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Is methylation required for serotonin production?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by jack blogs, Feb 26, 2017.

  1. jack blogs

    jack blogs

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    Can we make serotonin in other ways?
     
  2. echobravo

    echobravo Keep searching, the answer is out there

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    Digestive troubles might cause a reduction in available tryptophan, hence serotonin and other neurotransmitters too, according to a norwegian research team. The article "Functional food for functional disorders" iss found in Microbial Biology, Vol 48. An easy 1-page read. Links (childhood) antibiotics to fatigue (me/cfs), pain (fibromyalgia) and ibs (digestive troubles, ibs, low motility, dysbiosis).
     
  3. caledonia

    caledonia

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    If your body isn't messed up, you would eat food, digest it, methylate and make neurotransmitters. You can try repairing the various links in the chain if broken.

    Otherwise, you can take precursors to serotonin - tryptophan, 5htp or inositol.

    Or an SSRI, which doubles the amount of serotonin already present by blocking its reuptake.
     
  4. jack blogs

    jack blogs

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    But hypothetically - would tryptophan or 5htp even work if someone had 0 folate available to methylate with?
     
  5. alicec

    alicec Senior Member

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    What do you mean? Methylation reactions are not involved in synthesis of serotonin from tryptophan.
     
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  6. caledonia

    caledonia

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    The info I'm finding is that methylation is required for serotonin to be synthesized, and for the function of postsynaptic receptors. And that decarboxylation is the specific process by which 5htp is converted to serotonin. With a quick google search I'm not finding anything more specific than that.

    There is a drawing on this page of the conversion, but I'm not sure how methylation would fit into the picture.
    https://en.wikipedia.org/wiki/5-Hydroxytryptophan

    Anyway, assuming folate is a key player, there is a back up system for folate, which is methionine (from meat). So if a person had 0 folate, there could still be methionine to create methyl groups.

    If there was no methylation, a person couldn't create serotonin, however, such a person would quickly be dead.
     
  7. alicec

    alicec Senior Member

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    No, methylation is not involved.

    Serotonin is synthesised from tryptophan (Trp) in two steps.

    First Trp is converted to 5 - hydroxy-tryptophan (5HTP) by the enzyme tryptophan hydroxylase (TPH), then 5HTP is converted to serotonin (aka 5 hydroxy tryptamine, 5HT) by the enzyme aromatic L-amino acid decarboxylase (AADC or DCC).

    Here is an illustration of the pathway.

    The names of the enzymes describe their function. TPH is a hydroxylase, ie it adds a hydroxyl (OH) group to the substrate Trp. Here is info on this enzyme.

    It uses BH4 and non-haem iron as cofactors and is the rate-limiting step in the synthesis.

    AADC is a decarboxylase, ie it removes a carboxyl group (COOH) from the substrate 5-HTP. Here is info on this enzyme.

    It uses pyridoxal 5 phosphate as cofactor.

    Neither enzyme is a methyltransferase - neither reaction involves transfer of a methyl group (CH3).

    Neither enzyme uses folate as cofactor.

    Folate does scavenge peroxynitrile so has a BH4 sparing effect. Thus it could have an indirect effect on the first step.
     
    Last edited: Feb 27, 2017
  8. jack blogs

    jack blogs

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    I got that idea from this http://www.blueprintfitness.co.uk/serotonin-101-why-5-htp-does-not-work-for-you/


    "– 2. Conversion of 5-HTP into serotonin. The conversion of the precursor into the target neurotransmitter is done through a process called methylation. This crucial chemical reaction occurs all over the body and is particularly noticeable at the brain, liver, immune system plays a huge role in maintaining cardiovascular health. It requires an ongoing supply of B6, B12, folic acid and methyl donors (found in foods such as onions and garlic and in supplements like TMG, DMAE and SAMe). The conversion of 5-HTP to serotonin is also dependent on sufficient magnesium, a mineral that almost every Londoner I see is deficient in."
     
  9. Valentijn

    Valentijn The Diabolic Logic

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  10. alicec

    alicec Senior Member

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    Well that just goes to show you can't believe everything that circulates on the internet. That blogger doesn't understand basic biochemical pathways.

    5-HTP is converted to serotonin by a decarboxylation reaction, not a methylation. You just need to look at the chemical structures of 5-HTP and serotonin shown in the links I gave. The difference is that serotonin has had a carboxyl (COOH) group removed, it has not had a methyl group (CH3) added.

    You don't have to take my word for it - just google serotonin synthesis and you'll find any number of entries from various reputable sources.
     
    Last edited: Feb 28, 2017
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  11. jack blogs

    jack blogs

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    I believe you :woot:
    I was just asking the question

    I came to that link because I was googling "5htp cofactors"
    trying to understand what nutrition I would need in place to make sure 5htp converts to serotonin
     
  12. alicec

    alicec Senior Member

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    vit B6 in its active form is the cofactor for the decarboxylase enzyme..

    Then you need the things necessary to ensure B6 is converted to its active form. So B2 is necessary to convert pyridoxine (the form in supplements and vegetables) to pyridoxal, then you need the means to produce ATP to phosphorylate it (the active form is pyridoxal 5 phosphate), then you need magnesium to work with the ATP.

    Then you need the things necessary to ensure that B2 is converted to its active form, viz good thyroid function, the means to make ATP, some say molybdenum though I'm not so sure about that.

    In other words a network of nutritional factors.
     
    Last edited: Feb 28, 2017
  13. jack blogs

    jack blogs

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    Came across another source that claims folate is required for BH4 and serotonin production



    its at the start
     
  14. CCC

    CCC Senior Member

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    Which pretty well says that if your methylation is stuffed, then because this affects all those B vitamins, it could indirectly affect neurotransmitters.

    I know Yasko isn't the flavour of the month here, but I still like her diagram:
    http://www.dramyyasko.com/diagrams-listing/
     
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  15. alicec

    alicec Senior Member

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    He is referring to the role of the enzyme dihydrofolate reductase (DHFR) in regenerating BH4 from BH2, ie in reducing BH2 to its active co-factor form BH4. The active cofactor is in turn used by the enzyme tryptophan hydroxylase in the first step in serotonin synthesis, as I described above.

    Folate is not actually involved. Rather the enzyme acts on BH2 in a similar way to the way it acts on dihydrofolate. The enzyme act separately on two different substrates. This is possible because the basic structures of folate and biopterin are related and the enzyme can recognise both. This broad specificity is the reason the same enzyme can recognise folic acid, a substance not found in nature.

    As I also mentioned above, folate does affect BH4 indirectly since it acts as a peroxynitrile scavenger. The latter rapidly oxidises BH4, so folate can have a BH4 sparing effect.
     
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  16. alicec

    alicec Senior Member

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    There are some serious errors in that diagram and it doesn't show the role of the various B vitamins.
     
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  17. alicec

    alicec Senior Member

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    I didn't want to complicate my previous post but I thought later that I should point out that the situation with the aromatic amino acid hydroxylases (ie the three enzymes involved in the first steps of serotonin and dopamine biosynthesis) is more complex than my post and the video indicated.

    In these reactions, BH4 is converted to qBH2 (quinoid BH2), an isomeric form of BH2 which is not recognised by the DHFR enzyme which I discussed above.

    qBH2 is recycled to BH4 by a different enzyme, dihydropteridine reductase (DHPR).

    However qBH2 can spontaneously convert to BH2, in which case it is recycled to BH4 by DHFR.

    So the video has a bit of the story, but not all and doesn't understand how the DHFR enzyme works (thinking that folate is involved in BH4 regeneration).

    The most important enzyme for BH4 recycling needed for neurotransmitter synthesis is DHPR. DHFR does play a role but appears to be more important in ensuring the availability of BH4 for the NOS reaction.
     
  18. CCC

    CCC Senior Member

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    I've been away for a while, so I missed this. Sorry.

    Can you point us to a more accurate diagram that is simple enough for people to understand? I really would like something like this.
     
  19. alicec

    alicec Senior Member

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    I can't point you to a single diagram incorporating all the pathways in the Yasko diagram because the most serious error in the diagram is her artificial conflation of pathways.

    She claims connections that don't exist.

    She links the folate cycle (MTHFR in particular) with BH4 regeneration (DHPR in particular) and in turn links BH4 regeneration to the NOS reaction and then the NOS reaction to the urea cycle.

    These links DON'T EXIST. In addition, details within these pathways are incorrect.

    MTHFR does not run backwards and the enzyme plays no role in the regeneration of BH4.

    As explained in the post above, the aromatic amino acid hydroxylases which use BH4 as a cofactor in the synthesis of serotonin and dopamine, produce qBH2, NOT BH2 as Yasko claims. The enzyme DHPR recycles qBH2 to BH4.

    qBH2 can spontaneously convert to BH2 (they are isomeric forms of the substance). If this happens, DHFR recycles BH2 to BH4. (Perhaps this involvement of a folate cycle enzyme in BH4 regeneration is the source of the confusion for Yasko.)

    There is no linkage between recycling of BH4 by DHPR and the NOS reaction since BH4 is not changed by NOS - ie neither qBH2 or BH2 is generated by the enzyme.

    The NOS reaction generates nitric oxide and citrulline from arginine and oxygen, with electrons supplied by NADPH.

    I have no idea what she means by the arrows showing 2 BH4, 1 BH4 and 0 BH4 involved in forming NO, peroxynitrile and superoxide respectively by NOS. This simply does not happen.

    It is true that BH4 plays a critical role in keeping NOS bound to its substrate - ie coupled - and ensuring that NO is produced, rather than peroxynitrile and or superoxide, which happens if NOS is uncoupled from its substrate.

    It is the ratio of BH4 to BH2 which controls the coupling or uncoupling of NOS so anything that compromises the reduction state of BH4 - eg oxidative stress - can cause uncoupling of NOS and hence generation of peroxynitrile and/or superoxide instead of NO; these in turn can further oxidise BH4, creating a vicious cycle, but it has nothing to do with particular numbers of BH4 molecules.

    (There is an indirect link to the folate cycle here and again, perhaps this is the source of Yasko's confusion. If BH4 is oxidised to BH2 for any reason, the folate cycle enzyme DHFR will regenerate it. Also, methylfolate is a potent peroxynitrile scavenger so it can protect BH4 in the NOS reaction.)

    Finally she shows the NOS reaction running in reverse, and claims that this is part of the urea cycle which processes ammonia. From this egregious conflation she makes the startling claim that processing of ammonia uses up BH4.

    This is complete nonsense.

    NOS does not run in reverse and it has nothing to do with the urea cycle. Yes two reactants are held in common - viz arginine and citrulline but they react in a different sequence in different cellular compartments.

    I have uploaded a diagram of the folate cycle which is reasonably easy to follow and largely complete. It shows where various B vitamin cofactors fit in. Note it implies that vegetable folates are similar to DHF but this is not correct. Vegetable folates are mainly methylfolate and to a lesser extent folinic.

    Note that in the diagram folinic is 5 formylTHF.

    Here is a diagram showing synthesis and use of BH4 by the aromatic amino acid hydroxylases.

    Here is a diagram of the NOS reaction.

    I have uploaded a diagram of the urea cycle (note it shows the linkage to the Kreb's cycle).

    EDIT to add here is a better diagram of BH4 recycling and salvage which I couldn't find yesterday.
     

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    Last edited: Aug 16, 2017
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