The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Is there BH4 supplement/medicine?

Discussion in 'Genetic Testing and SNPs' started by tim0011, Mar 23, 2013.

  1. keenly

    keenly Senior Member

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    Received today
    Looks like nothing. Is this what 200mg really looks like?

    I wanted to split it, make it last 3 months, not going to be easy. I have ordered some ascorbic acid to mix with it. I will keep it in the fridge, as I am not going to have it for even 12 months.
     

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  2. Hip

    Hip Senior Member

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    For measuring out very small quantities of powder, I can recommend getting hold a weighting scale that measures down to just 1 mg (0.001 gram). You can buy these from as little as £15 from China on eBay. See here. The model I have is this one, which works well:

    Digital Weighing Scale: Measures Down to 0.001 Grams
    Scale 1 mg.png

     
    keenly likes this.
  3. keenly

    keenly Senior Member

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    Great. Thanks for that.

    I have also ordered the liquid BH4. Either needs to be mixed with ascorbic acid.
    http://atvb.ahajournals.org/content/atvbaha/26/11/2439.full.pdf

    'Ascorbic acid (Vitamin C) assists in BH4 stabilization primarily through antioxidant and other effects.76,77 Vitamin C also prevents formation of BH2 from the BH3 . radical by facilitating the recycling to BH4. 76 This may explain some of the benefits of ascorbate on endothelial function independent of superoxide scavenging'
     
  4. knackers323

    knackers323 Senior Member

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    hi @keenly did uou get any effect from the powder yet?

    did you order the powder and liquid from same place? thanks
     
  5. keenly

    keenly Senior Member

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    I only started using liquid today. About 1.5mg mixed in 200mg of Vit C powder.

    https://nootropicsource.com/shop/solutions/nootropic-solutions/tetrahydrobiopterin-solution/

    2 Bottles cam today. Solutions come with a 1 mL transfer pipette. The pipette is marked and has increments of 0.25, 0.5, 0.75, and 1. The compound’s label has the mg per mL for each solution. BH4 is 5mg/ml. Others ingredients are ethanol and deionized H2O. These need shaking.

    Dr Yasko presentation; BH4 NOS and Microglial Activation
     
    Last edited: Mar 2, 2017
  6. alicec

    alicec Senior Member

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    I'll be interested to hear how you go with the supplement also but Yasko is not a reliable source to understand how it might be exerting its effect.

    That diagram and Yasko's claims about BH4 are simply wrong. They are based on incorrect reading of research or on no evidence whatsoever and are contrary to every text book and scientific study on folate that I have looked at.

    The diagram claims that the MTHFR enzyme runs backwards and in the process regenerates BH4. An additional claim about this reaction, viz that the SNP rs1801131 (A1298C) affects this backwards reaction, is not shown on the diagram but is presumably in the video.

    There is no evidence whatsoever for the SNP claim while the claim for the reaction reversal is based on a single study which she misunderstood.

    This single study was published in 1980. It was an in vitro study (ie in a test tube, not in the body) which used qBH2 (closely related, but not BH2) and various other reactants under conditions which forced the MTHFR enzyme to run backwards. (The author was interested in the mechanism of action of the reaction).

    Under these conditions, qBH2 was converted to BH4. This reaction has never been shown to occur under physiological conditions in the body. If you consult any text book or scientific study on folate pathways you will find that, while some reactions are reversible, the MTHFR reaction is not.

    MTHFR and methylfolate play no role in the regeneration of BH4 used in neurotransmitter synthesis from tryptophan and tyrosine as shown in the diagram. And by the way there is another error here - in those reactions, BH4 is converted to qBH2, not BH2. The enzyme DHPR uses only qBH2 as substrate, not BH2. Methylfolate is not a cofactor.

    There is an indirect connection between methylfolate and BH4. Methylfolate is a peroxynitrile scavenger so it can have a BH4-sparing effect.

    The other incorrect claim about BH4 which Yasko makes and which I presume is covered in the video is that BH4 gets used up in processing ammonia in the NOS reaction (nitric oxide synthetase).

    BH4 has nothing to do with ammonia. I don't know where Yasko got this idea but I suspect she simply misread metabolic diagrams which show the NOS reaction (which uses BH4) and urea cycle (which uses ammonia) pathways side by side because they share arginine and citrulline as reactants. She somehow conflated the two independent pathways.

    NOS converts arginine to citrulline plus nitric oxide (NO). It uses BH4 as a cofactor (5 cofactors in total - a complicated enzyme). Ammonia has no part in this reaction.

    Ammonia is processed in the urea cycle. This is a more complicated cycle of interconversion which includes arginine and citrulline (though in a different sequence) along with other intermediates. Ammonia is incorporated into the cycle and the less toxic waste product urea is produced as a by-product.

    BH4 is not part of the urea cycle.
     
    Last edited: Mar 2, 2017
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  7. keenly

    keenly Senior Member

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    Personally I'd trust Dr Yasko over nearly anyone on the planet, but nobody knows everything. We are all still learning.

    Here's all the BH4 info you could want, anything contradict your statements? Or maybe confirms them?

    http://www.reactome.org/content/detail/1474151
     
  8. Valentijn

    Valentijn Senior Member

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    Why? Most of her claims are unsupported by any evidence, despite that she has had years to produce some. And many of her claims are directly contradicted by scientific research and basic biochemistry.
     
  9. keenly

    keenly Senior Member

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    Okay, and you are doing more to help autistic children are you? Great stuff.
     
  10. Valentijn

    Valentijn Senior Member

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    I'm not exploiting desperate populations by inventing bullshit to sell them supplements.
     
  11. keenly

    keenly Senior Member

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    WOW

    This confirms my suspicions about this forum.
     
  12. alicec

    alicec Senior Member

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    Yes my statements were confirmed, there was nothing to contradict them. Didn't find anything to support Yasko's version.

    Who you trust is entirely your prerogative and no-one expects her to know everything. Just some basic biochemical knowledge that has been available for a long time is all she would need to get the BH4 story straight. Since she is basing her supplement claims on just this basic biochemistry I don't think it unreasonable to expect her to get it right.
     
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  13. keenly

    keenly Senior Member

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    So please summarize your thoughts on BH4.
     
  14. alicec

    alicec Senior Member

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    In the earlier post I focused on the two aspects of BH4 metabolism that Yasko discusses and pointed out where she had it wrong. To make that even more simple -

    1) BH4 is a cofactor for the aromatic amino acid (phenylalanine, tyrosine, tryptophan) hydroxylases which are involved in neurotransmitter synthesis.

    In these reactions, BH4 is converted to qBH2 which is then regenerated to BH4 by the enzyme DHPR.

    MTHFR and methylfolate play no role in these reactions.

    2) BH4 is also a cofactor for the enzyme NOS which converts arginine to nitric oxide (NO) plus citrulline. Ammonia is not involved in this reaction.

    That is not the sum total of BH4 metabolism - there are several other aspects.

    3) In the NOS reaction, if BH4 is limiting, the enzyme becomes uncoupled from substrate and generates superoxide. This radical can react with NO and generate peroxynitrile which perpetuates the uncoupling by oxidising BH4 to BH2 and so limiting it further.

    This raises two additional considerations:-

    a) Methylfolate is a peroxynitrile scavenger so can have a BH4 sparing effect and rescue the NOS reaction.

    b) What determines BH4 availability?

    4) BH4 bioavailability is determined by a complex balance of enzymatic de novo synthesis and recycling, versus oxidative degradation within the cellular environment. The pathways are illustrated here.

    a) Three enzymes are involved in biosynthesis, the first of which, GTP cyclohydrolase 1 is rate limiting.

    b) When oxidative reactions in the cell convert BH4 to BH2, the enzyme dihydrofolate reductase (DHFR) is used to recycle it back to BH4. qBH2 (produced in the amino acid hydroxylase reactions ) can spontaneously convert to BH2. When this happens, DHFR rather than DHPR recycles it to BH4.

    5) BH4 is a cofactor for the enzyme glycerol ether monooxygenase which is involved in processing certain types of lipid into fatty acids.

    So in brief form these are the metabolic pathways involving BH4.

    The reactome site that you linked gives a good summary, shows the linkage of some of the metabolic pathways and gives references.

    From this summary the take away message is that enhancing BH4 in the cell might be achieved in several ways - viz
    by pharmacological supplementation, by enhancing the rate of de novo biosynthesis or by measures to reduce BH4 oxidation.

    The latter is an important consideration, particularly if direct supplementation of BH4 is contemplated, otherwise this could be counterproductive and lead to more NOS uncoupling.
     
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  15. keenly

    keenly Senior Member

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    Thanks for your input.
    This is indeed what I am interested in.

    It seems Vitamin C is important, but what else could we do? I have BH4 as pure power and liquid solution.
     
  16. knackers323

    knackers323 Senior Member

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    @keenly how has the trial gone?
     
  17. Jigsaw

    Jigsaw Senior Member

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    @keenly
    Ditto.

    Always felt a lot better on mega-dose vit C, now wondering if its role in BH4 may be part of that. Be very interested to hear how you're getting on with C supp, and at what dose. Also if you're using the BH4 supps, too, and if so, how those are working out for you.
     
  18. keenly

    keenly Senior Member

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    I only use low dose Vit C 500MG-1G.

    I am taking 2mg of BH4 2-3 times a week.

    It is hard to gauge the effects because I have been struggling for the last month now with breathing problems.
     
  19. Jigsaw

    Jigsaw Senior Member

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    @keenly
    Thanks for the update.

    Dose-dependent response, perhaps?

    I have no idea at all re: dosing BH4, but I think you're right in saying 500-1000mg vit C is a low dose of that.

    Therapeutic doses are much, much higher. Even 3g/d is considered a conservative maintenance dose by some.

    I'm sorry to hear you're having breathing problems. Have you found a way of getting on top of that?
     
  20. Jigsaw

    Jigsaw Senior Member

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    @Hip

    I have one very similar.

    Different brands of the same powders can weigh very differently, I have found.
     

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