Thiamin oxoglutarate dehydrogenase

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 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... 

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. 

Fig. 2. Mechanism of the oxidative decarboxylation of 2-oxoglutarate by the 2- oxoglutarate dehydrogenase complex EC 1.2.4.2). Enzyme, = 2-oxoglutarate decarboxylase. Enzym = lipoyl-redurtase-transacetylase (lipoyl reductase-t-transsuccinylase). Enzymej = dihydrolipoyl dehydrogenase, tpp-thiamin pyrophosphate. HSCoA = coenzyme A.

B1 (thiamine) Whoiegrain, pork, pouitry Coenzyme for pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase Beri-beri Wemicke-Korsakoff syndrome... 

Deficient activity of both pyruvate and 2-oxoglutarate dehydrogenase complexes has also been reported in three infant siblings, with pyruvic, lactic and 2-oxoglutaric aciduria, fasting hypoglycaemia and a fatal course in two of the siblings despite attempts at treatment with thiamin, iipoate, biotin. 

There are two 2-oxoacid dehydrogenase multienzyme complexes in E. coli. One is specific for pyruvate, the other for 2-oxoglutarate. Each complex is about the size of a ribosome, about 300 A across. The pyruvate dehydrogenase is composed of three types of polypeptide chains El, the pyruvate decarboxylase (an a2 dimer of Mr — 2 X 100 000) E2, lipoate acetyltransferase (Mr = 80 000) and E3, lipoamide dehydrogenase (an a2 dimer of Mr = 2 X 56 000). These catalyze the oxidative decarboxylation of pyruvate via reactions 1.6, 1.7, and 1.8. (The relevant chemistry of the reactions of thiamine pyrophosphate [TPP], hydroxyethylthiamine pyrophosphate [HETPPJ, and lipoic acid [lip-S2] is discussed in detail in Chapter 2, section C3.)... 

ThDP plays a crucial role as coenzyme for several enzymes and enzyme complexes such as transketolase (EC 2.2.1.1) and the enzyme complexes pyruvate (EC 1.2.4.1) and 2-oxoglutarate (EC 1.2.4.2) dehydrogenases, present in nearly all organisms. They play important catabolic roles and are key actors in cell energy metabolism (Figure 5.1). Reduced activity of these enzymes as a consequence of thiamin deficiency results in decreased glucose oxidation. As the brain heavily relies on oxidative metabolism, it is more severely affected by thiamin deficiency than other organs. 

Thiamine was the first vitamin to have its precise biochemical functions determined. In the form of its pyrophosphate, thiamine participates in several very important enzyme systems namely (1) pyruvate dehydrogenase (page 232) which converts pyruvate to acetyl-CoA and carbon dioxide in the course of carbohydrate breakdown (2) the reaction of the citrate cycle in which oxoglutarate is oxidatively decarboxylated to succinyl-CoA (page 242) (3) the transketolase reaction of the pentose phosphate pathway of glucose breakdown (page 233). 

Oxoglutarate undergoes oxidative decarboxylation to succinyl-CoA, via multi-enzyme reaction similar to the reaction pattern of pyruvate. The multi-enzyme complex (mw about 2 x 10 ) is an octamer of an elementary unit containing each of the three contributing enzyme proteins oxoglutarate decarboxylase, dihydro-lipoyl transacetylase, and dihydrolipoyl dehydrogenase. The overall reaction involves thiamine pyrophosphate, lipoic acid, CoASH and NAD succinyl-CoA is the end product ... 

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