Pyrimidine de novo Metabolism: ATCase Reaction

by Kevin Ahern, PhD

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    00:00 Okay, so that completes the synthesis in the de novo pathway of the purines. Now, let’s look at the de novo synthesis of the pyrimidines. You can see on the screen the schematic showing the 6 reactions that one goes in making pyrimidines, starting with very simple precursors and ending up with the first of the pyrimidine nucleotides UMP. Now, we’re looking at it from this sort of zoomed out view that I’ve described before to get an idea about how this is happening.

    00:45 We remember that the pyrimidine ring is made separately from the sugar and then later is attached.

    00:53 So, we see that happening here. In fact, we see the attachment of the ring in reaction number 5. The pentose sugar appears for the first time at that point, and in reaction number 6, we're making the UMP. Now, like the synthesis of the purines, we don’t need to go through every step to understand what’s happening in this process. There were 2 reactions I want to focus on, so that you can understand better what’s happening, and the most important of these is the very first one I’ll talk about, which is reaction number 2. The reaction number 2 is catalyzed by an enzyme known as ATCase, and I’ve described this enzyme in other lectures in this series but I want to now focus on this with respect to balancing of nucleotides. ATCase catalyzes the following reaction. Carbamoyl phosphate is converted into carbamoyl aspartate and that happens by adding an aspartate to the first molecule, carbamoyl phosphate. The enzyme catalyzing it of course, is ATCase. Now, that is the second reaction in the process. There are a series of reactions that happen. Converting carbamoyl aspartate into 1 molecule into another molecule and to another molecule, etc. There are 6 reactions to get to UMP. There’s about 10 reactions to get down to the final product there, which is CTP. Now, what’s important here is CTP is what we call the end-product of the pathway. CTP has an important function here. It inhibits the action of ATCase. This inhibition of an end-product of a pathway, inhibiting an enzyme early in the pathway is known as feedback inhibition. This feedback inhibition is important for controlling how many pyrimidine nucleotides are made. So, for example, if we have too much CTP, we don’t want the enzyme cranking out more pyrimidine nucleotides, so that we make more, be a waste of energy, and it would be an imbalance. So, by having CTP feedback and inhibit the enzyme, we see one control that is helping the cell to balance the appropriate amount of pyrimidine nucleotides to make. Well that’s not the only balance that’s involved with this enzyme. This enzyme is involved in balancing not only the amount of pyrimidine nucleotides that are made but also the relative amount of pyrimidine versus purine nucleotides and that’s done by this.

    03:18 ATP is a purine, so ATP’s ability to activate ATCase, as you see here, is essential for being able to balance the relative amounts of purines and pyrimidines because if we think about what happens with purines and pyrimidines in synthesizing a nucleic acid, we think of well A pairs with T and G pairs with C. Well, A is a purine, T is a pyrimidine, G is a purine, and C is a pyrimidine. We see that purines pair with pyrimidines. We should have approximately equal amounts of the two. If we have too much of one versus the other, we get the mutation I talked about. Now, this ATCase plays a very important role then in determining if the balance is proper. So let’s imagine, for example, we have a race that happens between CTP and ATP. The one that wins the race to the enzyme first affects the enzyme appropriately. So, if we have more CTP than we have ATP, then CTP will more likely win the race, it will get to the ATCase and turn it off. It turns off synthesis of pyrimidine nucleotides. Therefore, the purines get a chance to catch up by their synthetic pathway. If ATP wins the race, that means there is more purines than pyrimidines, it means that we want to start making more pyrimidines, ATCase gets activated, and the synthesis of pyrimidines continues. So, ATCase provides that balance. That's the third thing that helps the balance and it doesn’t have anything to do with nucleotides and it’s aspartate that we can see right here. Aspartate is important in that overall scheme as well but not from a nucleotide perspective. Remember that aspartate is an amino acid. If nucleotides are being made for cell division, then the cell has to have all of its materials in order. It has to have all the things that it needs and so if there’s abundant aspartate, then that’s an indication there’s plenty of amino acids the cell can go forward. So, aspartate activates ATCase and it tells the cell "We’ve got plenty of amino acids, let’s go forward with this" and if there’s not enough aspartate, then that will not be activated by that and the enzyme will be less likely to make the pyrimidine nucleotides. Balance is very important to pyrimidines and purines.

    About the Lecture

    The lecture Pyrimidine de novo Metabolism: ATCase Reaction by Kevin Ahern, PhD is from the course Purine and Pyrimidine Metabolism.

    Included Quiz Questions

    1. ATCase
    2. PRPP synthetase.
    3. PRPP amidotransferase
    4. IMP dehydrogenase
    5. Adenylosuccinate synthetase
    1. ATP and aspartate
    2. CTP and aspartate
    3. GTP and aspartate
    4. UTP and aspartate
    5. TTP and aspartate
    1. The higher concentrations of CTP inhibits the ATCase enzyme via feedback mechanism and hence stops further synthesis of pyrimidine nucleotides
    2. The higher concentrations of CTP inhibits the ATCase enzyme via feedback mechanism, and hence stops further synthesis of purine nucleotides
    3. The higher concentrations of CTP activates the ATCase enzyme, and hence synthesis of pyrimidine nucleotides gets enhanced
    4. The higher concentrations of CTP activates the ATCase enzyme, and hence synthesis of purine nucleotides gets enhanced
    5. The higher concentrations of CTP activates the ATCase enzyme, and hence synthesis of aspartate gets enhanced
    1. None of the answers are true
    2. All of the answers are true
    3. It is activated by CTP and ATP
    4. It is inhibited by aspartate
    5. It is inhibited by ATP

    Author of lecture Pyrimidine de novo Metabolism: ATCase Reaction

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    By Orel G. on 24. June 2017 for Pyrimidine de novo Metabolism: ATCase Reaction

    It was very clear and explained well- the subject itself is usually hard to explain