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BH4 needed for ammonia detox???

Discussion in 'General Treatment' started by wkl01, Jan 30, 2013.

  1. wkl01

    wkl01

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    I've got a question: if I understand correct, according to Yasko BH4 is needed to detox ammonia through the urea cycle.

    I don't understand this. Ornithine joins with Carbamoyl phosphate (which is formed from ammonia and other things) to form citrulline but this doesn't use BH4. NO synthase needs BH4 to form (also) citrulline, but that doesn't use ammonia.

    Can anyone help me clarify this?

    Wim
     
  2. Lotus97

    Lotus97 Senior Member

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  3. aaron_c

    aaron_c Senior Member

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    I'm new to this whole biochemistry thing, but looking at Yasko's diagram of the "methylation cycle" and double checking with wikipedia, I'm fairly sure I'm right: She seems to show two pathways in which ammonia could be detoxified. One is the one you have described that goes through ornithine. The other uses Nitric Oxide Synthase, which needs 5 cofactors, among them bh4.

    I've personally experienced this link: I have CBS++, and (thus?) B6 is a double-edged sword. In that past, taking a strong dose (100 mg) would have me feeling great for about a day, three at most, after which I would become extremely depressed for as long as I took the B6. I recently started taking it again, but about 15 mg / day, in doses of 2.5 mg at a time (to avoid diarrhea) Prior to starting the b6, I had stabilized the BH4 dose I needed at about .75 mg / day. More than this gave me a headache. Having started the B6 (plus 1g vitamin c with each B6 dose to recycle BH4) I still have to take about 25 mg of BH4/day--way way higher.

    My question is, is there some way yall know to support the urea cycle so ammonia is detoxed through ornithine, because the b6 is so helpful, but the BH4 is so expensive!

    as a side note, I started a separate discussion about B6 crashes at http://forums.phoenixrising.me/index.php?threads/b6-side-effects-get-better-then-worse.26908/

    Thanks everyone so much.
     
  4. caledonia

    caledonia

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    Molybdenum helps detoxify ammonia via SUOX.
     
    katim likes this.
  5. aaron_c

    aaron_c Senior Member

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    Thanks Caledonia, but could you source that? I have only ever seen molybdenum through SUOX as converting sulfites to sulfates. Here is what wikipedia says about suox (sulfite oxidase)

    Sulfite oxidase (EC 1.8.3.1) is an enzyme in the mitochondria of all eukaryotes. It oxidizes sulfite to sulfate and, via cytochrome c, transfers the electrons produced to the electron transport chain, allowing generation of ATP in oxidative phosphorylation.[1][2][3] This is the last step in the metabolism of sulfur-containing compounds and the sulfate is excreted.

    Of course both sulfites and ammonia would be produced in excess by a CBS upregulation, and thus both would need to be dealt with...

    Nice resource list, by the way.
     
  6. wkl01

    wkl01

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    Hi Calebtrask,
    NO synthase needs BH4 in order to create NO out of arginine (and without BH4 superoxide is created instead), but I cannot see how it should use up (detoxify) ammonia.
    The urea cycle however does use up ammonia, but doesn't need BH4.

    So, I don't understand why Yasko says (if I understand correct) that NO synthase needs BH4 and detoxifies ammonia.
     
  7. aaron_c

    aaron_c Senior Member

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    Thanks wkl01

    So I just had a lot of fun researching your question. I agree, everyone seems to say it helps detoxify ammonia, but no one says how. What I thought I saw on the yasko diagram was that it did so through NOS, but from what I now read, BH4 isn't used up in this process, it's just a necessary part of it. Moreover, as you pointed out, turning arginine to Citrulline plus NO doesn't help get ammonia out of the body. Wikipedia seems to say that the reaction could go either way, so maybe with excess ammonia we would get excess citrulline, and maybe in this case NOS would make arginine, which would then split the urea off to become ornithine, thus detoxing ammonia? And maybe this would use up BH4? I can't seem to find any research on this (I assume because everyone is interested in NO's vasodilatory effects, so why would one want less of it?)

    Ah well,

    *BUMP*
     
  8. wkl01

    wkl01

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    I hope you do find your answers. I'm still digging.
    In my case, I think it all starts with probably an infection, causing oxidative stress, causing low BH4, low methylation and high adenosine. At this moment I think dr. Jill James (just google it) has the right answer for me.
    Good luck to you.
     
  9. nandixon

    nandixon Senior Member

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    The Urea Cycle and the Nitric Oxide Cycle are interconnected by arginine as follows: Citrulline, made from ammonia (and ornithine), is recycled to arginine in the Urea Cycle. That arginine can then enter the Nitric Oxide Cycle where it is converted to nitric oxide by nitric oxide synthase using tetrahydrobiopterin (BH4). (Note that citrulline is also generated during the formation of nitric oxide from arginine.)

    Here's a diagram (from http://examine.com/supplements/Ornithine/):[​IMG]
     
  10. aaron_c

    aaron_c Senior Member

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    Thanks Nandixon,

    Ya, this is what we've been talking about. But here is a link to a study claiming that "These combined results exclude H4B as a stoichiometric reactant," meaning that in it's presence, NOS is more active in producing NO, but that it doesn't seem to be part of the actual reaction by, for example, donating electrons. (They call it H4B, but earlier they clarify that as tetrahydrobiopterin.) This abstract further (?) clarifies the meaning by saying that BH4 is not "consumed during the catalysis process."

    So either those studies are wrong (totally possible), or we need another mechanism for how ammonia eats up BH4. As I said above, I seem to experience a highly increased capacity for BH4 supplementation when I do things that should be raising my ammonia, so I'm not saying there isn't a mechanism by which BH4 detoxes ammonia.... But maybe we don't know what it is yet? Or do you see something in that diagram that I'm not getting?

    Cheers

    Edit: OK, now that I look at why they exclude BH4 as a reactant, I see that it is because for every 1 mol of BH4 it produces more that 15 mol of product. Maybe the second article draws the wrong conclusion from the first one. So maybe I was wrong, and NOS does use up BH4. But I still think that for NOS to help detox ammonia, it would need to turn NO and Cutrulline into Arginine, rather than visa versa. Turning Arginine into Citrulline and NO would be a lot of effort to bring ammonia to the wrong side of the urea cycle.
     
    Last edited: Dec 10, 2013
  11. nandixon

    nandixon Senior Member

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    Actually, I think you might be right about BH4 not actually being consumed.

    I'm pretty sure that what I wrote is what Yasko is thinking when she talks about the consumption of BH4 by ammonia. I don't see any other possibilities. But then, I'm a former organic chemist and not a biochemist.

    Having said that, though, what you've presented seems to be verified by a more recent article here:

    Recoupling the Cardiac Nitric Oxide Synthases: Tetrahydrobiopterin Synthesis and Recycling
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3406312/

    So Yasko seems to be wrong.
     
    Last edited: Dec 10, 2013
  12. aaron_c

    aaron_c Senior Member

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    So I have recently been traveling, and I have a theory about BH4 that I'm excited about. First, the story:

    I live in Portland OR. When I first started taking it, I could only take about...maybe 1-2.5 mg BH4 per day, at which point I would get a headache. Then I started taking B6 (I had been taking a lot of things, but on purpose, no B6). To avoid what can become a fairly serious depression as well as diarrhea, I need to take about 2 parts BH4 to 1 part B6. For the past month or so I have been taking 8 mg B6 and 16 mg BH4, divided into four doses daily.

    Then I went to Denver, CO. Suddenly, no matter that I was still taking the B6, I could not take BH4 without getting a headache. Also, I began getting diarrhea. When I first started the B6, I got diarrhea, which I fixed by taking one sixth of the dose (15 mg) six times a day. I have CBS C699T+/+, so I assume that B6 will end up creating a fair bit of ammonia and sulfites for me. The sulfites seem to be dealt with via molybdenum, so my assumption is that the diarrhea came from excess ammonia, particularly as the BH4 plus the divided dose of B6 seemed to prevent that.

    The final piece of the picture is my history with colorado: In the past eight years, I have lived in both oregon and colorado, and I have traveled (mostly from oregon to colorado) at least once, if not multiple times in a year. Each time I travel from oregon to colorado, a few changes to my health are to be expected: First, a mild depression that I associate with wet weather lifts. Second, my sleep gets worse. Third, I have periodic diarrhea.

    Based on this, I theorize that BH4, while necessary to the function of NOS when converting arginine to citrulline + NO, does not use BH4. This seems to be what all the studies agree on. I would continue to theorize that when converting citrulline + NO to arginine, it does use BH4. I suspect Yasko has seen some sort of study indicating this that we haven't found. Finally, I theorize that a difference in humidity, and possibly air pressure, change the body's need for NO, causing--in my case--NOS to switch what reaction it catalyzes based on climate.

    This would potentially explain why some people, in spite of getting enough vitamin D (I had a friend like this) always feel a little depressed in wetter climates.

    Has anyone had similar experiences? Nandixon, does your expertise cover this? Is it possible for an enzyme to use a cofactor when moving a reaction in one direction, but not in another?
     

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