2nd Unit / Ch 10 Gluconeogenesis

Question 1

Gluconeogenesis Overview 10.1

1. What is the function of gluconeogenesis, the pathway denoted by the blue arrows shown?
2. In what tissues does gluconeogenesis occur?
3. What subcellular locales are involved?
4. Which tissue is the primary gluconeogenesis site in a short-term fast?

Answer 1

1. Gluconeogenesis is the pathway that synthesizes glucose from noncarbohydrate precursor molecules, for example, pyruvate.

2. Gluconeogenesis occurs in the liver and the kidneys, with the majority of the reactions occurring in the cytosol. However, the enzyme that catalyzes reaction 1 ( pyruvate carboxylase ) is in the mitochondrial matrix, the enzyme that catalyzes reaction

2 ( PEPCK ) has cytosolic and mitochondrial isozymes, and the enzyme that catalyzes reaction 4 ( glucose 6-phosphatase ) is present in the ER membrane. Liver is the primary site in a short-term fast. [Note: The kidneys become major glucose producers in a long-term fast.]

Question 2

Gluconeogenesis Overview 10.1

What role does gluconeogenesis play in a long-term fast

( starvation)?

Answer 2

In a long-term fast ( starvation ), hepatic and renal gluconeogenesis provides sustained glucose synthesis that maintains blood glucose concentration, thereby ensuring glucose availability for those
tissues such as the brain and RBCs that require a continuous supply.

Question 3

Gluconeogenesis Substrates 10.2

What substrate for gluconeogenesis is denoted by the red question mark shown?
What cycle is depicted?

Answer 3

Lactate is the gluconeogenic substrate denoted. The glucose–lactate , or Cori cycle is shown.

Question 4

Gluconeogenesis Substrates 10.2

What additional substrates can be used in gluconeogenesis?

Answer 4

Glycerol, pyruvate, and the -keto acids generated by the degradation of glucogenic amino acids produced from muscle proteolysis are additional substrates for gluconeogenesis. [ Note: The a-keto acids, for example, a-ketoglutarate, enter
into the TCA cycle and result in a net gain of carbon atoms that can be used for gluconeogenesis.]

Question 5

Gluconeogenesis Substrates 10.2

Why cannot acetyl CoA be used as a substrate?

Answer 5

Acetyl CoA cannot be used as a substrate for gluconeogenesis because (1) the PDH reaction that oxidatively decarboxylates pyruvate to acetyl CoA is an irreversible reaction; (2) while two carbons enter the TCA cycle as acetyl CoA, two are released
as CO2 . Because there is no net gain of carbons, there is no net gain of glucose from acetyl CoA.

Question 6

Gluconeogenesis Substrates 10.2

How does the lack of glycerol kinase expression in adipose tissue support gluconeogenesis in the liver and the kidneys in the fasted state?

Answer 6

The lack of glycerol kinase in adipocytes allows the glycerol generated by the degradation of their stored TAGs in fasting to be sent out into the blood for use by the liver and kidneys, which do express the kinase. The glycerol 3-P thus formed can be
oxidized to DHAP for gluconeogenesis.

Question 7

Gluconeogenesis Reactions 10.3

What enzyme, catalyzing the first of four irreversible reactions of gluconeogenesis, is denoted by the red question mark?

Answer 7

The enzyme shown is PC , which catalyzes the first of four irreversible gluconeogenesis
reactions.

Question 8

Gluconeogenesis Reactions 10.3

What enzymes catalyze the other three irreversible reactions of the pathway?

Answer 8

PEPCK , FBP-2 , and glucose 6-phosphatase catalyze the other irreversible gluconeogenesis reactions.

Question 9

Gluconeogenesis Reactions 10.3

What water-soluble vitamin is the coenzyme for the enzyme shown? What other enzymes require this coenzyme?

Answer 9

Biotin, a water-soluble vitamin, is the coenzyme for PC. Other carboxylases requiring biotin are acetyl CoA carboxylase, propionyl CoA carboxylase, and methylcrotonyl CoA carboxylase.

[Note: Carboxylases also require ATP.]

Question 10

Gluconeogenesis Reactions 10.3

Why might decreased production of acetyl CoA result in hypoglycemia even though it cannot be used as a substrate for gluconeogenesis?

Answer 10

Acetyl CoA is the allosteric activator of PC . Because it also inhibits PDH, acetyl CoA (primarily from FA oxidation) diverts pyruvate from oxidative degradation and to gluconeogenesis. Consequently, a decrease in acetyl CoA can result in hypoglycemia.

Question 11

Gluconeogenesis Reactions 10.4

Why is OAA converted to malate for transport across the inner mitochondrial membrane, as shown?

Answer 11

OAA has no mitochondrial transporter. Reduction to malate by MD m (as NADH is oxidized), transport across the inner mitochondrial membrane, and oxidation by MD c (as NAD+ is reduced) makes the OAA and NADH needed for gluconeogenesis available in the cytosol. [ Note: With glycolysis, OAA ↔ malate is used to transfer
reducing equivalents in the opposite direction.]

Question 12

Gluconeogenesis Reactions 10.4

Is gluconeogenesis an endergonic or exergonic process? Why does it require NADH?

Answer 12

Gluconeogenesis is endergonic and uses energy from ATP and GTP hydrolysis. It requires NADH for the reduction of 1,3-bisphosphoglycerate to glyceraldehyde
3-Pby glyceraldehyde 3-phosphate dehydrogenase, an enzyme common to gluconeogenesis and glycolysis.

Question 13

Gluconeogenesis Reactions 10.4

Why does glucose 6-phosphatase deficiency result in severe fasting
hypoglycemia?

Answer 13

Glucose 6-phosphatase, an ER membrane protein unique to liver and kidney, dephosphorylates intracellular glucose 6-P to free glucose, which can be transported into the blood by GLUT-2. Glucose 6-phosphatase deficiency traps glucose 6-P within the cells of gluconeogenic tissues.

Question 14

Gluconeogenesis Regulation 10.5

What effect does a decrease in the insulin to glucagon ratio have on the activity of FBP-1 shown? Why?

Answer 14

A rise in glucagon results in decreased production of fructose 2,6-bisP, a FBP-1 inhibitor. Loss of the inhibitor increases FBP-1 activity and the rate of gluconeogenesis.

Question 15

Gluconeogenesis Regulation 10.5

How are gluconeogenesis (glucose synthesis) and glycolysis (glucose oxidation) coordinately regulated?

Answer 15

Fructose 2,6-bisP (a high glucose signal) and AMP (a low energy signal) coordinately downregulate gluconeogenesis (by inhibiting FBP-1 ) and upregulate glycolysis (by activating PFK-1 ).

Question 16

Gluconeogenesis Regulation 10.5

Why might FBP-1 deficiency cause hyperventilation ?

Answer 16

FBP-1 deficiency decreases gluconeogenesis. It does not affect glycolysis, which produces pyruvate or lactate that are substrates for gluconeogenesis. Accumulation of these acids causes a metabolic acidosis. The acidosis is compensated for by hyperventilation that decreases CO2 , thereby reducing

Question 17

Gluconeogenesis Regulation 10.6

What effect does the phosphorylation of hepatic PK (shown) have on its activity?

Answer 17

The hepatic isoform of PK is regulated by covalent phosphorylation (inactivated) and dephosphorylation (activated).

Question 18

Gluconeogenesis Regulation 10.6

In what pathway does this enzyme directly participate? How does its inhibition affect gluconeogenesis?

Answer 18

PK is an enzyme of glycolysis. PK inhibition by phosphorylation (or by allosteric effectors) decreases the conversion of PEP to pyruvate, thereby increasing PEP’s availability for gluconeogenesis.

Question 19

Gluconeogenesis Regulation 10.6

Is hypoglycemia an expected finding in an individual with hyperinsulinemia? Why or why not?

Answer 19

Hypoglycemia is an expected finding in hyperinsulinemia, because gluconeogenesis is decreased as a result of (1) decreased transcription of the gene for PEPCK (as a consequence of decreased glucagon); (2) PFK-2 and PK dephosphorylation (activation), favoring glycolysis; and (3) decreased availability of gluconeogenic substrates, particularly amino acids from muscle protein degradation
because insulin favors protein synthesis. [Note: Insulin decreases FA degradation, thereby decreasing production of acetyl CoA, a PC activator.]