The Conversion of Pyruvate to Acetyl CoA

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. 

Stepl of Figure 29.11 Addition of Thiamin Diphosphate The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamin diphosphate, a derivative of vitamin B(. Formerly called thiamin pyrophosphate, thiamin diphosphate is usually abbreviated as TPP. The spelling thiamine is also correct and frequently used. 

Figure 29.11 MECHANISM Mechanism of the conversion of pyruvate to acetyl CoA through a multistep sequence of reactions that requires three different enzymes and four different coenzymes. The individual steps are explained in the text.

Step 4 of Figure 29.12 Oxidative Decarboxylation The transformation of cr-ketoglutarate to succinyl CoA in step 4 is a multistep process just like the transformation of pyruvate to acetyl CoA that we saw in Figure 29.11. In both cases, an -keto acid loses C02 and is oxidized to a thioester in a series of steps catalyzed by a multienzynie dehydrogenase complex. As in the conversion of pyruvate to acetyl CoA, the reaction involves an initial nucleophilic addition reaction to a-ketoglutarate by thiamin diphosphate vlide, followed by decarboxylation, reaction with lipoamide, elimination of TPP vlide, and finally a transesterification of the dihydrolipoamide thioester with coenzyme A. 

The conversion of pyruvate to acetyl CoA and C02 A. is reversible. B. involves the participation of lipoic acid. C. is activated when pyruvate dehydrogenase complex is phosphorylated by a protein kinase in the pres ence of ATP. D. occurs in the cytosol. E. depends on the coenzyme biotin. Correct answer = B. Lipoic acid is an intermedi ate acceptor of the acetyl group formed in the reaction. Pyruvate dehydrogenase complex cat alyzes an irreversible reaction that is inhibited when the enzyme is phosphorylated. The enzyme is located in the mitochondrial matrix. 

Vitamin B1 (thiamine) has the active form, thiamine pyrophosphate. It is a cofactor of enzymes catalyzing the conversion of pyruvate to acetyl CoA, a-ketoglutarate to succinyl CoA, and the transketolase reactions in the pentose phosphate pathway. A deficiency of thiamine causes beriberi, with symptoms of tachycardia, vomiting, and convulsions. In Wernicke-Korsakoff syndrome (most common in alcoholics), individuals suffer from apa thy, loss of memory, and eye movements. There is no known toxicity for this vitamin. 

The conversion of pyruvate to acetyl-CoA. The reactions are catalyzed by the enzymes of the pyruvate dehydrogenase complex. This complex has three enzymes pyruvate decarboxylase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. In addition, five coenzymes are required thiamine pyrophosphate, lipoic acid, CoASH, FAD, and NAD+. Lipoic acid is covalently attached to... 

At this point in the oxidation of glucose, four electrons per glucose molecule have been lost in the oxidation of glyceraldehyde-3-phosphate and four more in the conversion of pyruvate to acetyl-CoA. Thus, of the total of 24 electrons lost in the oxidation of glucose to C02, 16 remain to be transferred to oxidizing agents in the course of the oxidation of two molecules of acetyl-CoA. A major func-... 

The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA. This conversion links the breakdown of carbohydrates to the processes of respiration and oxidative phosphorylation (Chap. 12). The overall reaction is ... 

The conversion of pyruvate to acetyl-CoA is catalysed by pyruvate oxidoreductase in the archaebacteria. The enzyme has been detected and characterised in Halobacterium halobium[i, 2i2 Tp. acidophilum, S. acidocaldarius and Desulfurococcus mobilis[i i], Pyrococcus furiosus [34] and in Methanobacterium thermoautotrophicum [35]. In the halophiles and thermophiles, ferredoxin serves as electron acceptor, whereas the methanogens use the deazaflavin derivative F420. 

Fig. 4. The enzymic reaction mechanisms for the conversion of pyruvate to acetyl-CoA,...

Sodium dichloroacetate (DCA) is a small molecule that has multiple effects on intermediary metabolism. Of primary interest in the current example is the ability of DCA to activate pyruvate dehydrogenase, the rate-limiting enzyme for the conversion of pyruvate to acetyl CoA. The pyruvate concentration is, in turn, replenished by oxidation of lactate, thereby replenishing concentrations of the latter. Such a reduction may decrease the morbidity in head trauma, where local (CSF) elevated lactate is thought to be neurotoxic. 

This highly exergonic reaction (AG° = -33.5 kJ/mol), an oxidative decarboxylation, is analogous to the conversion of pyruvate to acetyl-CoA catalyzed by pyruvate dehydrogenase. In both reactions, energy-rich thioester molecules are products, that is, acetyl-CoA and succinyl-CoA. Other similarities between the two multienzyme complexes are that the same cofactors (TPP, CoASH, lipoic... 

Location. Plant fatty acid synthesis appears to be limited to chloroplasts. A chloroplast isozyme of pyruvate dehyrogenase catalyzes the conversion of pyruvate to acetyl-CoA. Pyruvate is also derived from glycerate-3-phosphate, an intermediate in the Calvin cycle, a biosynthetic pathway in which plants incorporate COz into sugar molecules. (The Calvin cycle is discussed in Chapter 13.)... 

Under aerobic conditions pyruvate is converted to acetyl CoA. The coenzymes NAD+, FAD, thiamine pyrophosphate, and coenzyme A are required by the pyruvate dehydrogenase complex for the conversion of pyruvate to acetyl CoA. These coenzymes are synthesized from the vitamins niacin, riboflavin, thiamine, and pantothenic acid, respectively. If the vitamins are not available, the coenzymes will not be available and pyruvate cannot be converted to acetyl CoA. Because the complete oxidation of the acetyl group of acetyl CoA produces the vast majority of the ATP for the body, ATP production would be severely inhibited by a deficiency of any of these vitamins. 

In animals TPP-dependent decarboxylation reactions are essential to the production of energy needed for cell metahohsm. In these reactions a-ketoacids are converted to acyl CoA molecules and carbon dioxide. The reactions (e.g., the conversion of pyruvate to acetyl CoA) are an important part of the breakdown of carbohydrates, and of the conversion of several classes of molecules (carbohydrates, fats, and proteins) to energy, carbon dioxide, and water in the citric acid cycle. In other organisms, in addition to its participation in the above reactions, TPP is a required coenzyme in alcohol fermentation, in the carbon fixation reactions of photosynthesis, and in the hiosynthesis of the amino acids leucine and valine. 

Reduced ferredoxin reacts with proteins that participate in the dissimilatory reduction of sulfate to sulfide oxidized ferredoxin reacts with pyruvate dehydrogenase that catalyzes the conversion of pyruvate to acetyl CoA (phosphoroclastic reaction). In sulfate reduction, molecular hydrogen is the electron source, and in the phosphoroclastic reaction, protons are the terminal electron acceptor and hydrogenase mediates electron transfer between cytochrome c3 and protons or molecular hydrogen. 

The pyruvate dehydrogenase system is a group of three enzymes responsible for the conversion of pyruvate to acetyl-CoA. The pyruvate dehydrogenase system requires TPP and four other coenzymes lipoate, coenzyme A, FAD, and NAD. ... 

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