Pyrimidine de novo Metabolism: OMP Decarboxylase and Synthesis of UTP & CTP

by Kevin Ahern, PhD

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    00:00 Now, the second reaction I want to talk about in pyrimidine synthesis is the last one here. This is the conversion of the first pyrimidine intermediate called OMP, which is a very minor intermediate.

    00:15 It doesn’t really matter for our purposes. What matters is that we are making UMP. Now, this reaction you can see here was number 6 and it’s catalyzed by the enzyme OMP decarboxylase.

    00:27 This enzyme is a fascinating enzyme. We can see that the reaction isn’t that exciting of a reaction to see. What’s happening is that there’s a carboxyl on the right side of the ring that’s disappearing as we go over to the UMP. That’s a decarboxylation that’s happening and we’re losing a carboxyl group. So it’s not an exciting reaction but this enzyme is one of the most efficient enzymes known, okay. Now, we measure efficiency of an enzyme by how fast the reaction is catalyzed compared to how fast that reaction occurs if it’s uncatalyzed. So if we look at this reaction of OMP going to UMP without the enzyme, the half-life, meaning the time it would take for half of these molecules to react in this way, is about 38 million years. Well, we can’t exactly wait that long for a cell to get the nucleotides that it needs. In the presence of this enzyme, the reaction occurs in less than seconds. That’s a speed enhancement of over 10 to the 17th over the uncatalyzed reaction, and 10 of the 17th is 100 quadrillion times faster. Enzymes are magical.

    01:36 Enzymes do amazing things and this is one of the best examples we can see of what an enzyme actually does. The other remarkable thing about this enzyme is it doesn’t have any co-factors or coenzymes that it does. This reaction happens as a result of the evolution of this enzyme to this efficiency; an absolutely remarkable process. Well, I got a little ahead of myself in talking about CTP earlier. I had to do that to show you the ATCase regulation, but I didn’t show you how CTP was made. That’s what I want to show you here. Remember that UMP was the first of the pyrimidine nucleotides that appears in a nucleic acid that’s made in that synthetic pathway. UMP gets converted into UDP in a process that involves energy from ATP and that reaction is catalyzed by an enzyme known as UMP/CMP kinase. The names suggest that the enzyme works on both UMP and CMP, and it does work on both of those nucleotides. We find that in the pyrimidine synthesis there are commonly enzymes that interchange between working on uridine nucleotides or cytidine nucleotides, and this is a very good example. We remember that going from a diphosphate to a triphosphate always involves the same enzyme, and I hope you remember that that enzyme is NDPK and we see that enzyme involved here, and in the next step in the process, we see UTP being converted to CTP. This is a reaction that involves a transamination, right? We have glutamine that’s donating an amine group and becoming glutamate, and the process UTP is being converted into CTP. This reaction also requires energy, and the energy comes from ATP.

    03:19 This enzyme that catalyzes the reaction is known as CTP synthetase and we can actually see what’s happening in the process here. UTP is shown in the upper right part of the screen and CTP is shown in the lower right. The difference between those 2 molecules is an amine group and we see the oxygen starting out with the UTP and the amine appearing on the CTP. That’s the transamination reaction that’s being catalyzed. Now, CTP synthetase accomplishes this goal that it does in the way that you see on the screen here. There’s actually 3 steps in the process starting on the left with the UTP and ending up on the right with the CTP. The first step in the process involves a phosphorylation of that oxygen that’s on the top of the UTP. We can see that intermediate on as the second molecule there with a phosphate attached. In the second step of the process, an amine coming from the glutamine is attached at the second position on that ring as you can see here. In the last step of the process, the phosphate is cleaved off and released and the amine remains behind. Now, the enzyme CTP synthetase is inhibited by a couple of mechanisms. One is it’s inhibited by phosphorylation. That’s a covalent modification that happens on the enzyme and it actually occurs at 2 different places on the enzyme. In addition to the covalent modification, the CTP synthetase can be activated by GTP. Now, that should tell you something. What is GTP? GTP is a purine and CTP is a pyrimidine, so we see a purine activating synthesis of a pyrimidine and moreover in a nucleic acid, G pairs with C. So, if we have more GTP, then we want to turn this enzyme on to make more CTP, and if we have more CTP, we want to turn the enzyme off, so that we don’t make too much. The balance between purines and pyrimidines carries through all of these pathways that I’m talking about.

    About the Lecture

    The lecture Pyrimidine de novo Metabolism: OMP Decarboxylase and Synthesis of UTP & CTP by Kevin Ahern, PhD is from the course Purine and Pyrimidine Metabolism.

    Included Quiz Questions

    1. The second step is catalyzed by a regulatory enzyme.
    2. Aspartate and bicarbonate are the starting materials.
    3. CMP is the first pyrimidine made.
    4. The ring/pyrimidine base is synthesized after the attachment to a ribose-phosphate.
    5. UMP is the first pyrimidine synthesized.
    1. All of the answers are true.
    2. Two sequential reactions are required.
    3. Two kinases are involved.
    4. Two ATPs are required.
    5. No regulation occurs.
    1. A transamination occurs.
    2. Two ATPs are required.
    3. No regulation occurs.
    4. It is an energy-producing reaction.
    5. It is catalyzed by CTP synthetase.
    1. The OMP decarboxylase enzyme needs ATP as a co-factor to regulate the synthesis of pyrimidines.
    2. Orotidine monophosphate is the first pyrimidine intermediate metabolite that appears during the de novo synthesis of pyrimidines.
    3. The OMP decarboxylase enzyme fastens up the conversion of OMP to UMP 100 quadrillion times faster than an uncatalyzed reaction.
    4. The conversion of UTP to CTP involves a transamination reaction catalyzed by the CTP synthetase enzyme.
    5. The CTP synthetase enzyme is activated by GTP, whereas the CTP inhibits it to maintain the purine to pyrimidine balance in a cell.

    Author of lecture Pyrimidine de novo Metabolism: OMP Decarboxylase and Synthesis of UTP & CTP

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    By KARMELIA S. on 06. September 2020 for Pyrimidine de novo Metabolism: OMP Decarboxylase and Synthesis of UTP & CTP

    First of all, I like the depth of this lecture and Professor Ahern is clearly very knowledgeable and concise on the the topic being discussed. And I also like due to the fact that this video is clearly a high-yield resource which is very helpful for my upcoming medical exam. However, I believe that this could have been better had the previous cycles preceding the formation of OMP explained as well in order for us the students to be able to get the essence of the information better. That's all I have got to say