Pyruvate dehydrogenase gluconeogenesis

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

ATP-proton motive force interconversion Electron transport Entner-Doudoroff Fermentation Glycolysis/gluconeogenesis Pentose phosphate pathway Pyruvate dehydrogenase Sugars TCA cycle Methanogenesis Polysaccharides Other... 

Pyruvate dehydrogenase is inhibited by its product acetyl CoA. This control is important in several contexts and shoidd be considered along with pyruvate carboxylase, the other mitochondrial enzyme that uses pyruvate (introduced in gluconeogenesis, Chapter 14, Figure 1-14-5). 

In the brain, when ketones are metabolized to acetyl CoA, pyruvate dehydrogenase is inhibited. Glycolysis and subsequently glucose uptake in brain decreases. This important switch spares body protein (which otherwise would be catabolized to form glucose by gluconeogenesis in the liver) by allowing the brain to indirectly metabolize fetty acids as ketone bodies. 

Allosteric activation of hepatic pyruvate carboxylase by acetyl CoA occurs during fasting. As a result of excessive lipolysis in adipose tis sue, the liver is flooded with fatty acids (see p. 328). The rate of for mation of acetyl CoA by p-oxidation of these fatty acids exceeds the capacity of the liver to oxidize it to C02 and H20. As a result, acetyl CoA accumulates and leads to activation of pyruvate carboxylase. [Note Acetyl CoA inhibits pyruvate dehydrogenase (see p. 108). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle.]... 

During a fast, the liver is flooded with fatty acids mobilized from adipose tissue. The resulting elevated hepatic acetyl CoA produced primarily by fatty acid degradation inhibits pyruvate dehydrogenase (see p. 108), and activates pyruvate carboxylase (see p. 117). The oxaloacetate thus produced is used by the liver for gluconeogenesis rather than for the TCA cycle. Therefore, acetyl Co A is channeled into ketone body synthesis. 

Figure 7-1. Pathways of fuel metabolism and oxidative phosphorylation. Pyruvate may be reduced to lactate in the cytoplasm or may be transported into the mitochondria for anabolic reactions, such as gluconeogenesis, or for oxidation to acetyl-CoA by the pyruvate dehydrogenase complex (PDC). Long-chain fatty acids are transported into mitochondria, where they undergo [ -oxidation to ketone bodies (liver) or to acetyl-CoA (liver and other tissues). Reducing equivalents (NADH, FADII2) are generated by reactions catalyzed by the PDC and the tricarboxylic acid (TCA) cycle and donate electrons (e ) that enter the respiratory chain at NADH ubiquinone oxidoreductase (Complex 0 or at succinate ubiquinone oxidoreductase (Complex ID- Cytochrome c oxidase (Complex IV) catalyzes the reduction of molecular oxygen to water, and ATP synthase (Complex V) generates ATP fromADP Reprinted with permission from Stacpoole et al. (1997).

The second section of the book is Fuel Metabolism and Energetics. Important pathways and enzymes involved in fuel utilization are discussed in the chapters Pyruvate Dehydrogenase Complex Deficiency Mitochondrial En-cephalomyopathy, and Systemic Carnitine Deficiency. The role of gluconeogenesis in glucose homeostasis is illustrated by a discussion in the chapter Neonatal Hypoglycemia. 

In the normal fed state, pyruvate is oxidized via the pyruvate dehydrogenase complex (PDH), but in starvation. PDH is inactivated thus, pyruvate is converted into alanine (Fig. 15-16) which enters the blood and is conveyed to the liver, where gluconeogenesis takes place. 

ATP plays a central role in cellular maintenance both as a chemical for biosynthesis of macromolecules and as the major soirrce of energy for all cellular metabolism. ATP is utilized in numerous biochemical reactions including the eitric acid cycle, fatty acid oxidation, gluconeogenesis, glycolysis, and pyruvate dehydrogenase. ATP also drives ion transporters sueh as Ca -ATPase in the endoplasmic reticulum and plasma membranes, H+-ATPase in the lysosomal membrane, and Na+/K+-ATPase in the plasma membrane. Chemieal energy (30.5 kJ/mol) is released by the hydrolysis of ATP to adenosine diphosphate (ADP). 

Gluconeogenesis occurs under conditions in which pyruvate dehydrogenase, pyruvate kinase, phosphofructokinase 1, glucokinase, and hexoki-nase are relatively inactive. The low activity of these enzymes prevents futile cycles from occurring and ensures that, overall, pyruvate is converted to glucose. 

In tissues other than the RBC, pyruvate has alternative metabolic fates that, depending on the tissue, include gluconeogenesis, conversion to acetyl-CoA by pyruvate dehydrogenase for further metabolism to CO in the tricarboxylic acid (TCA) cycle, transamination to alanine or carboxylation to oxaloacetate by pyruvate carboxylase (Table 23-1). In the RBC, however, the restricted enzymatic endowment precludes all but the conversion to lactate. The pyruvate and lactate produced are end products of RBC glycolysis that are transported out of the RBC to the liver where they can undergo the alternative metabolic conversions described above. 

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