Thiamine pyrophosphate coenzyme

Thiamine pyrophosphate (XXXV) contains an V-alkylated thiazole and a pyrimidine. The function of this coenzyme is also to stabilise electron density and it is 

3-d orbitals, theoretical calculations indicate that this is not significant and that sulphur carbanions owe their stability to the large polarisability of sulphur [25]. 

Breaking the carbon-carbon bond of an a-keto acid to give carbon dioxide 

In summary, the chemical usefulness of thiamine pyrophosphate depends on its ease of carbanion formation at C-2 which is not only a good nucleophile but also a reasonably stable leaving group. In addition the cationic imine stabilises the formation of a carbanion on the adjacent carbon bonded to C-2. 

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The pyruvate dehydrogenase complex (PDC) is a noncovalent assembly of three different enzymes operating in concert to catalyze successive steps in the conversion of pyruvate to acetyl-CoA. The active sites of ail three enzymes are not far removed from one another, and the product of the first enzyme is passed directly to the second enzyme and so on, without diffusion of substrates and products through the solution. The overall reaction (see A Deeper Look Reaction Mechanism of the Pyruvate Dehydrogenase Complex ) involves a total of five coenzymes thiamine pyrophosphate, coenzyme A, lipoic acid, NAD+, and FAD. 

The reaction mixture contained 80 /xL of 130 mM Hepes-67 mM Tris buffer (pH 7.4) 10 ju,L each (to give final concentration of 1 mM) of NAD, thiamine pyrophosphate, coenzyme A, MgCl2, and dithiothreitol 20 /xL of tissue extract or enzyme source, and 30 /xL of bovine serum albumin (1 mg). The reaction was started by adding 20 fiL of a-ketoglutarate to give a final concentration of 10 mM After incubation at 30°C for 1, 5, or 20 minutes for purified enzyme from bovine heart, brain, or liver mitochondria, or platelet homogenates, the reaction was stopped by addition of 20 /xL of 60% perchloric acid and the denatured protein was removed by centrifugation. A 10 /xL aliquot was used for HPLC analysis. 

D. decarboxylate the hydroxyethyl group bound to the thiamine pyrophosphate coenzyme... 

D. Valine, isoleucine, and leucine (the branched-chain amino acids) are transaminated and then oxidized by an a-keto acid dehydrogenase that requires lipoic acid as well as thiamine pyrophosphate, coenzyme A, FAD, and NAD+. Four of the carbons of valine and isoleucine are converted to succinyl CoA. Isoleucine also produces acetyl CoA Leucine is converted to HMG CoA, which is cleaved to acetoacetate and acetyl CoA... 

See also FAD / FADH2, Thiamine Pyrophosphate, Coenzyme A, Biotin, Vitamin B12... 

The oxidation of pyruvic acid to form acetyl CoA was for many years the elusive active acetate . It was the target of active research in many laboratories since Peters demonstrated in the 1930s that cocarboxylase (thiamine pyrophosphate) is necessary for the process. The reaction implies an oxidative decarboxylation by which pyruvic acid loses CO2 and 2H to form acetyl CoA, and requires several enzymes and coenzymes (thiamine pyrophosphate, coenzyme A, NAD, lipoic acid and Mg +). 

Flavin adenine dinucleotide and its reduced form Thiamine pyrophosphate Coenzyme A... 

As shown in Eigure 18.17, thiamine is composed of a substituted thiazole ring joined to a substituted pyrimidine by a methylene bridge. It is the precursor of thiamine pyrophosphate (TPP), a coenzyme involved in reactions of carbo-... 

The mechanism of the pyruvate dehydrogenase reaction is a tour de force of mechanistic chemistry, involving as it does a total of three enzymes (a) and five different coenzymes—thiamine pyrophosphate, lipoic acid, coenzyme A, FAD, and NAD (b). 

Most coenzymes have aromatic heterocycles as major constituents. While enzymes possess purely protein structures, coenzymes incorporate non-amino acid moieties, most of them aromatic nitrogen het-erocycles. Coenzymes are essential for the redox biochemical transformations, e.g., nicotinamide adenine dinucleotide (NAD, 13) and flavin adenine dinucleotide (FAD, 14) (Scheme 5). Both are hydrogen transporters through their tautomeric forms that allow hydrogen uptake at the termini of the quinon-oid chain. Thiamine pyrophosphate (15) is a coenzyme that assists the decarboxylation of pyruvic acid, a very important biologic reaction (Scheme 6). 

Scheme 6. Coenzymes Thiamine Pyrophosphate and Its Role in the Decarboxylation of Pyruvic Acid...

Assisted decarboxylation of pyruvic acid by thiamine pyrophosphate (only the thiazole portion of the coenzyme is shown)... 

Coenzymes complement the catalytic action of the amino-acid functional groups. They are bound to apoenzymes (apoproteins) either covalently or non-covalently. It is interesting to note that non-covalently-bound coenzymes are polyanions at neutral pH as exemplified by the structures of glutathione (GSH) [17] and thiamine pyrophosphate [18]. Shinkai and Kunitake (1976b, 1977a) demonstrated the efficient binding of glutathione and coenzyme A (a polyphosphate) to cationic micelles and cationic polysoaps. Thus, the combina- ... 

The way in which thiamine participated in the oxidation of pyruvate became clearer when Lohmann and Schuster (1937) showed vitamin Bj to be present intracellularly as thiamine pyrophosphate. In yeast, decarboxylation of pyruvate yielded ethanal which was reduced by alcohol dehydrogenase to give ethanol. A cofactor was needed for this decarboxylation, co-carboxylase. Like the cofactor needed in animal cells for the decarboxylation of pyruvate, cocarboxylase was found to be identical to thiamine pyrophosphate. Vitamin Bj thus became the first vitamin whose intracellular function as a coenzyme had been established in vitro. Another aphorism therefore arose about vitamins—B vitamins are (parts of) coenzymes—an idea that was to be completely confirmed. 

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) ... 

Vitamin Bi, or thiamine, is a precursor to thiamine pyrophosphate, an essential coenzyme for several enzymes. Beriberi is a vitamin Bi deficiency disease. 

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. 

Vitamin B thiamine the precursor to the coenzyme thiamine pyrophosphate. 

Vitamin deficiency of Bj leads to the disease known as Beriberi. However, nowadays in the Western hemisphere, vitamin Bj deficiency is mainly found as a consequence of extreme alcoholism. In fact, the vitamin absorption by the gut is decreased and its excretion is increased by alcohol. Alcohol also inhibits the activation of vitamin Bj to its coenzyme form, thiamine pyrophosphate ester (TPP). There is no evidence of adverse effects of oral intake of thiamine [417]. The main food sources of vitamin Bj are lean pork, legumes, and cereal grains (germ fraction). It is soluble in water and stable at higher temperature and at pH lower than 5.0, but it is destroyed rapidly by boiling at pH 7.0 or above. 

PDH removes CO2 and transfers the remaining acetyl group to the enzyme-bound coenzyme thiamine pyrophosphate,... 

Figure 7-1. Conversion of pyruvate to acetyl CoA by the pyruvate dehydrogenase complex. The three enzymes, pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase, exist in a complex associated with the mitochondrial matrix. Each enzyme requires at least one coenzyme that participates in the reaction. TPP, thiamine pyrophosphate Lip, lipoic acid CoA, coenzyme A.

Thiamine pyrophosphate Is an essential coenzyme for several critical metabolic enzymes—PDH, a-ketoglutarate dehydrogenase, and transketolase of the pentose phosphate pathway. 

Thiamine (vitamin Bi) is phosphorylated by ATP to thiamine pyrophosphate. This is a coenzyme for, among others, alpha-ketoglutarate dehydrogenase, transketolase and pyruvate dehydrogenase. Thiamine pyrophosphate is involved in fatty acid... 

Thiamine pyrophosphate is a coenzyme and the active form of vitamin B. It functions as coenzyme in decarboxylation of a-keto acid and in hexose monophosphate shunt. 

The next coenzyme for which a mechanism was established was thiamin pyrophosphate [3]. Ronald Breslow used nmr spectroscopy to show that the hydrogen atom at C-2 of a thiazolium salt rapidly exchanges with deuterium in even slightly alkaline solutions (6), so that the coenzyme offers an anionic centre for catalysis (Breslow, 1957). With this established, Breslow could confidently offer the pathway shown in Scheme 2 for the action of the... 

Thiamine (vitamin B1 ) Essential vitamin required for synthesis of the coenzyme thiamine pyrophosphate Administered to patients suspected of having alcoholism (those exhibiting acute alcohol intoxication or alcohol withdrawal syndrome) to prevent Wernicke-Korsakoff syndrome Administered parenterally Toxicity None Interactions None... 

In the first step, pyruvate is decarboxylated in an irreversible reaction catalyzed by pyruvate decarboxylase. This reaction is a simple decarboxylation and does not involve the net oxidation of pyruvate. Pyruvate decarboxylase requires Mg24" and has a tightly bound coenzyme, thiamine pyrophosphate, discussed below. In the second step, acetaldehyde is reduced to ethanol through the action of alcohol dehydrogenase, with... 

The pyruvate decarboxylase reaction provides our first encounter with thiamine pyrophosphate (TPP) (Fig. 14-13), a coenzyme derived from vitamin B Lack of vitamin Bi in the human diet leads to the condition known as beriberi, characterized by an accumulation of body fluids (swelling), pain, paralysis, and ultimately death. 

The combined dehydrogenation and decarboxylation of pyruvate to the acetyl group of acetyl-CoA (Fig. 16-2) requires the sequential action of three different enzymes and five different coenzymes or prosthetic groups—thiamine pyrophosphate (TPP), flavin adenine dinucleotide (FAD), coenzyme A (CoA, sometimes denoted CoA-SH, to emphasize the role of the —SH group), nicotinamide adenine dinucleotide (NAD), and lipoate. Four different vitamins required in human nutrition are vital components of this system thiamine (in TPP), riboflavin (in FAD), niacin (in NAD), and pantothenate (in CoA). We have already described the roles of FAD and NAD as electron carriers (Chapter 13), and we have encountered TPP as the coenzyme of pyruvate decarboxylase (see Fig. 14-13). 

The conversion of pyruvate to ethanol occurs by the two reactions summarized in Figure 8.24. The decarboxylation of pyruvate by pyruvate decarboxylase occurs in yeast and certain microorganisms, but not in humans. The enzyme requires thiamine pyrophosphate as a coenzyme, and catalyzes a reaction similar to that described for pyruvate dehydrogenase (see p. 108). 

Coenzymes The pyruvate dehydrogenase complex contains five coenzymes that act as carriers or oxidants for the intermediates of the reactions shown in Figure 9.3. Ei requires thiamine pyrophosphate, Ep requires lipoic acid and coenzyme A, and E3 requires FAD and NAD+. [Note Deficiencies of thiamine or niacin can cause serious central nervous system problems. This is because brain cells are unable to produce sufficient ATP (via the TCA cycle) for proper function if pyruvate dehydrogenase is inactive.]... 

Pyruvate is decarboxylated to form a hydroxyethyl derivative bound to the reactive carbon of thiamine pyrophosphate, the coenzyme of pyruvate dehydrogenase. 

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