2-Oxoglutarate dehydrogenases

The situation is simpler for odd numbered fatty acyl derivatives as [3-oxidation proceeds normally until a 5-carbon unit remains, rather than the usual 4-carbon unit. The C5 moiety is cleaved to yield acetyl-CoA (C2) and propionyl-CoA (C3). Propionyl CoA can be converted to succinyl CoA and enter the TCA cycle so the entire molecule is utilized but with a slight reduction in ATP yield as the opportunity to generate two molecules of NADH by isocitrate dehydrogenase and 2-oxoglutarate dehydrogenase is lost because succinyl-CoA occurs after these steps in the Krebs cycle (Figure 7.18). 

Now this reaction is effectively a repeat of the pyruvate acetyl-CoA oxidative decarboxylation we saw at the beginning of the Krebs cycle. It similarly requires thiamine diphosphate, lipoic acid, coenzyme A and NAD+. A further feature in common with that reaction is that 2-oxoglutarate dehydrogenase is also an enzyme complex comprised of three separate enzyme activities. 2-Oxoglutarate is thus transformed into succinyl-CoA, with the loss of... 

The intermediary metabolism has multienzyme complexes which, in a complex reaction, catalyze the oxidative decarboxylation of 2-oxoacids and the transfer to coenzyme A of the acyl residue produced. NAD" acts as the electron acceptor. In addition, thiamine diphosphate, lipoamide, and FAD are also involved in the reaction. The oxoacid dehydrogenases include a) the pyruvate dehydrogenase complex (PDH, pyruvate acetyl CoA), b) the 2-oxoglutarate dehydrogenase complex of the tricarboxylic acid cycle (ODH, 2-oxoglutarate succinyl CoA), and c) the branched chain dehydrogenase complex, which is involved in the catabolism of valine, leucine, and isoleucine (see p. 414). 

The next step, the formation of succinyl CoA, also involves one oxidation and one decarboxylation. it is catalyzed by 2-oxoglutarate dehydrogenase, a multienzyme complex closely resembling the PDH complex (see... 

King RF, Macfie J, Hill G (1981) Activities of hexokinase, phosphofructokinase, fructose bisphosphatase and 2-oxoglutarate dehydrogenase in muscle of normal subjects and very ill surgical patients. Clin Sci 60 451-456... 

Electron microscopy of the core dihydrolipoyl transacylase from E. coli reveals a striking octahedral symmetry which has been confirmed by X-ray diffraction.306 3073 The core from pyruvate dehydrogenase has a mass of 2390 kDa and contains 24 identical 99.5-kDa E2 subunits. The 2-oxoglutarate dehydrogenase from E. coli has a similar but slightly less symmetric structure. Each core subunit is composed of three domains. A lipoyl group is bound in amide linkage to lysine 42 and protrudes from one end of the domain. 

Three modifications of the conventional oxidative citric acid cycle are needed, which substitute irreversible enzyme steps. Succinate dehydrogenase is replaced by fumarate reductase, 2-oxoglutarate dehydrogenase by ferredoxin-dependent 2-oxoglutarate oxidoreductase (2-oxoglutarate synthase), and citrate synthase by ATP-citrate lyase [3, 16] it should be noted that the carboxylases of the cycle catalyze the reductive carboxylation reactions. There are variants of the ATP-driven cleavage of citrate as well as of isocitrate formation [7]. The reductive citric acid... 

GA Rutter, RM Denton. The binding of Ca2+ ions to pig heart NAD+-isocitrate dehydrogenase and the 2-oxoglutarate dehydrogenase complex. Biochem J 263 453-462, 1989. 

Step 4 is the production of succinyl-CoA from 2-oxoglutarate and coenzyme A (CoASH), catalyzed by the 2-oxoglutarate dehydrogenase complex (which is often called a-ketoglutarate... 

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,... 

The studies of Peters in the 1920s and 1930s (Peters, 1963) established the coenzyme role of thiamin in the oxidative decarboxylation of pyruvate. Thiamin diphosphate is the coenzyme for three multienzyme complexes in mammalian mitochondria that are involved in the oxidative decarboxylation of oxo-acids pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase in central... 

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.

Early studies showed that the development of neurological abnormalities in thiamin deficiency did not follow the same time course as the impairment of pyruvate and 2-oxoglutarate dehydrogenase or transketolase activities. The brain regions in which metabolic disturbances are most marked were not those that are vulnerable to anatomical lesions. These studies suggested a function for thiamin in the nervous system other than its coenzyme role. 

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