. 5.7. In green sulfur bacteria and in some archaebacteria, a reverse citric acid cycle is used for the assimilation of C02. It must be assumed that this was the original function of the citric acid cycle that only secondarily took over the role as a dissimulatory and oxidative process for the degradation of organic matter. A major enzyme here is 2-oxoglutarate ferredoxin for C02 fixation. Note that it, like several other enzymes in the cycle, uses Fe/S proteins. One is the initial so-called complex I which has eight different Fe/S centres of different kinds but no haem (see also other early electron-transfer chains, e.g. in hydrogenases).

The two transamination steps in the pathways may be linked, as indicated in Fig. 17-5, to form a complete cycle that parallels the citric acid cycle but in which 2-oxoglutarate is oxidized to succinate via glutamate and y-aminobutyrate. No thiamin diphosphate is required, but 2-oxoglutarate is reductively aminated to glutamate. The cycle is sometimes called the y-aminobutyrate shunt, and it plays a significant role in the overall oxidative processes of brain tissue. 

If intermediates of the citric acid cycle enter the cycle via other reactions in the cell, are they oxidized If one molecule of 2-oxoglutarate, for example, were to enter the cycle, its metabolism through one turn of the cycle would be ... 

If a cell in which the citric acid cycle operates has the enzyme phosphoenolpyruvate carboxykinase, by what processes might it oxidize one molecule of 2-oxoglutarate to five molecules of C02 ... 

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