Gluconeogenesis: Reactions

by Kevin Ahern, PhD

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    00:00 The reaction of gluconeogenesis are shown on the screen here and this is a kind of a complicated pathway. So let's try to break it down a little bit.

    00:09 There are 7 enzymes, as I said, that are common between the two and they are shown in dark green here.

    00:15 I won't talk about those; because, the reactions of gluconeogenesis that use these enzymes are simply running a reactions of glycolysis backwards.

    00:26 The enzymes of gluconeogenesis that are different from glycolysis I wanna spend a little bit of time of talking about; because, they have some considerations for us.

    00:34 The first of these reactions that I will talk about is the reaction catalyzed by the enzyme known as pyruvate carboxylase, you can see it on the lower right, and in this reaction, pyruvate is being converted into oxaloacetate. What does that mean? Pyruvate has 3 carbons and for this reaction a carbon is actually added to pyruvate. That comes from the bicarbonate that you can see at the bottom of that image.

    01:01 Now ATP energy is required in order to make this happen and so we produced ADP in the process.

    01:08 These are the intermediates that we are talking about right here.

    01:12 Now why is the cell doing this? Why is the cell making oxaloacetate? Why didn't it just reverse the reaction to go from pyurvate to phosphoenolpyurate? Well that was the big bang of glycolysis and that reaction is essentially irreversible.

    01:26 The cell is having to take a two step around that.

    01:30 The first step of which we just now covered.

    01:34 The first step using the enzyme pyruvate carboxylase happens in the mitochondrion.

    01:40 The first step happens in the mitochondria is physically isolated from the reactions that are ocurring in the cytoplasm.

    01:47 After that reaction occurs in the mitochondrion, the oxaloacetate that's produced is moved out to the cytoplasm.

    01:56 Now here is the reaction that you just saw.

    01:58 The pyruvate carboxylase is an enzyme that uses a co-enzyme.

    02:03 Now co-enzymes are important helpers for enzymes.

    02:08 And what they usually do is they have a specific function.

    02:11 This specific function of pyruvate carboxylase is to grab hold of a carbon and put it onto something and that's what's happening here.

    02:19 The 3-carbon-intermediate-pyruvate is becoming the 4-carbon-intermediate-oxaloacetate.

    02:23 Biotin is helping pyruvate carboxylase to do this.

    02:30 Now after that reaction of making oxaloacetate, the oxaloacetate, as I said, is moved out to the cytoplasm. And in the cytoplasm there is an enzyme called phosphoenolpyruvate carboxykinase, yeah mouth full of name.

    02:45 PEPCK is actually one of the enzymes that is regulated at the gene level.

    02:51 Meaning that most of our cells of our body won't make this enzyme.

    02:55 And if they don't make this enzyme, then they can't do the next step in gluconeogenesis. So we can see how gene regulation helps to control a metabolic pathway.

    03:07 Cells that's don't have PEPCK, as we call it, can't go through gluconeogenesis because they can't catalyzes reaction.

    03:14 But this enzyme is activated and made in liver and kidney cells where gluconeogenesis occurs.

    03:21 Well, let's look at the reaction. In the reaction, that is happening right here.

    03:25 This reaction converts oxaloacetate, OAA, into phosphoenolpyruvate.

    03:31 And notice that it's using the triphosphate known as GTP to make it all happen.

    03:37 The GTP has the same energy as ATP.

    03:41 So in essence in going from pyruvate back to PEP we had to use two triphosphates to make that happen. That big bang was pretty hard to overcome.

    03:54 We have just seen the two steps. The cells have to go through to go form pyruvate back to PEP.

    03:59 The next steps will actually be quite easy for students to learn and the reason is because they are simply the reversal of the reactions that were catalyzed in the glycolysis pathway.

    04:08 The very same enzymes run in the backwards direction go from PEP back to fructose-1,6-bisphosphate.

    04:16 That fructose-1,6-bisphosphate; however, there is a different enzyme that's used to make gluconeogenesis work and there is a very good reason for that.

    04:26 The next reaction of gluconeogenesis is catalyzed not as the reverse of the PFK reaction.

    04:31 The first reason of that is not done is because PFK is catalyzing a reaction that is energetically favorable in the direction of glycolysis and it's difficult to overcome that.

    04:42 So rather than have to go through a 2 step, the cells are simply bypassing, as we will see here.

    04:50 The second is that PFK is setup very well to regulate glycolysis but it's useful to have a different enzyme to regulate gluconeogenesis and we will see how that happens in just a little bit.

    05:01 So the enzyme that is used in gluconeogenesis instead of the enzyme that's used in glycolysis, the enzyme gluconeogenesis is called FBPase, as you see in the abbreviation, or its longer name is fructose-1,6-bisphosphatase.

    05:17 Now this reaction is not the reverse of the reaction in glycolysis.

    05:21 And the reason it's not is because in glycolysis the PKF enzyme required ATP to put the phosphate on.

    05:28 In the reverse reaction, all we are doing is clipping the phosphate off.

    05:32 We are not regenerating the ATP that was used in glycolysis.

    05:37 So the cell is actually cheating here again.

    05:38 The reason it's cheating, it's not completely reversing the reaction even though the intermediate fructose-6-phosphate is still generated.

    05:48 What the cell is doing is it's using that high energy of the phosphate on position 1 to drive this reaction and all it takes is water.

    05:59 To go from fructose-6-phosophate to the end of the gluconeogenesis pathway is now pretty easy.

    06:03 What happen is, first of all, the fructose-6-phosophate is converted back to the glucose-6-phosophate by a reversal of the glycolysis pathway as we saw before.

    06:13 That leads us to glucose-6-phosophate that needs to be converted into glucose.

    06:17 And here the cell uses the same trick it used in converting fructose-1,6-bisphosophate into fructose-6-phosophate.

    06:25 It uses a different enzyme.

    06:26 The enzyme here is called G6Pase or glucose-6-phosphatase.

    06:31 And the reaction that is catalyzing is simply the clipping off of the phosphate from position 1.

    06:38 Notice again this is not the reversal of the hexokinase pathway the cheating that the cell is doing is, it's not recreating the ATP that would be required for the reversal of the reaction.

    06:47 So the energy is realized by not regenerating that ATP.

    06:52 This reaction is another reaction that does not occur in the cytoplasm.

    06:56 This reaction occurs in the endoplasmic reticulum. So, again, we see some sequestration that's happening and we also sort of see why all those other reactions were occurring in the cytoplasm and that was because many of them were using the same enzymes as glycolysis.

    About the Lecture

    The lecture Gluconeogenesis: Reactions by Kevin Ahern, PhD is from the course Carbohydrate Metabolism.

    Included Quiz Questions

    1. It is a reaction that requires biotin.
    2. It is a reaction that uses GTP.
    3. It is a reaction that produces phosphoenolpyruvate (PEP).
    4. It is the backward reaction of pyruvate kinase.
    5. The reaction takes place in the cytoplasm.
    1. It is made in the heart.
    2. It requires a triphosphate in the reaction it catalyzes.
    3. It has one four-carbon substrate.
    4. It produces a gluconeogenesis intermediate.
    5. It undergoes regulation at the gene level.
    1. It catalyzes a reaction that involves phosphate release.
    2. It requires ATP for catalysis.
    3. It involves phosphorylation of glucose-6-phosphate.
    4. It simply reverses the PFK reaction.
    1. It is found in the endoplasmic reticulum.
    2. It uses a phosphate in the reaction it catalyzes.
    3. It produces glucose from fructose-6-phosphate directly.
    4. It is found in the mitochondrion.
    5. It is the reversal of the hexokinase reaction.

    Author of lecture Gluconeogenesis: Reactions

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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