A-Ketoglutarate dehydrogenase complexes

Several enzymes of the intermediary metabolism require thiaminpyrophosphate (TPP, Fig. 1) as coenzyme, e.g., enzymes of the pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase complex, or pentose phosphate pathway. 

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),... 

There are some very interesting questions of stereospecificity posed by the structure and mode of operation of multienzyme complexes. Reed and Cox 35> have summarized available information on the pyruvate and a-ketoglutarate dehydrogenase complexes, and the fatty add synthetase. The mechanism of synthesis of the peptide antibiotics likewise presents interesting stereochemical problems 36>. 

C. Conversion of a-ketoglutarate to succinyl CoA, COj, and NADH is catalyzed by the a-ketoglutarate dehydrogenase complex. 

By analogy to the PDH complex, the a-ketoglutarate dehydrogenase complex is made up of three enzyme activities with a similar array of activities and coenzyme requirements. 

Arsenic can react Irreversibly with the critical sulfhydryl groups of the coenzyme Tipolc acid, which Inactivates the coenzyme and thus Inhibits the PDH complex and the a-ketoglutarate dehydrogenase complex. 

The answer is A. This patient exhibits several signs of acute arsenic exposure, including the cholera-like gastrointestinal symptoms and probable dehydration. He may currently be in hypovolemic shock and beginning chelation therapy is the only recourse. Arsenic is a metabolic toxin because it inhibits enzymes that require lipoic acid as a coenzyme the PDH complex, the a-ketoglutarate dehydrogenase complex, and trans-ketolase of the pentose phosphate pathway. 

The next step is another oxidative decarboxylation, in which a-ketoglutarate is converted to succinyl-CoA and C02 by the action of the a-ketoglutarate dehydrogenase complex NAD+ serves as electron acceptor and CoA as the carrier of the succinyl group. The energy of oxidation of a-ketoglutarate is conserved in the formation of the thioester bond of succinyl-CoA ... 

Answer Thiamine is required for the synthesis of thiamin pyrophosphate (TPP), a prosthetic group in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes. A thiamin deficiency reduces the activity of these enzyme complexes and causes the observed accumulation of precursors. 

Lipoamide dehydrogenase can be isolated from the multienzyme complexes that carry out these oxidative decarboxylations from the a-ketoglutarate dehydrogenase complex of heart (41, 119-1 SI) or E. coli (12S), or from the pyruvate dehydrogenase complex of heart (9S, 123, 124) or... 

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

The TCA cycle is the major final common pathway of oxidation of carbohydrates, lipids, and proteins, since their oxidation yields acetyl-CoA. Acetyl-CoA also serves as precursor in the synthesis of fatty acids, cholesterol, and ketone bodies. All enzymes of the cycle are located in the mitochondrial matrix except for succinate dehydrogenase, which is embedded in the inner mitochondrial membrane. Thus, the reducing equivalents generated in the cycle have easy access to the electron transport chain. TCA cycle enzymes, with the exception of a-ketoglutarate dehydrogenase complex and succinate dehydrogenase, are also present outside the mitochondria. The overall TCA cycle is shown in Figure 13-12. 

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