Pyrimidine de novo Metabolism: ATCase Reaction

by Kevin Ahern, PhD

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    00:01 Okay. So that completes the synthesis in the de novo pathway of the purines.

    00:06 Now let's look at the de novo synthesis of the pyrimidines.

    00:09 You can see on the screen the schematic showing these -- the six reactions that one goes in making pyrimidines, starting with very simple precursors and ending up with the first of the pyrimidine nucleotides; UMP.

    00:22 Now, we're looking at it from this sort of zoomed out view that I described before to get an idea about how this is happening.

    00:28 We remember that the pyrimidine ring is made separately from the sugar and then later is attached. So we see that happening here.

    00:39 In fact we see the attachment of the ring in reaction number five.

    00:43 The pentose sugar appears for the first time at that point.

    00:46 And in reaction number six, we're making the UMP.

    00:50 Now, like the asynthesis of the purines, we don't need to go through every step to understand what's happening in this process.

    00:57 There are two reactions I wanna focus on so that you can understand better what's happening.

    01:01 And the most important of these is the very first one I'll talk about which is reaction number two.

    01:06 The reaction number two is catalyzed by an enzyme known as ATCase.

    01:11 And I've described this enzyme in other lectures in the series, but I wanna now focus on this with respect to balancing of nucleotides.

    01:18 ATCase catalyzes the following reaction: carbamoyl phosphate is converted into carbamoyl aspartate.

    01:25 And that happens by adding an aspirate to the first molecule carbamoyl phosphate.

    01:32 The enzyme catalyzing it of course is ATCase.

    01:36 Now, that is the second reaction in the process.

    01:39 There are a series of reactions that happen.

    01:42 Converting carbamoyl aspartate into one molecule into another molecule into another molecule, etc.

    01:48 There are six reactions to get to UMP.

    01:50 There's about 10 reactions to get down to the final product there which is CTP.

    01:55 Now, what's important here is CTP is what we call the end product of the pathway.

    02:01 CTP has an important function here.

    02:04 It inhibits the action of ATCase.

    02:08 This inhibition of an end product of a pathway inhibiting an enzyme early in the pathway is known as feedback inhibition.

    02:17 This feedback inhibition is important for controlling how many pyrimidines nucleotides are made.

    02:23 So, for example; if we have too much CTP, we don't want enzyme cranking out more pyrimidine nucleotides so then we make more.

    02:31 And we wasted energy, and it would be an imbalance.

    02:34 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.

    02:45 Well, that's not the only balance that's involved with this enzyme.

    02:48 This enzyme is involved in balancing.

    02:50 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.

    03:01 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.

    03:14 Because if we think about what happens with purines and pyrimidines in synthesizing a nucleic acid, we think of what? 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.

    03:30 We see that purines pair with pyrimidines.

    03:33 We should have approximately equal amounts of the two.

    03:35 We have too much of one versus the other, we get the mutation I talked about.

    03:39 Now, this ATCase placed a very important role then in determining if the balance is proper.

    03:45 So let's imagine for example we have a race that happens between CTP and ATP.

    03:51 The one that wins the race to the enzyme first affects the enzyme appropriately.

    03:57 So if we have more CTP than we have ATP, then CTP will more likely win the race and will get to the ATCase and turn it off.

    04:07 Turns off synthesis of pyrimidine nucleotides.

    04:11 Therefore the purines get a chance to catch up by their synthetic pathway.

    04:16 If ATP wins the race that means there's more purines than pyrimidine.

    04:21 It means that we wanna start making more pyrimidines, ATCase gets activated and the synthesis of purines -- of pyrimidines are continuous.

    04:30 So, ATCase provides that balance.

    04:33 Now, it'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.

    04:39 Aspartate is important in that overall scheme as well but not from a nucleotide perspective.

    04:45 Remember that aspartate is an amino acid.

    04:49 If the 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.

    05:00 And so if there's abundant aspartate, then that's an indication there's plenty of amino acids the cell can go forward.

    05:07 So, aspartate activates ATCase, and it tells the cell we've got plenty of amino acids, let's go forward with this.

    05:15 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.

    05:23 Balance is very important, 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 inhibit the ATCase enzyme and therefore stop the further synthesis of pyrimidine nucleotides.
    2. The higher concentrations of CTP inhibit the ATCase enzyme via a feedback mechanism and hence stop the further synthesis of purine nucleotides.
    3. The higher concentrations of CTP activate the ATCase enzyme, and hence synthesis of pyrimidine nucleotides is enhanced.
    4. The higher CTP concentrations activate the ATCase enzyme, and hence synthesis of purine nucleotides is enhanced.
    5. The higher CTP concentrations activate the ATCase enzyme, and hence synthesis of aspartate is enhanced.
    1. ATCase requires one aspartate to produce carbamoyl aspartate.
    2. ATC requires one asparagine to produce carbamoyl asparagine.
    3. It is activated by CTP and ATP.
    4. It is inhibited by abundant 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