A-Ketoglutarate dehydrogenases

Mode of Action. The fundamental biochemical lesion produced by arsenicals is the result of reaction between As " and the sulfhydryl groups of key respiratory enzymes such as pymvate and a-ketoglutarate dehydrogenases. 

Lipoic acid is an acyl group carrier. It is found in pyruvate dehydrogenase zard a-ketoglutarate dehydrogenase, two multienzyme complexes involved in carbohydrate metabolism (Figure 18.34). Lipoie acid functions to couple acyl-group transfer and electron transfer during oxidation and decarboxylation of a-keto adds. 

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. 

Pyruvate and a-ketoglutarate dehydrogenase have complex systems involving lipoate and FAD prior to the passage of electrons to NAD, while electron trans-... 

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),... 

B, Thiamin Coenzyme in pyruvate and a-ketoglutarate, dehydrogenases, and transketolase poorly defined function in nerve conduction Peripheral nerve damage (beriberi) or central nervous system lesions (Wernicke-Korsakoff syndrome)... 

A somewhat more trivial thing to remember about the HMP pathway is that this is one of the places you ve seen the vitamin thiamin pyrophosphate. This cofactor is necessary for the transketolase reaction that is in the middle of the HMP pathway. The transketolase reaction converts two C-5 sugars to a C-7 and a C-3. The other place you ve seen thiamin pyrophosphate as a cofactor is in the pyruvate dehydrogenase and a-ketoglutarate dehydrogenase reactions. 

Thiamine deficiency results in early decreases in activity of the mitochondrial enzyme a-ketoglutarate dehydrogenase in brain. Wernicke s encephalopathy, also known as the Wernicke-Korsakoff syndrome is a neuropsychiatric disorder characterized by ophthalmoplegia, ataxia and memory loss. Wernicke s encephalopathy is encountered in chronic alcoholism, in patients with HIV-AIDS and in other disorders associated with grossly impaired nutritional status. The condition results from thiamine deficiency. 

This is not the only example of Nature inventing the assembly line a long time before Henry Ford—both pyru-vate dehydrogenase and a-ketoglutarate dehydrogenase, mentioned earlier in the chapter, are also multi-enzyme complexes. 

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>. 

GLUTAMATE DEHYDROGENASE GLUTAMATE SYNTHASE a-KETOGLUTARATE DEHYDROGENASE LEUCINE AMINOTRANSFERASE LYSINE 6-AMINOTRANSFERASE LYSYL HYDROXYLASE... 

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