Chapter 17 - Gluconeogenesis

Question 1

How Do We Maintain Blood Glucose Levels Above 2.5 mmol/L?

Answer 1

1) Diet (sporadic)
2) Glycogen (limited)
3) Gluconeogenesis

Question 2

Gluconeogenesis

Answer 2

The ability to make glucose from noncarbohydrate precursors (pyruvate tends to be the main source). The liver is the main glyconeogenic tissue but some also occurs in the kidney. Is important during fasting or starvation. Is the primary fuel for the brain and the only fuel for red blood cells. Is an anabolic process (molecules are being used to make glucose). No energy is produced (uses energy to form glucose).

Question 3

Non-Carbohydrate Precurosors of Gluconeogenesis

Answer 3

1) Pyruvate.
2) The carbon skeletons of some amino acids.
3) Glycerol (can be converted into dihydroxyacetone phosphate which can be processed by gluconeogenesis or glycolysis).

Question 4

Gluconeogenic Pathway

Answer 4

Pyruvate to glucose (reversal of glycolysis). Reversible enzymes are shared but gluconeogenesis is not a complete reversal of glycolysis (3 irreversible steps + 1 distinct enzyme).

Question 5

3 Irreversible Steps to Gluconeogenesis

Answer 5

1) glucose 6-phosphate + H2O → glucose + Pi via glucose 6-phosphatase
2) fructose 1,6-bisphosphate + H2O → fructose 6-phosphate + Pi via fructose 1,6-bisphosphatase
3) pyruvate + CO2 + ATP + H2O → oxaloacetate + ADP + Pi via pyruvate carboxylase

Question 6

Phosphoenolpyruvate Carboxykinase (PEPCK)

Answer 6

Oxaloacetate + GTP → phosphoenolpyruvate + GDP + CO2. Reversible under bench conditions but under the kinetic environment of human metabolism it is a one-way reaction. Adding the phosphoryl group to pyruvate is very unfavourable. Decarboxylation reactions are favourable and are used to power the phosphorylation. CO2 that was added by pyruvate carboxylase comes off in this step.

Question 7

Pyruvate Carboxylase

Answer 7

Pyruvate (3 C) into oxaloacetate (4 C). Located in the mitochondria. 3 stages. 1) Bicarbonate phosphorylated. 2) CO2 transferred to biotin arm of enzyme which is called carboxybiotin. It requires the vitamin biotin (B7) as a cofactor. 3) CO2 added to pyruvate.

Question 8

Biotin

Answer 8

Serves as the carrier of activated CO2. Its carboxylate group is linked to lysine. Is covalently attached to the biotin carboxyl carrier domain. It transports CO2 from the biotin carboxylase active site to the pyruvate carboxylase active site of an adjacent subunit. Acts as a swing arm or tether. It requires Acetyl CoA to be present (allosteric regulation).

Question 9

Glucose 6-Phosphatase

Answer 9

ER membrane anchored. Takes place in the liver on the inner surface of the endoplasmic reticulum. Reverses activity of glucokinase in the liver. It allows phosphate to be removed and glucose to move out GLUT transporters. Other tissues (ex. muscle) lack this phosphatase, glucose 6-phosphate is used for glycogen synthesis instead.

Question 10

Fructose 2,6-Bisphosphate

Answer 10

Activator of phosphofructokinase and inhibitor of fructose 1,6-bisphosphatase.

Question 11

Bifunctional Enzyme For Liver Glycolysis/Gluconeogenesis Regulation

Answer 11

One domain is phosphofructokinase 2 (PFK2) and the other domain is fructose 2,6-bisphosphatase (FBPase2). Is regulated by glucagon signal (phosphorylation of serine residue via protein kinase A). Turning off kinase automatically turns on phosphatase and vice versa.

Question 12

Low Blood Glucose (Fasting)

Answer 12

Glucagon signalling results phosphorylation and inactivation of PFK2 and activation of FBPase2. F-2,6-bP gets converted to F-6-P and PFK stimulation removed so glycolysis is inhibited.

Question 13

High Blood Glucose (After Feeding)

Answer 13

Insulin signal replaces glucagon signal. G-6-P in cell increases and F-6-P accumulates. F-6-P activates phosphoprotein phosphatase to remove phosphate from PFK2-FBPase2 that activates PFK2 and inhibits FBPase2. F-2,6-bP is made that activates PFK which stimulates glycolysis.

Question 14

Liver

Answer 14

Supports glucose needs of other tissues. Convert lactate from other tissues to glucose. Muscle and erythrocytes are big sources of lactate.

Question 15

Cori Cycle

Answer 15

Muscle-liver lactate exchange.