Catabolism of Guanine & Hypoxanthine and Purine Nucleotide Salvage

by Kevin Ahern, PhD

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    00:00 The hypoxanthine, as I said, is an important intermediate in the salvage of purine nucleotides.

    00:07 We see the hypoxanthine that was produced from the breakdown of the adenine nucleotides and we see that it gets converted into xanthine by the enzyme xanthine oxydase. Xanthine oxydase is a very interesting enzyme that I’ll say something about in just a second but before I talk about that, I want to note that guanine is broken down into xanthine as well in a reaction catalyzed by guanase. So, xanthine, as we can see, is central to this overall process. A xanthine oxydase is an important enzyme from a medical perspective as we’ll talk about, and it’s an interesting enzyme in being able to work on a couple of different substrates. It’s acting on both hypoxanthine and it’s acting on xanthine. The final product of those 2 reactions being uric acid. Now, from my lectures on the metabolism of nitrogen in the urea cycle, you may recall that uric acid was one of the forms that some organisms use for excretion of extra nitrogens and humans have this reaction going on in them. We don’t use uric acid as the primary means of getting rid of nitrogen but we do produce uric acid as part of the breakdown of purine nucleotides. It can be excreted for example, in the feces. Well, uric acid turns out to have some important considerations medically because uric acid is not very soluble in water and the problem is if a person has too much uric acid what will happen is the uric acid will start to precipitate out of the water that makes us. So, what will happen then is that uric acid forms crystals, and the place for those crystals will typically form the lower parts of the body because they started to accumulate down there.

    01:55 The joints are very susceptible to crystals of uric acid and the nerves associated with those joints are very sensitive to that. The crystallization of uric acid causes the condition known as gout.

    02:09 Gout is a very painful disease or a very painful situation for a person to experience because the nerves are directly affected by that. Avoiding of foods that are high in purines is one traditional way to avoid the formation of uric acid but purines happen to be in a lot of things that we eat especially in a modern diet. So there must be treatments available to slow or reduce production of uric acid than there are. So, allopurinol that you can see on the bottom part of the screen is a molecule that’s very much like xanthine and hypoxanthine, and it interacts with the xanthine oxydase to inhibit the enzyme. It inhibits the production of uric acid. Well what happens in that case if we inhibit the production of uric acid is hypoxanthine and guanine are used to go back and make more purine nucleotides, instead of just completely breaking everything down the salvage pathway is enhanced. Now, one interesting side note about gout that I want to make and that’s shown on the lower part of the screen here, is that gout sufferers tend to have a lower incidence of multiple sclerosis. It’s not completely understood why that’s the case but there is some thinking that uric acid may have some protective effects acting as an anti-oxidant. We’ll let’s take a second to consider the structure of allopurinol in comparison to the molecules I’ve been talking about. I noted that allopurinol is very similar to xanthine and hypoxanthine, and you can see that in this figure here. Xanthine structure is on the left, allopurinol structure on the right. The difference between these is very subtle. You can see the repositioning of the double bond and the positioning of the nitrogen here and xanthine compared to allopurinol there. It’s no surprise therefore that allopurinol can bind to the active site of the xanthine oxydase enzyme. Allopurinol, as I said, forces salvage to occur and prevents the formation of uric acid, which is the way to simply completely break down the purine nucleotides.

    04:15 Well, that brings us to talking about how nucleotides were salvaged for the purines. So, if we consider the overall salvage, we could think of starting in a variety of ways. One way we could start would be to start with the base and then build an adenosine nucleotide from that. That occurs in this reaction here where adenine is combined with PRPP by the enzyme adenine phosphoribosyltransferase and that remakes AMP, splitting out a pyrophosphate in the process. Once we get AMP, we know, of course, it’s a trivial process to go from AMP to ADP by adenylate kinase and then from ADP to ATP using NDPK. If we have, on the other hand, guanine present, then we can do the same type of reaction using hypoxanthine/guanine phosphoribosyltransferase. That’s a mouthful of an enzyme, and that’s why people call this enzyme HGPRT. This enzyme turns out to be very interesting but suffice it to say that we see a parallel reaction going on here, a pyrophosphate being split out and one phosphate going on to the guanine to make GMP. GMP kinase, of course, catalyzes the addition of a phosphate to make GDP and NDPK catalyze the condition of the last phosphate to make GTP. The hypoxanthine, which was one of the breakdown product, can also be joined with PRPP by the same enzyme, HGPRT. The product of that reaction is a pyrophosphate and that branch molecule that we saw earlier, IMP, the branch molecule you recall can go in this direction of synthesis of AMP or in the direction of synthesis of GMP by the reactions that we’ve already seen. So hypoxanthine participating in the salvage allows the cell to go either direction to make either adenosine or guanosine nucleotides as appropriate. Now, this enzyme is very important from a medical perspective because the deficiency of this enzyme causes a syndrome known as the Lesch-Nyhan Syndrome. This is a very severe and very odd disorder. Absence of this enzyme causes people to have very severe neurological problems. One of which is they will literally eat their lips and their fingers if they’re allowed to and they have to be restrained.

    06:35 It’s a very difficult and disturbing syndrome.

    About the Lecture

    The lecture Catabolism of Guanine & Hypoxanthine and Purine Nucleotide Salvage by Kevin Ahern, PhD is from the course Purine and Pyrimidine Metabolism. It contains the following chapters:

    • Catabolism of Guanine and Hypoxanthie
    • Purine Nucleotide Salvage

    Included Quiz Questions

    1. ...allopurinol inhibits xanthine oxidase.
    2. ...xanthine oxidase catalyzes the conversion of guanine into xanthine.
    3. ...uric acid is formed directly from guanine.
    4. All of the answers are true.
    5. None of the answers are true.
    1. All of the answers are true.
    2. None of the answers are true.
    3. It is caused by crystals of uric acid.
    4. It is treated with allopurinol.
    5. It may be a problem with a purine-rich diet.
    1. It results in Lesch-Nyhan syndrome if HGPRT is absent.
    2. It includes only the purine bases.
    3. It requires ribose-5-phosphate as a source of ribose.
    4. All of the answers are true.
    5. None of the answers are true.

    Author of lecture Catabolism of Guanine & Hypoxanthine and Purine Nucleotide Salvage

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    By David D. on 01. October 2017 for Catabolism of Guanine & Hypoxanthine and Purine Nucleotide Salvage

    Fantastic lecture, just the amount of information I needed to cover and retain the topic.