Pyruvate dehydrogenase complex structure

Wieland OH (1983). The mammalian pyruvate dehydrogenase complex structure and regulation. Rev... 

Zhou ZH, McCarthy DB, O Connor CM, et al. The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes.Proc Natl Acad Sci USA 98 14802-14807, 2001. 

Although the structure of an intact member of the pyruvate dehydrogenase complex family has not yet been determined in atomic detail, the structures of all of the component enzymes are now known, albeit from different complexes and species. Thus, it is now possible to construct an atomic model of the complex to understand its activity (Figure 17.7). 

Despite the apparent simplicity of this highly exergonic reaction (AG° = -33.5 kJ/mol), its mechanism is one of the most complex known. The pyruvate dehydrogenase complex is a large multienzyme structure that contains three enzyme activities pyruvate dehydrogenase (Ej), also known as pyruvate decarboxylase, dihydrolipoyl transacetylase (E2), and dihydrolipoyl dehydrogenase (E3). Each enzyme activity is present in multiple copies. Table 9.3 summarizes the number... 

Figure 4 Structure of the lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex of Bacillus stearothermophilus solved by NMR (PDB 1 LAB). The lysyl residue that bears the lipoyl group (Lys42), found at the tip of a /3-hairpin, is shown as sticks, and individual atoms are color-coded (gray, carbon blue, nitrogen red, oxygen). The structure was prepared using the PyMOL Molecular Graphics (http //www.pymol.org).

Komuniecki, R., Rhee, R., Bhat, D., Duran, E., Sidawy. E. and Song, H. (1992) The pyruvate dehydrogenase complex from the parasitic nematode, Ascaris suum novel subunit composition and domain structure of the dihydrolipoyl transacetylase component. Arch. Biochem. Biophys. 296 115 121. 

The a-ketoglutarate dehydrogenase complex is one of a three-member family of similar a-keto acid dehydrogenase complexes. The other members of this family are the pyruvate dehydrogenase complex, and the branched chain amino acid a-keto acid dehydrogenase complex. Each of these complexes is specific for a different a-keto acid structure. In the seqnence of reactions catalyzed by the complexes, the a-ketoacid is decarboxylated (i.e., releases the carboxyl gronp as CO2) (Fig.20.8). The keto gronp is oxidized to the level of a carboxylic acid, and then combined with CoASH to form an acyl CoA thioester (e.g., succinyl CoA). 

FIGURE 19.5 The structure of the pyruvate dehydrogenase complex, (a) 24 dihydrolipoyl transacetylase (TA) subunits, (b) 24 afi dimers of pyruvate dehydrogenase are added to the cube (two per edge), (c) Addition of 12 dihydrolipoyl dehydrogenase subunits (two per face) completes the complex. 

Transformation of pyruvate to acetyl-CoA is linked to glycolysis and to the Krebs cycle and oxidative phosphorylation. The pyruvate dehydrogenase complex (PDHc) catalyzes the oxidative decarboxylation of pyruvate and acetylation of coenzyme A (CoA) to acetyl-CoA. This enzyme has been viewed as a potential herbicide target [238], In the perspective of structural optimization of a potent new herbicide, He et al. synthesized a series of structures 307 [239-241], which were a priori designed to inhibit the PDHc. 

Pyruvate dehydrogenase complex is a multienzyme complex which converts pyruvate to acetyl CoA. It consists of three enzymes pyruvate dehydrogenase, dihydrolipoyl transacetylase. And dihydrolipoyl dehydrogenase. It has five coenzymes NAD, CoA, lipolc acid, thiamine P3Tophosphate. and FAD. The enzyme dihydrolipoyl dehydrogenase is centrally placed m the crystal. It possesses a lipoic acid moiety attached to a lysine and it is hypothesized that u is this structure that moves around the crystal of tae enzyme as a swinging arm bringing successive intermediates to the other enzymes in order that the reaction proceeds Do we have any experimental support for this hypothesis ... 

In the structure of pyruvate dehydrogenase complex, the E2 component forms the central core of the complex. PDHc from Gram-negative bacteria possesses an octahedral E2 core while the Gram-positive and eukaryotic PDHc are based on an icosahedral core [22]. The El and E3 components are attached noncovalently to the E2 core. The El component occurs in two forms depending on the symmetry of the complex. In octahedral complexes, El component is an (a,) homodimer with a subunit mass of approximately 100 kDa, while in icosahedral complexes, it exists as an (a2P2) heterotetramer with subunits of approximately 41 kDa and 36 kDa [23,24]. 

Packman, L.C., and Perham, R.N. (1982) Quaternary structure of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus studied by a new reversible cross-linking procedure with bis(imidoesters). Biochemistry 21, 5171-5175. 

There are some very interesting questions of stereospecificity posed by the structure and mode of operation of multienzyme complexes. Reed and Cox 35> have summarized available information on the pyruvate and a-ketoglutarate dehydrogenase complexes, and the fatty add synthetase. The mechanism of synthesis of the peptide antibiotics likewise presents interesting stereochemical problems 36>. 

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