The biochemistry of the pyruvate dehydrogenase complex*

Abstract

In the Westernized world the daily dietary caloric requirements are roughly provided as follows: 40% from carbohydrates, 40% from fats, and 20% from proteins. In some populations in developing countries the daily caloric contribution from carbohydrate is even higher due to its readily available sources and relatively low cost. Glucose, the principal product of carbohydrate digestion, passes through a series of enzymatic steps first in the non-oxidative glycolytic pathway (from glucose to pyruvate) followed by efficient oxidative metabolism via the tricarboxylic acid cycle (from acetyl-CoA to CO 2 and H 2 O) to harness a portion of its potential energy as ATP. Interestingly, these two major pathways are directly linked by the pyruvate dehydrogenase complex (PDC) 1 localized in the mitochondrial matrix (Fig. 1). In the fed state acetyl-CoA generated from pyruvate (derived mostly from glucose and some dietary amino acids) is also utilized for the biosynthesis of lipids such as long chain fatty acids and cholesterol by lipogenic tissues (such as liver and adipose tissues and under special conditions in mammary glands during lactation and in the brain during the prenatal and early postnatal development). Additionally, amino acids from excess dietary protein are metabolized by several specialized reactions or pathways generating intermediates that have to be ultimately converted to pyruvate first and then to acetylCoA via PDC either for complete oxidation to CO 2 and H 2 O or for lipogenesis. PDC is the only known reaction in most eukaryotes to generate acetyl-CoA (two-carbon compound) from pyruvate (three-carbon compound). Since this is a physiologically irreversible reaction and since there is no other known reaction or pathway to convert the two-carbon compound to pyruvate (or its equivalent) for the synthesis of glucose in animals, the flux through PDC is tightly regulated to meet the specific metabolic and energetic needs of different tissues during the fed and fasting (starvation) states. This is accomplished by covalent modification of the ratelimiting component of the complex involving sophisticated interplay among the components of the complex and allosteric modulations by acetyl-CoA and NADH, the products of the reaction (and also of fatty acid oxidation). It is evident from these simple considerations that PDC plays a key role as a gatekeeper of both caloric and glucose homeostasis in mammals. In this review, we will discuss recent developments concerning the structure-function relationship of this multienzyme complex from various organisms with emphasis on regulatory aspects of the mammalian complex. Detailed accounts of various aspects of this complex can be found in several excellent reviews [1][2][3][4][5][6][7][8][9][10][11]. STRUCTURE AND ORGANIZATION OF PDCPDC is present in most prokaryotic and eukaryotic organisms. It catalyzes several sequential reactions of oxidative decarboxylation of pyruvic acid by the action of its three catalytic components: (i) pyruvate dehydrogenase (E1) catalyzing the de...

Diabetes-altered gene expression in rat skeletal muscle corrected by oral administration of vanadyl sulfate

“…In contrast, four probe sets representing the gene for dihydrolipoamide acetyltransferase, a component of the pyruvate dehydrogenase complex, were downregulated by diabetes. This change would lower the availability of acetyl-CoA for the tricarboxylic acid cycle (37). Thus the opposing regulation of pyruvate dehydrogenase complex activity in the D:N and D/VS:D comparisons seen in our experiments is caused by expression changes for different genes.…”

The Pyruvate Dehydrogenase Complexes: Structure-based Function and Regulation

“…The E1 is a thiamin diphosphate (ThDP)-dependent enzyme and catalyzes two consecutive steps (refer to Fig. 1, bottom): (i) the decarboxylation of pyruvate to CO 2 with the formation of C2␣-hydroxyethylideneThDP (enamine) intermediate (k 2 , k 3 ) and (ii) the reductive acetylation of the lipoyl groups covalently attached to the E2 (k 4 , k 5 ). The E2 catalyzes the transfer of an acetyl moiety to CoA to form acetyl-CoA (k Ϫ7 /k 7 ).…”

“…), and GM061791 (to W. one lipoyl domain, the E3-binding domain, and a catalytically incompetent C-terminal domain (Fig. 1, top right) (4,(21)(22)(23).…”

Tissue-specific pyruvate dehydrogenase complex deficiency causes cardiac hypertrophy and sudden death of weaned male mice

“…PDC is a highly organized multienzyme complex composed of three catalytic components (PDH, dihydrolipoamide acetyltransferase, and dihydrolipoamide dehydrogenase), one binding protein (dihydrolipoamide dehydrogenase-binding protein), and two regulatory enzymes (a family of PDH kinases and a family of PDH phosphatases) (18). Activity of PDC is regulated through phosphorylation/ dephosphorylation of the ␣-subunit of the PDH component of the complex catalyzed by PDH kinases and PDH phosphatases (10,23).…”