Conversion of Pyruvate to Acetyl CoA

Is it the pro-R or pro-S hydrogen that is removed in step 5 of glycolysis, the isomerization of dihydroxyacetone phosphate to glyceraldehyde 3-phosphate You might want to review Section 5.11 on prochirality. 

STEP I OF FIGURE 22.7 ADDITION OF THIAMIN DIPHOSPHATE The conversion of pyruvate to acetyl CoA begins by reaction of pyruvate with thiamin diphosphate, a derivative of vitamin B. Because it was originally called thiamin pyrophosphate, thiamin diphosphate is usually abbreviated as TPP. The spelling thiamine is also correct and frequently used. 

O Nucleophilic addition of thiamin diphosphate (TPP) ylide to pyruvate gives an alcohol addition product. 

O Elimination of thiamin diphosphate ylide from the hemithioacetal intermediate yields acetyl dihydrolipoamide. .. 

FIGURE 22.7 MECHANISM Mechanism of the conversion of pyruvate to acetyl CoA through a multistep sequence of reactions that requires three different enzymes and five different coenzymes. The individual steps are explained in the text. 

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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. 

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 PDHC catalyzes the irreversible conversion of pyruvate to acetyl-CoA (Fig. 42-3) and is dependent on thiamine and lipoic acid as cofactors (see Ch. 35). The complex has five enzymes three subserving a catalytic function and two subserving a regulatory role. The catalytic components include PDH, El dihydrolipoyl trans-acetylase, E2 and dihydrolipoyl dehydrogenase, E3. The two regulatory enzymes include PDH-specific kinase and phospho-PDH-specific phosphatase. The multienzyme complex contains nine protein subunits, including... 

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.

The overall rate of the citric acid cycle is controlled by the rate of conversion of pyruvate to acetyl-CoA and by the flux through citrate synthase, isocitrate dehydrogenase, and a-lcetoglutarate dehydrogenase. These fluxes are largely determined by the concentrations of substrates and products the end products ATP and NADH are inhibitory, and the substrates NAD+ and ADP are stimulatory. 

Regulation of the Pyruvate Dehydrogenase Complex In animal tissues, the rate of conversion of pyruvate to acetyl-CoA is regulated by the ratio of active, phosphory-lated to inactive, unphosphorylated PDH complex. Determine what happens to the rate of this reaction when a preparation of rabbit muscle mitochondria containing the PDH complex is treated with (a) pyruvate dehydrogenase kinase, ATP, and NADH (b) pyruvate dehydrogenase phosphatase and Ca2+ (c) malonate. 

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. 

Oxidative decarboxylations of a-keto acids are mediated by either enzymes having more than one cofactor or complex multienzyme systems utilizing a number of cofactors. For example, pyruvate oxidase uses TPP and FAD as coenzymes, the function of the latter being to oxidize the intermediate (41). Conversion of pyruvate to acetyl-CoA requires a multienzyme complex with the involvement of no less than five coenzymes, TPP, CoA, dihydrolipoate, FAD and NAD+ (74ACR40). 

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 role of thirimin diphosphate in pyruvate dehydrogenase means that, in deficiency, there is imprdred conversion of pyruvate to acetyl CoA, and hence impaired entry of pyruvate into the citric acid cycle. Especially in subjects on a relatively high carbohydrate diet, this results in increased plasma concentrations of lactate and pyruvate, which may lead to life -threatening lactic acidosis. 

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,...

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