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Introduction

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High-Yield Terms

  • PDH kinases: allosteric regulated family of kinases that modify the activity of the PDHc

  • Malate-aspartate shuttle: principal mechanism for the movement of reducing equivalents (in the form of NADH) from the cytoplasm to the mitochondria

  • Substrate-level phosphorylation: the succinyl-CoA synthetase–catalyzed reaction involves the use of the high-energy thioester of succinyl-CoA to drive synthesis of a high-energy nucleotide phosphate (GTP). This process is referred to as substrate-level phosphorylation

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The bulk of ATP used by many cells to maintain homeostasis is produced by the oxidation of pyruvate in the TCA cycle. During this oxidation process, NADH and FADH2 are generated. The NADH and FADH2 are principally used to drive mitochondrial oxidative phosphorylation, a process for converting the reducing potential of NADH and FADH2 into the synthesis of high-energy phosphate in ATP.

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Oxidative Decarboxylation of Pyruvate

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The fate of pyruvate depends on the cell energy charge. In liver, intestine, and kidney under conditions of high-energy charge, pyruvate is directed toward gluconeogenesis. However, when the energy charge is low, pyruvate is preferentially oxidized to CO2 and H2O in the TCA cycle. The oxidation of the carbon atoms of pyruvate results in the generation of 15 equivalents of ATP per pyruvate. The enzymatic activities of the TCA cycle (and of oxidative phosphorylation) are located in the mitochondrion. When transported into the mitochondrion, pyruvate encounters 2 principal metabolizing enzymes: pyruvate carboxylase (PC) and the pyruvate dehydrogenase complex (PDHc).

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With a high cell-energy charge, coenzyme A (CoA) is highly acylated, principally as acetyl-CoA, and able to allosterically activate PC, directing pyruvate toward gluconeogenesis (see Chapter 13). When the energy charge is low, CoA is not acylated and PC is inactive. Under these conditions, pyruvate is preferentially metabolized to CO2 and H2O via the PDHc and the enzymes of the TCA. Reduced NADH and FADH2 generated during the oxidative reactions can then be used to drive ATP synthesis via oxidative phosphorylation.

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The Pyruvate Dehydrogenase Complex

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The Pyruvate Dehydrogenase Complex (PDHc) is composed of multiple copies of 3 separate enzymes: pyruvate dehydrogenase (PDH, E1: 20-30 copies), dihydrolipoamide S-acetyltransferase (DLAT, E2: 60 copies), and dihydrolipoamide dehydrogenase (DLD, E3: 6 copies). The complex also requires 5 different coenzymes: CoA, NAD+, FAD+, lipoic acid, and thiamine pyrophosphate (TPP). The factors required for the function of the PDHc can be remembered by the mnemonic: Tender (thiamine) Loving (lipoate) Care (coenzyme A) For (flavin) Nancy (nicotinamide), TLCFN. Three of the coenzymes of the complex are tightly bound to enzymes of the complex (TPP, lipoic acid, and FAD+) and 2 are employed as carriers of the products of PDHc activity (CoA and NAD+) (Figure 16-1).

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FIGURE 16-1:

Oxidative decarboxylation of pyruvate by the pyruvate dehydrogenase complex. Lipoic acid is joined by an ...

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