3. Induction of enzyme synthesis: Glucagon increases transcription of the gene for PEPCK via the transcription factor cAMP response element– binding (CREB) protein, thereby increasing the availability of this enzyme as levels of its substrate rise during fasting. [Note: Cortisol (a glucocorticoid) also increases expression of the gene, whereas insulin decreases expression.]
B. Substrate availability
The availability of gluconeogenic precursors, particularly glucogenic amino acids, significantly influences the rate of glucose synthesis. Decreased insulin levels favor mobilization of amino acids from muscle protein to provide the carbon skeletons for gluconeogenesis. The ATP and NADH coenzymes required for gluconeogenesis are primarily provided by FA oxidation.
C. Allosteric activation by acetyl CoA
Allosteric activation of hepatic PC by acetyl CoA occurs during fasting. As a result of increased TAG hydrolysis in adipose tissue, the liver is flooded with FA (see p. 330). The rate of formation of acetyl CoA by β-oxidation of these FA exceeds the capacity of the liver to oxidize it to CO2 and water.
As a result, acetyl CoA accumulates and activates PC. [Note: Acetyl CoA inhibits the PDHC (by activating PDH kinase; see p. 111). Thus, this single compound can divert pyruvate toward gluconeogenesis and away from the TCA cycle (Fig. 10.9).]
D. Allosteric inhibition by AMP
Fructose 1,6-bisphosphatase is inhibited by AMP, a compound that activates PFK-1. This results in reciprocal regulation of glycolysis and gluconeogenesis seen previously with fructose 2,6-bisphosphate (see p. 121). [Note: Thus, elevated AMP stimulates energy-producing pathways and inhibits energy-requiring ones.]
V. CHAPTER SUMMARY
Gluconeogenic precursors include glycerol released during triacylglycerol hydrolysis in adipose tissue, lactate released by cells that lack mitochondria and by exercising skeletal muscle, and α-keto acids (for example, αketoglutarate and pyruvate) derived from glucogenic amino acid metabolism (Fig. 10.10). Seven of the reactions of glycolysis are reversible and are used for gluconeogenesis in the liver and kidneys. Three reactions, catalyzed by pyruvate kinase, phosphofructokinase-1, and glucokinase/hexokinase, are physiologically irreversible and must be circumvented. Pyruvate is converted to oxaloacetate and then to phosphoenolpyruvate (PEP) by pyruvate carboxylase (PC) and PEPcarboxykinase (PEPCK ). PC requires biotin and ATP and is allosterically activated by acetyl coenzyme A. PEPCK requires guanosine triphosphate. Transcription of its gene is increased by glucagon and cortisol and decreased by insulin. Fructose 1,6-bisphosphate is converted to fructose 6phosphate by fructose 1,6-bisphosphatase. This enzyme is inhibited by a high adenosine monophosphate (AMP)/ATP ratio. It is also inhibited by fructose 2,6-bisphosphate, the primary allosteric activator of glycolysis. Glucose 6-phosphate is dephosphorylated to glucose by glucose 6phosphatase. This enzyme of the endoplasmic reticular membrane catalyzes the final step in gluconeogenesis and in glycogen degradation. Its deficiency results in severe, fasting hypoglycemia.
dioxide.
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