Gluconeogenesis

Question 1

describe purpose of gluconeogenesis

Answer 1

• provision of glucose for cells that need glucose as metabolic fule (RBC, brain, renal medulla)
• synthesis of glucose from non-carbohydrates and release into the blood
• sole provider for blood glucose once glycogen is depleted in the liver

Question 2

where in the body and when is gluconeogenesis performed?

Answer 2

• gluconeogenesis occurs in liver (periportal cells) and kidneys
• gluconeogenesis takes place during fasting or flight and fight situations
  
  • after an overnight fast gluconeogenesis occurs:
    
    • 90% in liver and 10% in kidney
  • during prolonged starvation, gluconeogenesis occurs:
    
    • 60% in liver and 40% in kidney

Question 3

which cellular compartments are involved in gluconeogenesis?

Answer 3

• most of the enzymes for gluconeogenesis are in the cytosol
  
  • the reversible steps are shared with enzymes of glycolysis
• glucose 6-phosphatase is found in the ER
• pyruvate carboxylase is found in the mt
• PEP carboxykinase is found in the mt and in cytosol

Question 4

gluconeogenesis takes place mainly in _____ and glycolysis mainly in _____

Answer 4

gluconeogenesis takes place mainly in periportal cells and glycolysis mainly in perivenous cells

they do not take place at the same time

Question 5

the (4) enzymes catalyzing the irreversible steps of gluconeogenesis are:

Answer 5

1. pyruvate carboxylase
2. PEP carboxykinase
3. fructose 1,6 bisphosphatase
4. glucose 6-phosphatase

Question 6

what are the substrates for gluconeogenesis?

Answer 6

• during fasting, the liver obtains via the blood:
  
  • amino acids from degradation of tissue proteins, especially muscle during fasting. major source for gluconeogenesis
    
    • ​alanine and glutamine
  • lactate from exercising muscle or from RBC
  • glycerol from degradation of TAGs in fat cells

Question 7

what is the importance of acetyl CoA in gluconeogenesis?

Answer 7

• acetyl CoA from B-oxidation is used as allosteric activator for pyruvate carboxylase

Question 8

describe the glucose-alanine cycle

Answer 8

• the glucose-alanine cycle describes hepatic gluconeogenesis using alanine released by muscle during fasting
  
  • the formed glucose is released into the blood and can be taken up by muscle
• this cycle is costly regarding ATP but is needed to provide blood glucose during fasting independent of muscle exercise

Question 9

describe the Cori cycle

Answer 9

• the Cori-cycle describes hepatic gluconeogenesis using the lactate formed by anaerobic glycolysis in muscle and release of glucose for uptake into muscle for glycolysis
• the release of lactate from RBC or other cells performing anaerobic glycolysis is somtimes included in the Cori cycle

Question 10

describe enzymes involved in pyruvate formation from the glucose-alanine cycle and the Cori cycle

Answer 10

• pyruvate is formed from:
  
  • alanine catalyzed by alanine aminotransferase
  • lactate catalyzed by lactate dehydrogenase

Question 11

describe the carboxylation of pyruvate

Answer 11

• pyruvate is transported into mt and is carboxylated to oxaloacetate catalyzed by pyruvate carboxylase
  
  • the enzyme needs the vitamin biotin as a coenzyme and the allosteric activation by acetyl CoA
• acetyl CoA is formed during fasting by mt fatty acid degradation and not by pyruvate dehydrogenase which is inhibited

Question 12

how does pyruvate carboxylase form oxaloacetate?

Answer 12

• pyruvate carboxylase uses pyruvate, CO2, ATP and forms oxaloacetate
• pyruvate carboxylase is found in mt and needs acetyl CoA as an absolute allosteric activator otherwise it is not active

Question 13

describe the PEP carboxykinase rxn

Answer 13

• oxaloacetate formed in mt cannot pass through the inner mt membrane, therefore it is turned into malate which can travel to the cytosol, combines with NAD+, and is converted back to oxaloacetate
• oxaloacetate is now a substrate for cytosolic PEP carboxykinase
• PEP carboxykinase uses GTP and forms PEP, GDP and CO2
  
  • this enzyme is induced by cortisol

Question 14

describe function of fructose 1,6-bisphosphatase

Answer 14

• fructose 1,6-bisphosphatase is the ultimately short-term regulated enzyme
• inhibition of F1,6BPase by:
  
  • AMP at low energy levels (high AMP signals low ATP)
  • fructose 2,6-bisphosphate (formed when insulin is high)

Question 15

how and when is hepatic frucose 2,6 bisphosphate formed and inhibits gluconeogenesis?

Answer 15

• it is formed by the bifunctional enzyme when the serum insulin/glucagon ratio is high
  
  • this enzyme has a phosphorylation site that responds to hormonal regulation
• at high blood glucose levels, hepatic glycolysis is favored and gluconeogenesis is inhibited

Question 16

describe the function of the bifunctional enzyme

Answer 16

• only one gene and one protein for both irreversible enzyme activities
• insulin leads to dephosphorylated bifunctional enzyme that forms fructose 2,6-bisP and promotes glycolysis (PFK-2 is active)
• glucagon leads to the phosphorylated bifunctional enzyme that degrades frucose 2,6-bisP and promotes gluconeogenesis (PFK-2 is inactive)

Question 17

what are the energy requirements of gluconeogenesis?

Answer 17

• glucose synthesis from 2 pyruvates needs 4 ATP, 2 GTP and 2 NADH
• fatty acid degradation in mt provides the energy needed for hepatocytes during gluconeogenesis

Question 18

describe location and function of glucose 6-phosphatase

Answer 18

• glucose 6-phosphatase is an enzyme that is bound in the ER membrane and acts toward the ER lumen
• glucose 6-phosphate is transported from the cytosol into the ER lumen and is cleaved by glucose 6-phosphatase to free glucose and inorganic phosphate which are transported into cytosol

Question 19

glucose 6-phosphatase is used in both ____ and _____

Answer 19

• glucose 6-phosphatase is used in both gluconeogenesis and glycogen degradation