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DENF 1521 Biochemistry

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Gluconeogenesis

Lesson 7.1 Basic Pathway and Reactions

Instructions
  1. Please enter your name below to be sure you get credit (before doing anything else).
  2. Then study Lesson 7.1 at your own pace. When Practice Exercises appear, click the appropriate button to choose your answer. Then press the "Get Feedback..." button to find out how you did. Continue to try again if you miss.
  3. After studying Lesson 7.1, and responding to all practice exercises, follow instructions at the end to submit your responses for Lesson 7.1 participation credit.
NAME:
Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis

7.1A Lesson objectives

The objectives of this lesson are to understand that:

  1. Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors
  2. Gluconeogenesis is not the reversal of glycolysis
  3. The bypass reactions make the synthesis of glucose thermodynamically feasible
  4. Gluconeogenesis and glycolysis are reciprocally regulated

7.1B Introduction to the gluconeogenesis pathway

The main purpose of gluconeogenesis is to synthesis glucose from non-carbohydrate precursors. This process occurs mainly in the liver and kidney. Gluconeogenesis is very important since it provides glucose for the brain which is absolutely dependent on glucose as its primary fuel source. Therefore, the major function of gluconeogenesis is to provide glucose for the brain and muscle. The main precursors used by this pathway are lactate, alanine, and glycerol.

Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis
Gluconeogenesis
Practice
Exercise 1: 		Which of the following compounds CANNOT serve as a precursor for the synthesis of glucose by the gluconeogenesis pathway?

No Response
Glycerol
Alanine
Lactate
Leucine
Practice
Exercise 2:

Gluconeogenesis can occur in the liver and kidney.

No Response
True
False
Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis

The reactions which make up the gluconeogenesis pathway are not simply the reversal of the reactions of glycolysis. There are 3 steps of glycolysis which have a negative and are not reversible. In order to accomplish this, a net hydrolysis of 4 "ATP" molecules are used. Note: 6 "ATP's" are used to synthesize glucose from pyruvate, but glycolysis generates 2 ATP's. Therefore, gluconeogenesis uses 4 ATP's. The irreversible glycolysis reactions are:

1.      Glucose + ATP

ARROW
glucose 6-phosphate + ADP

2.       Fructose 6-phosphate + ATP

ARROW
fructose 1, 6-bisphosphate + ADP

3.        Phosphoenolpyruvate + ADP

ARROW pyruvate + ATP

 

These irreversible steps are replaced by the bypass reactions of gluconeogenesis. The conversion of pyruvate to phosphoenolpyruvate is carried out in two steps.

Pyruvate + CO2 + ATP + H2O

ARROW


oxaloacetate + ADP + Pi + 2 H+

Oxaloacetate + GTP ARROW
phosphoenolpyruvate + GDP + CO2

 

The overall for the sum of the above two reactions is 0.2 kcal/mol and therefore, thermodynamically feasible. Another important aspect of the above 2 reactions is that they are carried out in different subcellular locations. The formation of oxaloacetate from pyruvate is carried out by the enzyme pyruvate carboxylase and occurs in the mitochondria. The formation of phosphoenolpyruvate from oxaloacetate occurs in the cytoplasm and is catalyzed by the enzyme phosphoenolpyruvate carboxylase. The complete gluconeogenesis pathway is shown below. The enzymes catalyzing the bypass reactions are shown in blue.

Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis
Gluconeogenesis
Practice
Exercise 3: 		The purpose of the bypass reactions of gluconeogenesis is to

No Response
Increase the production of ATP
Generate large amounts of NADPH for biosynthesis
Overcome the irreversible steps of glycolysis
Allow gluconeogenesis to take place entirely in the mitochondria
Practice
Exercise 4:

Which of the following gluconeogenesis enzymes are found in the mitochondria?

No Response
Glucose 6-phosphatase
Pyruvate carboxylase
Phosphoenolpyruvate carboxykinase
Fructose 1,6-bisphosphatase
Practice
Exercise 5:

The enzyme glucose 6-phosphatase is found only in muscle.

No Response
True
False
Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis



7.1C Pyruvate carboxylase

The enzyme pyruvate carboxylase is found in the mitochondria and catalyzes the reaction

Pyruvate + CO2 + ATP + H2O ARROW
oxaloacetate + ADP + Pi + 2 H+

The enzyme contains an important cofactor, biotin which is a carrier of activated CO2. Biotin is a vitamin and is covalently attached to pyruvate carboxylase through a lysine residue on the enzyme.

The structure of carboxy-biotin

The CO2 molecule in red is the one which will be transferred.
Biotin

Pyruvate is allosterically activated by acetyl CoA which must be bound to the enzyme in order for the carboxylation of biotin to occur. This reaction is also critical for maintaining the levels of intermediates in the citric acid cycle. High levels of acetyl CoA signal the need for oxaloacetic acid, the product of the pyruvate carboxylase reaction. Therefore, oxaloacetate serves 2 purposes.

  1. Stoichiometric intermediate in gluconeogenesis
  2. Catalytic intermediate in the citric acid cycle

The energy charge (ATP levels) of the cell determine the fate of oxaloacetate. If the energy charge is high, then gluconeogenesis predominates. If the energy charge is low, the citric acid cycle predominates.

7.1D Transport out of the mitochondria

Once formed in the mitochondria, oxaloacetate must be transported out of the mitochondria to be used for gluconeogenesis. Oxaloacetate is oxidized to malate which is transported out of the mitochondria and then reduced to reform oxaloacetate.

Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis
Gluconeogenesis
Practice
Exercise 6: 		Which of the following cofactors is found in the enzyme pyruvate carboxylase?

No Response
Folate
Pyridoxal phosphate
Thiamin pyrophosphate
Biotin
Practice
Exercise 7:

The role of acetyl CoA in the reaction catalyzed by the enzyme pyruvate carboxylase is as a(n)

No Response
Substrate in the reaction
Activator of carbon dioxide
Allosteric activator of the enzyme
Competitive inhibitor of the reaction
Dental Biochemistry Brush
DB Bullet Lesson 7.1 Gluconeogenesis

7.1E Summary

After completing this lesson you should understand the following about gluconeogenesis.

  1. The purpose of gluconeogenesis is to synthesize glucose from non-carbohydrate precursors.
  2. A series of bypass reactions are used to reverse the irreversible glycolysis steps.
  3. Pyruvate carboxylase, a biotin containing enzyme, catalyzes a key reaction in the mitochondria.
  4. The remainder of the reactions occur in the cytoplasm
  5. The enzyme glucose 6-phosphatase is found in the liver and key to the release of glucose

Final Instructions


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End Lesson 7.1
Gluconeogenesis


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