Pyruvate dehydrogenase system

Recently, the fungitoxic action of copper(II) ions has also been explained in terms of the inhibition of specific processes. Thus, it is thought possible that copper has an inhibiting effect on the pyruvate dehydrogenase system (Kaars Sijpesteijn,... 

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. ... 

Nonenzyme-bound FAD is a stronger oxidizing agent than NAD. How, then, can NAD oxidize the reduced flavoenzyme in the pyruvate dehydrogenase system ... 

The matrix compartment contains most of the citric acid cycle enzymes, the pyruvate dehydrogenase-system, the fatty acid oxidation system, and many other enzymes. It also contains ATP, ADP, AMP, phosphate,... 

Pyruvate dehydrogenase of propionibacteria differs from that of aerobic bacteria in that it does not depend on lipoate and has a similarity with pyruvate cytochrome b oxidoreductase. Castberg and Morris (1978) reported the isolation from cells of P. shermanii of pyruvate oxidase (reducing 2,6-dichlorophenolindophenol (DCIP)) and pyruvate dehydrogenase system (reduces NAD). The pyruvate oxidase could not use NAD as an electron acceptor, and the NAD-dependent enzyme did not transport electrons to DCIP. Unlike the pyruvate oxidase of E. coli, the enzyme from P, shermanii was not activated by phosphatydylcholine in the presence of SDS, and the presence of thiamine diphosphate and Mg " was not required for the activity of purified preparations. 

Notice the similar function of TPP in all TPP-requiring enzymes. In each reaction, the TPP ylide adds to a carbonyl carbon of the substrate and allows a bond to that carbon to be broken because the electrons left behind can be delocalized into the thiazoUum ring. The acyl group is then transferred—to a proton in the case of pyruvate decarboxylase, to coenzyme A (via lipoate) in the pyruvate dehydrogenase system, and to a carbonyl group in Problems 9,10, and 11. 

Upon entry into the mitochondrial matrix, pyruvate may be converted into acetyl-CoA by the action of a multienzyme complex called the pyruvate dehydrogenase system. The overall non-equilibrium reaction (Figure 12.2a) is exergonic to an... 

FIGURE 12.2 Oxidative decarboxylation of pyruvate, (a) Overall reaction, (b) Mechanism of action of the pyruvate dehydrogenase system... 

FIGURE 12.3 Structure of two coenzymes involved in the pyruvate dehydrogenase system, (a) Thiamin diphosphate (TDP). (b) Lipoate... 

Covalent interconversion of enzymes is well established as a fundamental theme in metabolic regulation. The prototypic reversible interconverting systems include the sequence of phosphorylation/dephosphorylation steps in the activation of mammalian glycogen phosphorylase and pyruvate dehydrogenase as well as the nucleotidyla-tion/denucleotidylation using UTP and ATP in the bacterial glutamine synthetase cascade (see Fig. 1.). 

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.]... 

Several derivatives of Eosin have been prepared and employed to study biological systems. Their main applications are as singlet energy acceptors and as triplet probes [93-97] to measure the rotational mobility of virus particles [98] and proteins in membranes and in solution. Examples of proteins studied using Eosin derivatives include myosin [99,100], band 3 protein [101,102], pyruvate dehydrogenase [103,104], and Sarcoplasmic... 

Elaborate cascades initiate the clotting of blood (Chapter 12) and the action of the protective complement system (Chapter 31). Cascades considered later in the book are involved in controlling transcription (Fig. 11-13) and in the regulation of mammalian pyruvate dehydrogenase (Eq. 17-9), 3-hydroxy-3-methyl-glutaryl-CoA reductase and eicosanoids (Chapter 21), and glutamine synthetase (Chapter 24). 

NAD+ serves as the oxidant. The reaction is catalyzed by a complex of enzymes whose molecular mass varies from 4 to 10 x 106, depending on the species and exact substrate.297 Separate oxoacid dehydrogenase systems are known for pyruvate,298-300 2-oxoglut-arate,301 and the 2-oxoacids with branched side chains derived metabolically from leucine, isoleucine, and... 

Fatty acids are generated cytoplasmically while acetyl-CoA is made in the mitochondrion by pyruvate dehydrogenase.This implies that a shuttle system must exist to get the acetyl-CoA or its equivalent out of the mitochondrion. The shuttle system operates in the following way Acetyl-CoA is first converted to citrate by citrate synthase in the TCA-cycle reaction. Then citrate is transferred out of the mitochondrion by either of two carriers, driven by the electroos-motic gradient either a citrate/phosphate antiport or a citrate/malate antiport as shown in Figure 2-2. 

Lewisite is the most important of the organo-arseni-cal CW agents. Exposure to lewisite is quite painful, and onset of symptoms occurs rapidly (seconds to minutes) (31) in contrast to sulfur mustard for which a latency period occurs of several hours between exposure and symptoms (32). Although it is not known to have been used as a CW agent, lewisite is still considered a potential threat due to the relative ease of production and its rapid onset of action. Moreover, substantial stockpiles of lewisite are present in the United States, Russia, and in China abandoned by the Japanese Imperial Army. This may constitute a potential hazard for public health (33). The toxicity of lewisite is inter alia caused by the high affinity for the vicinal di-thiol system present in dihydrolipoic acid, a component of the pyruvate dehydrogenase complex, as is the case for other arsenicals (34). This prevents the formation of acetyl coenzyme A from pyruvate. 

Pyruvate produced by the glycolytic pathway may be transported into the mitochondria (via an antiport with OH"), where it is converted to acetyl-CoA by the action of the enzyme complex pyruvate dehydrogenase. The pertinent enzyme activities are pyruvate dehydrogenase (PD), lipoic acid acetyltransferase, and dihydrolipoic acid dehydrogenase. In addition, several cofactors are utilized thiamine pyrophosphate (TPP), lipoic acid, NAD+, Co A, and FAD. Only Co A and NAD+ are used in stoichiometric amounts, whereas the others are required in catalytic amounts. Arsenite and Hg2+ are inhibitors of this system. The overall reaction sequence may be represented by Figure 18.5. The NADH generated may enter the oxidative phosphorylation pathway to generate three ATP molecules per NADH molecule reduced. The reaction is practically irreversible its AGq = -9.4 kcal/mol. 

The regulatory role of calcium ions in intermediary metabolism is well documented. Calcium has been shown to be involved in activation or inhibition of specific enzyme systems [105], For example, it activates cyclic nucleotide phosphodiesterase, phosphofructokinase, fructose 1 6 biphosphatase, glycerol phosphate dehydrogenase, pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase. Calcium ions inhibit pyruvate kinase, pyruvate carboxylase, Na+/K+-AT-Pase and adenylate cyclase. 

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