Pyruvate dehydrogenase complexes

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 conversion occurs through a multistep sequence of reactions catalyzed by a complex of enzymes and cofactors called the pyruvate dehydrogenase complex. The process occurs in three stages, each catalyzed by one of the enzymes in the complex, as outlined in Figure 29.11 on page 1152. Acetyl CoA, the ultimate product, then acts as fuel for the final stage of catabolism, the citric acid cycle. All the steps have laboratory analogies. 

Several enzymes of the intermediary metabolism require thiaminpyrophosphate (TPP, Fig. 1) as coenzyme, e.g., enzymes of the pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase complex, or pentose phosphate pathway. 

Many metabolic fuels are oxidized in the mitochondrial matrix. Pyruvate is oxidatively decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex (PDH)... 

The pyruvate dehydrogenase complex consists of a number of polypeptide chains of each of the three component enzymes, all organized in a regular spatial configuration. Movement of the individual enzymes appears to be restricted, and the metabofic intermediates do not dissociate freely but remain bound to the enzymes. Such a complex of enzymes, in which the sub-... 

Figure 17-5. Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an amide link to a lysine residue of the transacetylase component of the enzyme complex. It forms a long flexible arm, allowing the lipoic acid prosthetic group to rotate sequentially between the active sites of each of the enzymes of the complex. (NAD nicotinamide adenine dinucleotide FAD, flavin adenine dinucleotide TDP, thiamin diphosphate.)...

Metabolic Transitions and the Role of the Pyruvate Dehydrogenase Complex During Development of Ascaris suum... 

Mitochondria from body wall muscle and probably the pharynx lack a functional TCA cycle and their novel anaerobic pathways rely on reduced organic acids as terminal electron acceptors, instead of oxygen (Saz, 1971 Ma et al, 1993 Duran et al, 1998). Malate and pyruvate are oxidized intramitochondrially by malic enzyme and the pyruvate dehydrogenase complex, respectively, and excess reducing power in the form of NADH drives Complex II and [3-oxidation in the direction opposite to that observed in aerobic organelles (Kita, 1992 Duran et al, 1993 Ma et al,... 

Fig. 14.1. Role ofthe pyruvate dehydrogenase complex (PDC) during aerobic/ anaerobic transitions in the development of Ascaris suum. PDC, pyruvate dehydrogenase complex AD, acyl CoA dehydrogenase ER, enoyl CoA reductase FR, fumarate reductase SDH, succinate dehydrogenase.

This chapter focuses on the developmental regulation of the pyruvate dehydrogenase complex (PDC). The PDC plays diverse and pivotal roles in the entry of glycolytically generated carbon into the TCA cycle in aerobic stages and the metabolism of mitochondrially generated pyruvate in anaerobic stages (Fig. 14.1). 

Fig. 14.2. Regulation of the pyruvate dehydrogenase complex (PDC) from adult A suum muscle. PDC, pyruvate dehydrogenase complex E1, pyruvate dehydrogenase subunit of the PDC PDK, pyruvate dehydrogenase kinase PDP, pyruvate dehydrogenase phosphatase.

Fig. 14.4. Expression of subunits of the pyruvate dehydrogenase complex during the development of A suum. Homogenates of different A suum larval stages and adult tissues were immunoblotted with polyclonal antisera prepared against individual subunits of the A suum PDC isolated from adult muscle, as described in detail in Klingbeil etal. (1996). UE, unembryonated egg M, adult body wall muscle p45, E3-binding protein (E3BP).

In summary, it is clear that A. suum undergoes a number of metabolic transitions during development and, in the case of the pyruvate dehydrogenase complex at least, is constantly fine-tuning the subunit-specific expression and function of the PDC during the course of development. 

Bowker-Kinley, M.M., Davis, W.I., Wu, P., Harris, R.A. and Popov, KM. (1998) Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Bio chemicalfournal 329, 191-196. 

Klingbeil, M.M., Walker, D.J., Arnette, R., Sidawy, E., Hayton, K, Komuniecki, P.R. and Komuniecki, R. (1996) Identification of a novel dihydrolipoyl dehydrogenase-binding protein in the pyruvate dehydrogenase complex of the anaerobic parasitic nematode, Ascaris suum. Journal of Biological Chemistry 271, 5451-5457. 

Patel, M.S. and Roche, T.E. (1990) Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEBJournal4, 3224—3233. 

Ravindran, S., Radke, G.A., Guest, J.R. and Roche, T.E. (1996) Lipoyl domain-based mechanism for the integrated feedback control of the pyruvate dehydrogenase complex by enhancement of pyruvate dehydrogenase kinase activity. Journal of Biological Chemistry 271,653-562. 

Roche, T.E. and Cate, R.L. (1977) Purification of porcine liver pyruvate dehydrogenase complex and characterization of its catalytic and regulatory properties. Archives of Biochemistry and Biophysics 183, 664-677. 

Snoep, J.L., de Graef, M.R., Westphal, A.H., de Kok, A., Teixeira, de Mattos, M.J. and Neijssel, O.M. (1993) Differences in sensitivity to NADH of purified pyruvate dehydrogenase complexes of Enterococcus faecalis, Lactococcus lactis, Azotobacter vinelandii and Escherichia colt, implications for their activity in vivo. FEMS Microbiology Letters 114, 279-283. 

Thissen, J., Desai, S., McCartney, P. and Komuniecki, R. (1986) Improved purification of the pyruvate dehydrogenase complex from Ascaris suum body wall muscle and characterization of PDHa kinase activity. Molecular and Biochemical Parasitology 21, 129-138. 

Fig. 1. Modification of plant metabolic pathways for the synthesis of poly(3HB) and poly(3HB-co-3HV). The pathways created or enhanced by the expression of transgenes are highlighted in bold, while endogenous plant pathways are in plain letters. The various transgenes expressed in plants are indicated in italics. The ilvA gene encodes a threonine deaminase from E. coli. The phaARe, phaBRe, and phaCRe genes encode a 3-ketothiolase, an aceto-acetyl-CoA reductase, and a PHA synthase from R. eutropha, respectively. The btkBRe gene encodes a second 3-ketothiolase isolated from R. eutropha which shows high affinity for both propionyl-CoA and acetyl-CoA [40]. PDC refers to the endogenous plant pyruvate dehydrogenase complex...

Fig. 3. Generation of propionyl-CoA from the isoleucine biosynthetic pathway. The intermediate 2-ketobutyrate can be decarboxylated by either the 2-oxoacid dehydrogenase complex or at low efficiency by the pyruvate dehydrogenase complex. Inhibition of the threonine deaminase by isoleucine and of the acetolactate synthase by herbicides are indicated with dashed arrows...

Lipoic acid (the other names are a-lipoic acid or thioctic acid) (Figure 29.9) is a natural compound, which presents in most kinds of cells. Lipoic acid (LA) is contained in many food products, in particular in meat, but it is also synthesized in human organism from fatty acids. Earlier, it has been shown that in humans lipoic acid functions as a component of the pyruvate dehydrogenase complex. However, later on, attention has been drawn to the possible antioxidant activity of the reduced form of lipoic acid, dihydrolipoic acid (DHLA) (Figure 29.9). 

The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose 543... 

Lissens, W., De Meirleir, L., Seneca, S. et al. Mutations in the X-linked pyruvate dehydrogenase (El) alpha subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency. Hum. Mut. 15 209-219, 2000. 

PDHC pyruvate dehydrogenase complex RCDP rhizomelic chondrodysplasia punctata... 

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