bmsc 230 module 3 gluconeogenesis

Gluconeogenesis

The production of glucose from non-carbohydrate precursors. It assists in maintaining glucose levels in the blood.

What are gluconeogenesis precursors ?

Lactate, Amino acids, Glycerol

Irreversible reactions of gluconeogenesis

1. Synthesis of phosphoenolpyruvate from pyruvate (with oxaloacetate intermediate)

2. Synthesis of fructose-6-phosphate from fructose-1,6-bisphosphate

3. Production fo glucose from glucose-6-phoshpate

Bifunctional enzyme

A single protein that possesses two catalytic activities

Cori Cylce

A metabolic pathway which lactate is produced by glycolysis in the muscle is transported to the liver via bloodstream for gluconeogenesis. Glucose generated is returned to the muscle.

Obligate Allosteric Activator

required to be bound to an enzyme for it to have catalytic activitiy

ex. Acetyl CoA

Reciprocal Regulation

Where an allosteric molecule inhibits one pathway and activates the opposing pathway.

ex. glycolysis and gluconeogensis.

Which organ is the biggest consumer of glucose?

The brain. it uses about 120 grams of glucose per day.

What does the brain use for energy when glucose is low?

Ketone bodies

When is glucoeneogenesis important for the body?

During times of fasting such as when sleeping or starvation

Where does gluconeogenesis occur?

Only in the liver and the kidney. However, the liver is the largest contributor.

How is glucose transported throughout the body?

When the liver or kidney produces glucose, it is passed across the cell membrane into the blood so that other tissues (brain and muscle) can extract it from the blood to meet their metabolic demands.

Main function of liver

To maintain glucose levels

What is glucose in plants used for?

To synthesize starch, cellulose, and sucrose.

What is pyruvate formed from for gluconeogenesis?

non-carbohydrate precursors such as lactate and amino acids.

Glycerol can enter the gluconeogenesis pathway in later steps.

How many molecules should enter the gluconeogenesis pathway?

two pyruvates

How does pyruvate turn to lactate in glycolysis?

by lactate dehydrogenase. This reaction is reversible.

How is lactate produced and how does it enter gluconeogenesis?

in muscles during anaerobic metabolism. it is then released into blood and then taken by liver.

In the liver, it is converted by lactate dehydrogenase into pyruvate and enters gluconeogenesis.

enters through the Cori Cycle

How do amino acids enter gluconeogensis?

derived from diet, or from protein degradation. They are metabolized into intermediates for glucose.

How does glycerol enter gluconeogenesis?

1. Breakdown of triacylglycerol

2. released into blood and taken up in the liver.

3. converted into dihydroxyacetone phosphate in a two step process and then enters gluconeogenesis as glyceraldehyde 3-phosphate (converted by triosephosphate isomerase)

Similarities and Differences between glycolysis and gluconeogenesis

Glycolysis - converts glucose to pyruvate

Gluconeogenesis - converts pyruvate to glucose

Overall free energy of both pathways must be negative to proceed

Three reactions of glycolysis are irreversible, these reactions are different in gluconeogenesis.

Are glycolysis and gluconeogenesis reversal pathways of each other?

No

Where does the conversion of pyruvate to phosphenolpyruvate begin in gluconeogenesis?

mitchondria

How does pyruvate become oxaloacetate?

goes through carboxylation using pyruvate carboxylase

This involves the hydrolysis of ATP to drive the reaction forward.

Where is oxaloacetate formed?

mitochondria.

How is oxaloacetate converted to phosphoenolpyruvate?

in the mitochondria, is is first converted to malate by malate dehydrogenase to be transported into the cytosol.

Once in the cytosol, malate is converted back into by malate dehydrogenase.

Then it is converted to phosphoenolpyruvate by phosphoenolpyruvate carboxykinase.

Pyruvate Carboxylase

Carboxylizes pyruvate into oxaloacetate.

What does pyruvate carboxylase require to function?

biotin and acetyl CoA.

What does biotin do for pyruvate carboxylase?

a bound prosthetic group that carries CO2 to facilitate reactivity with pyruvate.

What does Acetyl CoA do for pyruvate carboxylase?

It is an obligate allosteric activator that catalyzes carboxylation. Without it, carboxylation doesn't occur.

Why must oxaloacetate be transported into the cytosol?

the enzyme for it, phosphoenolpyruvate carboxykinase, is found in the cytosol.

What is an important regulatory step in gluconeogenesis?

The conversion of fructose 1,6-bisphosphate to fructose-6-P. Fructose 1-6-bisphosphatase is regulated allosterically.

Where is glucose-6-phosphatase found?

inside the lumen of the endoplasmic reticulum

Where is glucose-6-P produced and where is it shipped off to?

made in the cytosol and is shipped to the endoplasmic reticulum because glucose-6-phosphatase is found in the lumen.

Which part of the cell is glucose made and where does it go?

It is made in the endoplasmic reticulum. Glucose and Pi are transported back to cytosol where glucose is transported into the blood.

How many phosphorylation groups are spent in synthesizing glucose?

Six

What makes the spending of phosphorylation groups in gluconeogenesis possible?

coupled with reactions that give energy like hydrolysis of ATP and GTP.

When is glycolysis favoured?

When glucose is abundant

when is gluconeogenesis favoured?

When glucose is scarce

Similarities between fructose-1,6-phosphatase and phosphofrutokinase?

They both regulate major points in gluconeogenesis and glycolysis.

They are both allosterically regulated in the liver with molecules that reflect energy state of the cell.

AMP

An allosteric regulator that regulates glycolysis and gluconeogenesis. reflects a low energy state.

Effects of AMP

• Activates phosphofrutokinase (for glycolysis)

• Generates ATP

• Inhibts Fructose 1,6-bisphosphatase (slows gluconeogenesis)

Citrate

An allosteric regulator that regulates glycolysis and gluconeogenesis.

It reflects a high energy state in the cell

How is citrate made?

It is an intermediate of the citric acid cycle

Effects of Citrate

Inhibits phosphofrutokinase

Stimulates fructose-1,6,-bisphosphatase and increases the rate of gluconeogenesis

What inhibits pyruvate kinase?

Molecules that reflect a high energy state like ATP and alanine

What inhibits the conversion of pyruvate to phosphoenolpyruvate?

This is a part of gluconeogenesis. High levels of ADP (low energy state) inhibits gluconeogenesis and gives flux to glycolysis.

How does the liver balance between glycolysis and gluconeogenesis?

Through blood glucose concentration

How does blood sugar/glucose levels influence the concentration of fructose-2,6-bisP?

phosphofructokinase and fructose-2,6-bisphosphatase. These are on the same protein with a kinase and a phosphatase domain.

What influences the two enzymes phosphofructokinase and fructose-2,6-bisphosphatase

The levels of glucagon.

What happens when glucagon is rising?

it stimulates cAMP to phosphorylate serine.

Phosphorylation activates phosphatase domain and inhibits kinase domain.

What happens when the phosphatase domain is activated on the protein.

Fructose-2,6-bisphosphate is lowered, and this increases gluconeogenesis.

What happens when glucagon is falling?

Insulin increases leading to less phosphorylation of the serine residue on the bifuntional enzyme. This activates the kinase domain and inhibits the phosphatase domain.

Fructose-2,6-bisP increases and favours glycolysis.

Type 2 Diabetes

Insulin inhibits gluconeogenesis. This disease has insulin resistance that causes the cell to keep making glucose even when glucose is sufficient. This gives large amount of sugar in the blood

What happens with large amount of sugar in the blood?

It increases the osmolarity of the blood. Water is drawn out of tissues leading to excessive thirst and frequent urination.

What causes insulin resistance?

It is unknown but is is associated with obesity.

What do drugs for Type 2 Diabetes do?

• Inhibit liver gluconeogenesis
• increase insulin sensitivity
• stimulate the ability of pancreas to release insulin

What is the purpose of the Cori Cycle?

To replenish blood glucose