Purine de novo Metabolism Regulation

by Kevin Ahern, PhD

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    00:00 Well, you've now seen how the adenosine and guanosine nucleotides were made but we haven't learned about how that balance that I said that was so important occurs. That will be the subject of what I'm talking about on this slide. Regulation, as I said, of the synthesis of all the nucleotides is important because if it's not balanced properly, mutation will result. So, along the way as I've described this, I've mentioned 4 different enzymes involved in catalyzing intermediates in purine synthesis and how they were important from a regulatory perspective.

    00:33 So let's look at those individually and the things that affect their activity. The first of those enzymes was PRPP synthetase that would catalyze the very first reaction and I said that that reaction or that enzyme catalyzing that reaction was really determining whether or not the entire pathway occurred. Because if you stop the first enzyme, none of the other reactions after that will occur. Well, this enzyme is actually inhibited by high concentrations of phosphate and ADP. Why is that important? Well, ADP in high concentrations indicates that the cell does not have a lot of energy. Why are cells making nucleotides? Well, they may be making nucleotides to divide, for example, and if a cell doesn't have enough energy, it should not be committing itself to a process of cell division. So having a low energy indicator stop this overall process is important. The second enzyme that is important from a regulatory perspective is with the one that catalyzes the very second reaction. This is PRPP amidotransferase, and the regulation here is really interesting. Now I'm going to show a schematic in a minute that will hopefully help to clarify this but suffice it to say that this enzyme is partly inhibited by AMP or GMP but it's fully inhibited by both when both are present. So one will slow it down, either one will slow it down but both are necessary to completely turn it off. The third enzyme is the one involved in the synthesis of making the guanosine nucleotides. That was the pathway that went upwards.

    02:17 This enzyme is inhibited by GMP, a product of the reaction that is the guanosine nucleotide inhibits the enzyme. Well, this makes sense. If you have too much guanine nucleotides, then you want to turn off that synthetic pathway, and you turn it off at the branchpoint. So the branch has been inhibited for a reaction by one of the products, in this case GMP. The enzyme catalyzing the reaction in the direction of the adenosine nucleotides, Adenylosuccinate synthetase, is inhibited by, you could probably guess it, the end product here, AMP. Now, so we start to see that there's important balance that's happening between the relative amounts of the guanine nucleotides and the adenine nucleotides. Now, let's go back and step back out and look at that pathway from the perspective I gave you originally and see how this plays out.

    03:13 The PRPP amidotransferase, I said, was fully inhibited by AMP and GMP but it was only partially inhibited by either one. Why is that important? Well, if the cell has abundant AMP and GMP, there's no reason to run this pathway. So if they're both present in high quantities, they will shut off the enzyme but let's imagine the cell has a lot of AMP but not a lot of GMP. That wouldn't make sense to completely turn the enzyme off because the cell would have no way of making GMP.

    03:49 So if that's the case, then you want to leave the enzyme at least partly active and you want to shut off synthesis of the AMP but not the GMP side. Right? So, we have a lot of AMP. We shut off this pathway on the left because that pathway on the left is fully inhibited by AMP and if there's no GMP, the other side will not be inhibited. Only when the other side has plenty of GMP will the other side of the pathway be inhibited. Similarly, if we had a lot of GMP and very little AMP, then the left pathway will be favored and the right pathway would be inhibited. So, we see this intricate system of regulation is designed at balancing the amounts of AMP and GMP very, very carefully.

    About the Lecture

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

    Included Quiz Questions

    1. Both of the enzymes acting on IMP are feedback inhibited.
    2. PRPP amidotransferase is fully inhibited by either AMP or GMP.
    3. Low phosphate and AMP will inhibit the first enzyme of the pathway.
    4. ATP inhibits Adenylosuccinate synthetase.
    5. IMP dehydrogenase is inhibited by GMP.
    1. Nucleoside diphosphate kinase
    2. PRPP synthetase
    3. PRPP amidotransferase
    4. IMP dehydrogenase
    5. Adenylosuccinate synthetase
    1. Nucleoside diphosphate kinase — inhibited by an excess of ribose-5-phosphate.
    2. PRPP synthetase — inhibited by high levels of phosphate and ADP.
    3. PRPP amidotransferase — partly inhibited by AMP or GMP, but fully inhibited by both AMP and GMP.
    4. IMP dehydrogenase — inhibited by GMP to stop GTP synthesis.
    5. Adenylosuccinate synthetase — inhibited by AMP to stop ATP synthesis.

    Author of lecture Purine de novo Metabolism Regulation

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    By Ajit P. on 29. July 2020 for Purine de novo Metabolism Regulation

    beautifuly explained. thankyou!! Every point in every step was explained nicely.

    Clear and to the point
    By nasan A. on 28. March 2019 for Purine de novo Metabolism Regulation

    I loved how I understood the bigger picture in the end of the lecture