Thiamin citric acid cycle

Coenzymes Involved in Pyruvate Oxidation and the Citric Acid Cycle Thiamine Pyrophosphate (Figure 14.6)... 

Thiamine pyrophosphate is a coenzyme for several enzymes involved in carbohydrate metabolism. These enzymes either catalyze the decarboxylation of oi-keto acids or the rearrangement of the carbon skeletons of certain sugars. A particularly important example is provided by the conversion of pyruvic acid, an oi-keto acid, to acetic acid. The pyruvate dehydrogenase complex catalyzes this reaction. This is the key reaction that links the degradation of sugars to the citric acid cycle and fatty acid synthesis (chapters 16 and 18) ... 

In this reaction, pyruvic acid is oxidized to carbon dioxide with formation of acetyl-SCoA and NAD+ is reduced to NADH. As noted in chapter 15, this reaction requires the participation of thiamine pyrophosphate as coenzyme. Here too the NADH formed is converted back to NAD+ by the electron transport chain. As noted above, the acetyl-SCoA is consumed by the citric acid cycle and CoASH is regenerated. 

The oxidative cleavage of an a-oxoacid is a major step in the metabolism of carbohydrates and of amino acids and is also a step in the citric acid cycle. In many bacteria and in eukaryotes the process depends upon both thiamin diphosphate and lipoic acid. The oxoacid anion is cleaved to form C02 and the remaining acyl group is combined with coenzyme A (Eq. 15-33). 

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. 

Vitamin Influences. The involvement of NAD and NADP in many carbohydrate reactions explains the importance of nicotinamide in carbohydrate melaholism. Thiamine, in the form or thiamine pyrophosphate (cocarboxylase), is the cofaclor necessary in the decarboxylation of pyruvic acid, in the iraru-kelolase-calalyzed reactions of the pentose phosphaie cycle, and in the decarboxylation of alpha-keloglutaric acid in the citric acid cycle, among other reactions. Biotin is a hound cofaclor in the fixation of carbon dioxide to form nxalacetic acid from pyruvic acid. Pantothenic acid is a part of the C oA molecule. There are separate alphabetical entries in this volume on the various specific vitamins as well as a review entry on Vitamin. 

TPP also mediates the oxidative decarboxylation of a-ketoglutaric acid, another intermediate of carboxydrate metabolism in the citric acid cycle. The nutritional requirement for thiamine increases as dietary carbohydrate increases because of a greater demand for TPP. 

Figure 19-1. Pathways for the metabolic disposal of phenylalanine. There are two competitive pathways for the disposal of phenylalanine. One pathway involves a transaminase enzyme phenylpyruvate, while the first step in the second pathway requires phenylalanine to be initially converted to tyrosine. Continued metabolism of the phenylpyruvate produced by the first pathway leads to products that cannot be further metabolized, while tyrosine can be converted into citric acid cycle intermediates. Glu, glutamate aKG CoASH, coenzyme A BH4, tetrahydrobiopterin TPP, thiamine pyrophosphate.

The role of thiamin diphosphate in pymvate dehydrogenase means that, in deficiency, there is impaired conversion of pymvate to acetyl GoA, and hence impaired entry of pymvate into the citric acid cycle. Especially in subjects on a relatively high carbohydrate diet, this results in increased plasma concentrations oflactate and pymvate, which may lead to life-threateninglactic acidosis. 

Thiamine is required by the body as the pyrophosphate (TPP) in two general types of reaction, the oxidative decarboxylation of a keto acids catalyzed by dehydrogenase complexes and the formation of a-ketols (ketoses) as catalyzed by transketolase, and as the triphosphate (TTP) within the nervous system. TPP functions as the Mg -coordinated coenzyme for so-called active aldehyde transfers in mul-tienzyme dehydrogenase complexes that affect decarboxyia-tive conversion of a-keto (2 oxo) acids to acyl-coenzyme A (acyl-CoA) derivatives, such as pyruvate dehydrogenase and a-ketoglutarate dehydrogenase. These are often localized in the mitochondria, where efficient use in the Krebs tricarboxylic acid (citric acid) cycle follows. 

Bj (thiamine) Aldehyde transfer, decarboxylation in alcoholic fermentation and citric acid cycle Sections 17.4,19.3... 

Many of these deficiency conditions in animals can be explained in terms of the role of TPP in the oxidative decarboxylation of pyruvic acid. On a thiamin-deficient diet animals accumulate pyruvic acid and its reduction product lactic acid in their tissues, which leads to muscular weakness. Nerve cells are particularly dependent on the utilisation of carbohydrate and for this reason a deficiency of the vitamin has a particularly serious effect on nervous tissue. Since acetyl coenzyme A is an important metabolite in the synthesis of fatty acids (see p. 220), lipogenesis is reduced. The pentose phosphate pathway is also impaired by a deficiency of thiamin but there is little effect on the activity of the citric acid cycle. 

What acyl group is transferred by thiamine pyrophosphate in the fourth reaction of the citric acid cycle ... 

Some reactions of thiamine, such as decarboxylation of a-oxocarboxylic acids, are features of primary metabolism (decarboxylation of pyruvic acid to acetaldehyde in glycolysis and transformation of pyruvic acid to acetyl-CoA prior to its entry into the citric acid cycle) that depend on thiamine diphosphate as a coenzyme. The thiamine ring has an acidic hydrogen and is thus capable of producing the carbanion that acts as a nucleophile towards carbonyl groups. Analogous reactions proceed non-enzymatically and can thus be included among the so-called... 

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