Gluconeogenesis

Question 1

Gluconeogenesis

Answer 1

• Metabolic pathway to make glucose from Amino Acids, Lactate, and Glycerol
• Occurs when fasting: allows body to maintain glucose
• Primarily occurs in Liver Cells; also occurs in the Epithelial Cells of the Kidney and Intestine
• Occurs in the Cytoplasm, Endoplasmic Reticulum, and Mitochondria of the cells in these tissues
• Makes Glucose from scratch
• Main provider of blood glucose after 12h of fasting
• Uses ATP to convert Pyruvate into Glucose (opposite of Glycolysis)
• Similar to reverse Glycolysis; except there are 3 irreversible reactions that need to be bypassed

Question 2

Where and how is glucose stored?

Answer 2

Glucose is stored in the Liver as Glycogen which are glucose molecules connected together

Question 3

Why is it important to still have glucose when fasting?

Answer 3

Glucose is needed for the RBCs and the Brain when fasting

Question 4

Glycogenolysis

Answer 4

• In a fasting state, the liver will break down Glycogen into individual Glucose molecules
• Maintains glucose levels for 12-24 hours of fasting
• Glycogen stores are finite

Question 5

What are the main sources of Pyruvate in Gluconeogenesis?

Answer 5

• Lactate (Biproduct of Anaerobic Respiration in RBCs and exercising muscle cells)
• Amino Acids (All except Leucine and Lysine) –> Fasting for a long time breaks down Amino Acids from Skeletal Muscle –> Main Amino Acid used is Alanine

Question 6

How is Lactate converted to Pyruvate?

Answer 6

• Via Enzyme Lactate Dehydrogenase

- This produces 1 NADH in the process

Question 7

How is Alanine converted to Pyruvate?

Answer 7

• Via Enzyme Alanine Transaminase
• During this reaction Alpha Ketoglutarate is also converted to Glutamate
• This reaction requires Pyridoxine (Vitamin B6)

Question 8

How are fats broken down during fasting to create ATP?

Answer 8

• Low insulin and presence of Epinephrine and ACTH cause Adipocytes (Fat Cells) to stimulate Hormone Sensitive Lipase (HSL), an Enzyme that breaks down Triacylglycerides to 3 Fatty Acids and Glycerol

Question 9

What happens with the pancreas during fasting?

Answer 9

Pancreatic a-cells sense decrease in glucose –> Release Glucagon –> Triggers Glycogenolysis: conversion of stored glycogen in the liver to glucose, which can be released into the bloodstream

Question 10

Beta Oxidation

Answer 10

Breakdown of Fatty Acids to Acetyl-CoA and ATP in the Hepatocyte Mitochondria

Question 11

After Triglyceride breakdown, what is Glycerol used for?

Answer 11

Glycerol is used to make Glucose in Gluconeogenesis

Question 12

What molecules will be used in Gluconeogenesis to make Glucose?

Answer 12

• Glycerol (From Triglycerides)
• Lactate (Biproduct of Anaerobic Respiration in RBCs and exercising muscle cells)
• All Amino Acids (Except Leucine and Lysine)

Question 13

First step of Gluconeogenesis

Answer 13

• Pyruvate –> Enzyme Pyruvate Carboxylase –> Oxaloacetate –> Malate Shuttle –> Enzyme PEPCK –> Phosphoenolpyruvate (PEP)
• Note: In Glycolysis: PEP –> Pyruvate Kinase –> Pyruvate (irreversible)

Question 14

What Cofactors do Carboxylase Enzymes need?

Answer 14

• ATP (From Fatty Acid Oxidation)
• Biotin
• CO2
• Carboxylase Enzymes need their ABCs

Question 15

What enhances Carboxylase activity?

Answer 15

• Acetyl-CoA (Made during Fatty Acid Oxidation)

Question 16

What is the Malate Shuttle?

Answer 16

1. ) Oxaloacetate can’t exit the Mitochondria to the Cytoplasm
2. ) Malate Dehydrogenase (MDH) converts Oxaloacetate into Malate which can leave the Mitochondria into the Cytoplasm
3. ) MDH then converts Malate back to Oxaloacetate

Question 17

What promotes the PEPCK Enzyme?

Answer 17

Stress Hormones:

1. ) Glucagon
2. ) Epinephrine
3. ) Cortisol

This speeds up Gluconeogenesis

Question 18

Second step of Gluconeogenesis

Answer 18

• Multiple reversible reactions (similar to Glycolysis) –> Ultimately converted to DHAP
• Glycerol from HSL Activity can also be used to make DHAP

Question 19

How is Glycerol converted to DHAP?

Answer 19

Glycerol –> (Glycerol Kinase, uses ATP) –> G3P –> (G3P Dehydrogenase) –> DHAP

Question 20

Third step of Gluconeogenesis

Answer 20

DHAP –> (Aldolase) –> Fructose-1-6-Bisphosphate

Question 21

Fourth step of Gluconeogenesis

Answer 21

Fructose-1-6-Bisphosphate –> (Fructose-1-6-Bisphosphatase) –> Fructose-6-Phosphate

RATE LIMITING STEP OF GLUCONEOGENESIS

Question 22

What is the rate limiting step of Gluconeogenesis?

Answer 22

Fructose-1-6-Bisphosphate –> (Fructose-1-6-Bisphosphatase) –> Fructose-6-Phosphate

Question 23

What enhances the Enzyme Fructose-1-6-Bisphosphatase?

Answer 23

• ATP Enhances (Fatty acids burned in the liver yiel lots of ATP; liver needs energy to carry out Gluconeogenesis)
• Glucagon Enhances
• Insulin Inhibits

Question 24

Fifth step of Gluconeogenesis

Answer 24

Fructose-6-Phosphate –> (Isomerase) –> Glucose-6-Phosphate

Note: A phosphate keeps the glucose in the cell; must remove the phosphate in order to let the glucose leave the cell and enter the bloodstream

Question 25

Sixth step of Gluconeogenesis

Answer 25

Glucose-6-Phosphate --> (Glucose-6-Phosphatase) --> Glucose Note: Now that the phosphate group has been removed the glucose can exit the cell and enter the bloodstream

Question 26

How does alcohol relate to Gluconeogenesis?

Answer 26

- Alcohol (Ethanol) is processed in Liver Cells - Results in buildup of NADH and ATP in the Cytoplasm - Increased NADH levels signal the Lactic/Malate/G3P Dehydrogenases Enzymes in Gluconeogenesis to reverse the direction and go from Pyruvate to Lactate, from Oxaloacetate to Malate, and DAHP to G3P - Increase in ATP --> decreases Fatty Acid Beta Oxidation --> Causes accumulation of Fat in the Liver - All of the above impairs Gluconeogenesis --> Leads to Chronic Low Blood Sugar when Fasting

Question 27

What are the 3 irreversible reaction Enzymes in Glycolysis and what enzymes in Gluconeogenesis overcome these?

Answer 27

1. ) Pyruvate Kinase (Glycolysis), overcome by Pyruvate Carboxylase, Malate Dehydrogenase, and PEPCK in (Gluconeogenesis) 2. ) PFK1 (Glycoylsis), overcome by Fructose-1-6-Bisphosphate in (Gluconeogenesis) 3. ) Hexokinase (Glycolysis), overcome by Glucose-6-Phosphatase in (Gluconeogenesis)