Glyceraldehyde 3-phosphate dehydrogenase of glycolysis and isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase of the tricarboxylic acid cycle utilize oxidized nicotinamide adenine dinucleotide (NAD+) as a source. Note that oxidized flavin adenine dinucleotide (FAD) and NAD+ are required by E3 of the pyruvate dehydrogenase complex. Certain tissues like the brain, red blood cells (RBC), kidney medulla, lens and cornea of the eye, testes, and exercising muscle have a continuous need for glucose as a metabolic fuel. The liver glycogen, which is crucial for glucose supply after a meal, can sustain these needs for less than 24 hours in the absence of carbohydrate intake. However, during prolonged fasting, the liver glycogen stores are depleted, and glucose is produced from noncarbohydrate precursors. This synthesis of glucose is not a simple reversal of glycolysis as the equilibrium of glycolysis strongly favors pyruvate formation. Instead, glucose is synthesized through gluconeogenesis, a specialized pathway that requires both mitochondrial and cytosolic enzymes. Hypoglycemia can occur due to deficiencies in gluconeogenic enzymes. During an overnight fast, approximately 90% of gluconeogenesis occurs in the liver, while the remaining 10% occurs in the kidneys. However, during prolonged fasting, the kidneys become significant glucose-producing organs, contributing around 40% of the total glucose production. The small intestine can also produce glucose. The relationship of gluconeogenesis to other essential pathways of energy metabolism is shown in Figure 10.1. Gluconeogenic precursors, such as glycerol, lactate, and α-keto acids derived from the metabolism of glucogenic amino acids, play a crucial role in glucose synthesis. Glycerol is released during the breakdown of triacylglycerols (TAG) in adipose tissue and transported to the liver through the bloodstream. In the liver, glycerol is phosphorylated to glycerol 3-phosphate by glycerol kinase. Lactate, produced by anaerobic glycolysis, is released into the blood by exercising skeletal muscle and cells lacking mitochondria, like RBC. The Cori cycle involves the uptake of lactate by the liver, its oxidation to pyruvate, and conversion to glucose, which is then released back into circulation (Fig. 10.2). Amino acids also serve as gluconeogenic precursors. All amino acids except leucine and lysine are glucogenic.
Oxidized nicotinamide adenine dinucleotide (NAD+) is used by glyceraldehyde 3-phosphate dehydrogenase of glycolysis and by isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, and malate dehydrogenase of the tricarboxylic acid cycle. [Note: E3 of the pyruvate dehydrogenase complex requires oxidized flavin adenine dinucleotide (FAD) and NAD+.]
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I. OVERVIEW
Some tissues, such as the brain, red blood cells (RBC), kidney medulla, lens and cornea of the eye, testes, and exercising muscle, require a continuous supply of glucose as a metabolic fuel. Liver glycogen, an essential postprandial source of glucose, can meet these needs for <24 hours in the absence of dietary intake of carbohydrate (see p. 125). During a prolonged fast, however, hepatic glycogen stores are depleted, and glucose is made from noncarbohydrate precursors. The formation of glucose does not occur by a simple reversal of glycolysis, because the overall equilibrium of glycolysis strongly favors pyruvate formation (that is, the change in standard free energy [∆G0] is negative). Instead, glucose is synthesized de novo by a special pathway, gluconeogenesis, which requires both mitochondrial and cytosolic enzymes. [Note: Deficiencies of gluconeogenic enzymes cause hypoglycemia.] During an overnight fast, ~90% of gluconeogenesis occurs in the liver, with the remaining ~10% occurring in the kidneys. However, during prolonged fasting, the kidneys become major glucose-producing organs, contributing ~40% of the total glucose production. [Note: The small intestine can also make glucose.] Figure 10.1 shows the relationship of gluconeogenesis to other essential pathways of energy metabolism.
carbon dioxide.
II. SUBSTRATES
Gluconeogenic precursors are molecules that can be used to produce a net synthesis of glucose. The most important gluconeogenic precursors are glycerol, lactate, and α-keto acids obtained from the metabolism of glucogenic amino acids. [Note: All but two amino acids (leucine and lysine) are glucogenic (see p. 262).]
A. Glycerol
Glycerol is released during the hydrolysis of triacylglycerols (TAG) in adipose tissue (see p. 190) and is delivered by the blood to the liver. Glycerol is phosphorylated by glycerol kinase to glycerol 3-phosphate,
B. Lactate
Lactate from anaerobic glycolysis is released into the blood by exercising skeletal muscle and by cells that lack mitochondria such as RBC. In the Cori cycle, this lactate is taken up by the liver and oxidized to pyruvate that is converted to glucose, which is released back into the circulation (Fig. 10.2).
C. Amino acids