Chapter Summary, Study Questions - Gluconeogenesis

CHAPTER SUMMARY

Gluconeogenic precursors include the intermediates of glycolysis and the tricarboxylic acid cycle, glycerol released during the hydrolysis of triacylglycerols in adipose tissue, lactate released by cells that lack mitochondria and by exercising skeletal muscle, and α-keto acids derived from the metabolism of glucogenic amino acids (Figure 10.10). Seven of the reactions of glycolysis are reversible and are used for gluconeogenesis in the liver and kidneys. Three reactions are physiologically irreversible and must be circumvented. These reactions are catalyzed by the glycolytic enzymes pyruvate kinase, phosphofructokinase, and hexokinase. Pyruvate is converted to oxaloacetate and then to phosphoenolpyruvate (PEP) by pyruvate carboxylase and PEP-carboxykinase. The carboxylase requires biotin and ATP and is allosterically activated by acetyl coenzyme A. PEP-carboxykinase requires GTP. The transcription of its gene is increased by glucagon and the glucocorticoids and decreased by insulin. Fructose 1,6-bisphosphate is converted to fructose 6-phosphate by fructose 1,6-bisphosphatase. This enzyme is inhibited by elevated levels of AMP and activated when ATP levels are elevated. The enzyme is also inhibited by fructose 2,6-bisphosphate, the primary allosteric activator of glycolysis. Glucose 6-phosphate is converted to glucose by glucose 6-phosphatase. This enzyme of the endoplasmic reticular membrane is required for the final step in gluconeogenesis as well as hepatic and renal glycogen degradation. Its deficiency results in severe, fasting hypoglycemia.

Figure 10.10 Key concept map for gluconeogenesis. TCA = tricarboxylic acid. CoA = coenzyme A; cAMP = cyclic adenosine monophosphate; P = phosphate; PG = phosphoglycerate; BPG = bisphosphoglycerate.

Study Questions

Choose the ONE best answer.

10.1 Which one of the following statements concerning gluconeogenesis is correct?

A. It is an energy-producing (exergonic) process.

B. It is important in maintaining blood glucose during a fast.

C. It is inhibited by a fall in the insulin-to-glucagon ratio.

D. It occurs in the cytosol of muscle cells.

E. It uses carbon skeletons provided by fatty acid degradation.

Correct answer = B. During a fast, glycogen stores are depleted, and gluconeogenesis maintains blood glucose. Gluconeogenesis is an energy-requiring (endergonic) pathway (both ATP and GTP get hydrolyzed) that occurs in liver, with kidney becoming a major glucose-producing organ in prolonged fasting. It utilizes both mitochondrial and cytosolic enzymes. Gluconeogenesis is stimulated by a fall in the insulin/glucagon ratio. Fatty acid degradation yields acetyl coenzyme A (CoA), which cannot be converted to glucose. This is because there is no net gain of carbons from acetyl CoA in the tricarboxylic acid cycle, and the pyruvate dehydrogenase reaction is physiologically irreversible. It is the carbon skeletons of most amino acids that are gluconeogenic.

10.2 Which reaction in the diagram below would be inhibited in the presence of large amounts of avidin, an egg white protein that binds and sequesters biotin?

Correct answer = C. Pyruvate is carboxylated to oxaloacetate by pyruvate carboxylase, a biotin-requiring enzyme. B (PDH complex) requires thiamine pyrophosphate, lipoic acid, FAD, coenzyme A, NAD; D (transaminase) requires pyridoxal phosphate; E (lactate dehydrogenase) requires NADH.

10.3 Which one of the following reactions is unique to gluconeogenesis?

A. 1,3-Bisphosphoglycerate → 3-phosphoglycerate

B. Lactate → pyruvate

C. Oxaloacetate → phosphoenolpyruvate

D. Phosphoenolpyruvate → pyruvate

Correct answer = C. The other reactions are common to both gluconeogenesis and glycolysis.

10.4 Use the chart below to show the effect of adenosine monophosphate (AMP) and fructose 2,6-bisphosphate on the listed enzymes of gluconeogenesis and glycolysis.

Both fructose 2,6-bisphosphate and adenosine monophosphate downregulate gluconeogenesis through inhibition of fructose 1,6-bisphosphatase and upregulate glycolysis through activation of phosphofructokinase-1. This results in reciprocal regulation of the two pathways.

10.5 The metabolism of ethanol by alcohol dehydrogenase produces reduced nicotinamide adenine dinucleotide (NADH). What effect is the change in the NAD⁺/NADH ratio expected to have on gluconeogenesis? Explain.

The increase in NADH as ethanol is oxidized will decrease the availability of oxaloacetate (OAA) because the reversible oxidation of malate to OAA by malate dehydrogenase of the tricarboxylic acid cycle is driven in the reverse direction by the high availability of NADH. Additionally, the reversible reduction of pyruvate to lactate by lactate dehydrogenase of glycolysis is driven in the forward direction by NADH. Thus, two important gluconeogenic substrates, OAA and pyruvate, are decreased as a result of the increase in NADH during ethanol metabolism. This results in a decrease in gluconeogenesis.

10.6 Given that acetyl coenzyme A cannot be a substrate for gluconeogenesis, why is its production in fatty acid oxidation essential for gluconeogenesis?

Acetyl coenzyme A inhibits the pyruvate dehydrogenase complex and activates pyruvate carboxylase, pushing pyruvate to gluconeogenesis and away from oxidation.