Module 3 - Gluconeogenesis Flashcards

1
Q
A
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2
Q

What is the function of gluconeogenesis?

A

the primary function of gluconeogenesis is to assist in maintaining adequate glucose levels in the blood

particularly important during periods of fasting (e.g., when you are sleeping) or starvation

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3
Q

Where does gluconeogenesis take place in the animal?

A

occurs only in liver and kidney, with liver being the largest contributor

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4
Q

Gluconeogenesis

A

The synthesis of glucose from non-carbohydrate precursors

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5
Q

Bifunctional Enzyme

A

A single protein that possesses two catalytic activities

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6
Q

Cori Cycle

A

A metabolic pathway in which lactate produced by glycolysis in muscle is transported via the bloodstream to the liver, where it is used for gluconeogenesis. The glucose that is generated is returned to muscle

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7
Q

Obligate Allosteric Activator

A

An allosteric activator which is required to be bound to an enzyme for it to have catalytic activity

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8
Q

Reciprocal Regulation

A

A situation where an allosteric molecule inhibits one pathway and activates the opposing pathway, such as that which occurs with glycolysis and gluconeogenesis

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8
Q

Gluconeogenic precursor: Lactate

A

one of the fates of pyruvate from glycolysis is that it can be reduced to lactate

This reaction, catalyzed by lactate dehydrogenase, is a reversible reaction

Most of the lactate formed in our bodies is produced in active muscle during anaerobic metabolism, which is released into the blood and eventually taken up by liver

it is converted back to pyruvate by lactate dehydrogenase and thereby enters the gluconeogenesis pathway

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9
Q

Gluconeogenic precursor: Amino Acids

A

Some amino acids, that are derived from the diet or from protein degradation, can be metabolized to intermediates in the gluconeogenic pathway

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10
Q

Gluconeogenic precursor: Glycerol

A

Triacylglycerols, the form of fat that we store in our bodies, can be broken down into fatty acids and glycerol

While fatty acids are used by various organs in our body for fuel, the glycerol is released from the adipose tissue into the blood and is taken up by the liver

There, glycerol is converted to dihydroxyacetone phosphate in a two-step process

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11
Q

How does pyruvate convert into Phosphoenolpyruvate?

A

In glycolysis, the conversion of phosphoenolpyruvate to pyruvate is catalyzed by pyruvate kinase and generates ATP as a second product

It is a strongly exergonic reaction, and thus not reversible

for gluconeogenesis to proceed, another mechanism involving different enzyme(s) has to be found in order to convert pyruvate to phosphoenolpyruvate

The process starts in the mitochondria with the carboxylation of pyruvate to form a four-carbon molecule called oxaloacetate

the reaction involves the hydrolysis of ATP which provides the energy to drive this reaction forward

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12
Q

Pyruvate carboxylase

A

requires a covalently bound prosthetic group called biotin (derivative of vitamin B7) that carries the CO2 in a manner that facilitates its reactivity with pyruvate

also requires that acetyl CoA is bound to the enzyme in order for it to catalyze carboxylation

In the absence of bound acetyl CoA, carboxylation does not occur

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13
Q

How does oxaloacetate move into the cytoplasm?

A

Oxaloacetate is converted to malate (by malate dehydrogenase), which is able to leave the mitochondria.

Once in the cytosol, malate is converted back to oxaloacetate by the same enzyme

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14
Q

How does oxaloacetate convert to phosphoenolpyruvate?

A

Happens in the cytosol

uses the enzyme phosphoenolpyruvate carboxykinase

Note that the hydrolysis of GTP rather than ATP is used to drive this reaction forward, at least in animals. Some bacterial forms of the enzyme use ATP.

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15
Q

How does phosphoenolpyruvate convert to fructose 1,6-bisP?

A

Once phosphoenolpyruvate is formed, it is metabolized by the enzymes of glycolysis to fructose 1,6-bisP.

This is possible because the reactions are all close to equilibrium at intracellular conditions, and therefore are reversible.

16
Q

Conversion of Fructose 1,6-Bisphosphate to Fructose 6-P

A

The enzyme used is fructose 1,6-bisphosphatase, a hydrolase which cleaves off the phosphate group using water from carbon 1 on fructose.

This step is an important regulatory point of gluconeogenesis and the enzyme involved is regulated allosterically

17
Q

fructose 6-P to glucose 6-P

A

fructose 6-P formed is readily converted to glucose 6-P since the reaction catalyzed by phosphoglucose isomerase, which we encountered in glycolysis, is reversible

18
Q

glucose 6-P to Glucose

A

Free glucose is produced by the hydrolytic removal of the phosphate group from glucose 6-P by glucose 6-phosphatase

19
Q

Where does the conversion of glucose 6-P to glucose take place?

A

The enzyme glucose 6-phosphatase resides in the lumen (i.e., inside) of the endoplasmic reticulum, thus requiring that the glucose 6-P produced in the cytosol be shuttled into the ER.

The products of the reaction, Pi and glucose, are subsequently transported back out to the cytosol which allows glucose to be transported out of the cell into the blood

20
Q

What is the overall reaction of gluconeogenesis?

A

the synthesis of glucose from pyruvate is energetically unfavourable except for the fact that it is coupled with reactions that release energy, such as the hydrolysis of ATP and GTP

21
Q

Gluconeogenesis and Glycolysis Are Reciprocally Regulated

A

Because these two pathways essentially go in opposite directions,it would not make sense that these pathways would be highly active at the same time.

A fundamental principle is that when glucose is abundant, glycolysis is favoured, while when glucose is scarce, gluconeogenesis is prominent

22
Q

What is the major point of regulation in gluconeogenesis?

A

the step where fructose 1,6-bisP is converted to fructose 6-P catalyzed by fructose 1,6-bisphosphatase.

23
Q

What is the major point of regulation in glycolysis?

A

the conversion of fructose 6-P to fructose 1,6-bisP catalyzed by phosphofructokinase

24
Q

note the reciprocal effects AMP on the two key enzymes

A

AMP, which reflects a low energy charge, activates phosphofructokinase and thus stimulates glycolysis and produces ATP, while at the same time it inhibits fructose 1,6-bisphosphatase, thereby slowing down gluconeogenesis.

Thus, under a low energy state of the cell, the net flux through this step would highly favour glycolysis.

25
Q

note the reciprocal effects of fructose-2,6-bisP on the two key enzymes

A

Fructose 2,6-bisP has a similar effect, and interestingly the concentration of this biomolecule increases in the fed state, when one would want to metabolize the glucose that is available.

26
Q

note the reciprocal effects of citrate on the two key enzymes

A

Citrate is an intermediate of the citric acid cycle which is the major pathway for oxidizing fuels when oxygen is available.

Thus, citrate reflects a high-energy state in the cell.

Not surprisingly, citrate inhibits phosphofructokinase but stimulates fructose 1,6-bisphosphatase, and thus signals for a net flux in the direction of gluconeogenesis.

27
Q

The interconversion of pyruvate and phosphoenolpyruvate is another point of reciprocal regulation

A

Pyruvate kinase is inhibited by biomolecules that reflect a high-energy charge, such as ATP and alanine.

Conversely, high levels of ADP which occur in a low energy state of the cell, inhibit the conversion of pyruvate to phosphoenolpyruvate, which leads to a net flux favouring glycolysis and ATP production.

28
Q

How do allosteric regulators work?

A

The effect of an allosteric regulator, whether an activator or an inhibitor, is highly dependent on its concentration.

The higher its concentration, the greater its effect, and vice versa.

The effect is rarely all or nothing (there are rare exceptions), but rather acts like a dimmer switch, that gradually changes the amount of light coming from a fixture and not like an on/off switch.

This allows for a very fine-tuned control of enzyme activity to match the needs of the cell.

29
Q

The Balance Between Glycolysis and Gluconeogenesis in Liver Is Sensitive to the Blood Glucose Concentration

A

One of the liver’s major responsibilities is to maintain blood sugar levels, which it does by adjusting the rates of glycolysis and gluconeogenesis.

It follows then that the blood sugar levels somehow influence the rates of these pathways.

It turns out that it achieves this through the allosteric modifier fructose 2,6-bisP.

Fructose 2,6-bisP activates phosphofructokinase, thus activating glycolysis; but it also inhibits fructose 1,6-bisphosphatase, thus slowing up gluconeogenesis

30
Q

how do blood sugar levels influence the concentration of fructose 2,6-bisP?

A

The relative activities of PFK-2 and FBPase-2 determine the concentration of fructose 2,6-bisP in the cell and thus the activities of glycolysis and gluconeogenesis.

As scientists began researching these two enzymes in order to understand how they were regulated, they found something very surprising: both were present in the same protein

Further research found that there was a single serine residue in the regulatory domain that became phosphorylated when glucose was scarce, such as when we are asleep and not eating

This occurred as a result of a rise in the hormone glucagon which is secreted by the pancreas as blood sugar levels fall.

Glucagon stimulates a cAMP signal cascade that leads to the phosphorylation of the single serine residue

31
Q

what does the phosphorylation of the serine residue result in?

A

it activates the phosphatase activity domain but at the same inhibits the kinase domain activity.

Together, this results in the lowering of fructose 2,6-bisP in the cell.

32
Q

The Cori Cycle

A

Recall that during strenuous activity when oxygen may become limiting, muscle produces a significant amount of lactate from pyruvate which is released into the blood.

Much of this lactate is taken up by the liver, converted back to pyruvate by the enzyme lactate dehydrogenase, and then converted to glucose by the gluconeogenesis pathway.

In this way, the liver helps to replenish the blood glucose levels in the blood, which provides the contracting muscle with the glucose it needs to generate ATP via glycolysis.

These combined reactions in the muscle and liver constitute the Cori Cycle

33
Q
A