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High-Yield Terms

  • Cori cycle: describes the interrelationship between lactate production during anaerobic glycolysis and the use of lactate carbons to produce glucose via hepatic gluconeogenesis

  • Endogenous glucose production: designated EGP, refers to the process of glucose production via gluconeogenesis

  • Glucose-alanine cycle: describes the interrelationship between pyruvate transamination and alanine during skeletal muscle glycolysis and delivery to the liver where the alanine is deaminated back to pyruvate, which is then diverted into hepatic gluconeogenesis

Critical Bypass Reactions of Gluconeogenesis

Gluconeogenesis is the biosynthesis of new glucose, (ie, not glucose from glycogen). The production of glucose from other carbon skeletons is necessary during periods of fasting and starvation. This is acutely true for the testes, erythrocytes, and kidney medullary cells since each is exclusively dependent upon glucose oxidation for ATP production. The brain, although not restricted solely to glucose, requires adequate rates of gluconeogenesis since it is the organ of highest daily glucose consumption. In addition to glucose, the brain can derive energy from ketone bodies (Chapter 25). The primary carbon skeletons used for gluconeogenesis are derived from pyruvate, lactate, glycerol, and the amino acids alanine and glutamine. The liver is the major site of gluconeogenesis; however, as discussed below, the kidney and the small intestine also have important roles to play in this pathway (Figure 13-1).

FIGURE 13-1:

Major pathways and regulation of gluconeogenesis and glycolysis in the liver. Entry points of glucogenic amino acids after transamination are indicated by arrows extended from circles. The key gluconeogenic enzymes are enclosed in double-bordered boxes. The ATP required for gluconeogenesis is supplied by the oxidation of fatty acids. Propionate is of quantitative importance only in ruminants. Arrows with wavy shafts signify allosteric effects; dash-shafted arrows, covalent modification by reversible phosphorylation. High concentrations of alanine act as a “gluconeogenic signal” by inhibiting glycolysis at the pyruvate kinase step. Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil PA. Harper's Illustrated Biochemistry, 29th ed. New York, NY: McGraw-Hill; 2012.

Pyruvate to Phosphoenolpyruvate, Bypass 1

Conversion of pyruvate to phosphoenolpyruvate (PEP) requires the action of 2 enzymes. The first is an ATP-requiring reaction catalyzed by pyruvate carboxylase (PC), which catalyzes the carboxylation of pyruvate to the TCA cycle intermediate, oxaloacetic acid (OAA). The second enzyme of bypass 1 is the GTP-dependent PEP carboxykinase (PEPCK), which converts OAA to PEP. Since PC incorporated CO2 into pyruvate and it is subsequently released in the PEPCK reaction, no net fixation of carbon occurs. Human cells contain almost equal amounts of mitochondrial and cytosolic PEPCK (designated PEPCK-m and PEPCK-c, respectively), so this second reaction can occur in either cellular compartment.

If OAA is converted to PEP by PEPCK-m, it is transported to the cytosol where it is a direct substrate for gluconeogenesis ...

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