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An often overlooked part of methylation cycle dysfunction

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by mgk, Dec 28, 2017.

  1. mgk

    mgk Senior Member

    As most of you know, the predominant approach when it comes to treating methylation issues is to support the pathway with methyl-B12, methylfolate, TMG, SAMe, and other methyl donors. However, there's one player that seems to be overlooked most of the time: the role of the GNMT enzyme. GNMT is responsible for getting rid of excess methyl groups, and it does so by using up glycine.

    The reason this is important in people with MTHFR mutations is that GNMT is strongly inhibited by methylfolate. So if there's a deficiency of methylfolate, GNMT will fail to be inhibited even if there aren't excessive methyl groups.

    What does this mean in practical terms? People with MTHFR mutations will probably run low in glycine, and if they eat lots of methionine or take extra methyl groups in the form of SAMe, not only are they not going to get much benefit from those methyl groups, they're also going to waste even more glycine in the process.

    So what can be done about this? It would seem like the best strategy is to take methylfolate, but there's a problem with that approach. A folate molecule is typically recycled through the MTHFR pathway thousands of times per day. After giving up its methyl group to homocysteine, the folate part of the methylfolate is going to be stuck at MTHFR again. You would need to take absurd amounts of methylfolate to make a difference in that sense. We want the methylfolate to hang around so that it can inhibit GNMT.

    Another approach is to look at what uses up methylfolate and reduce the demand on it. If we generate less homocysteine, we'll need less methylfolate to recycle it. 40-45% of methyl groups are used by the GAMT enzyme in synthesizing creatine. Another 40-45% are used by the PEMT enzyme in synthesizing phosphatidylcholine. By supplying more of these compounds through diet, we can theoretically cut the need for methyl groups by a huge amount and therefore keep methylfolate around so that it can do the important job of inhibiting GNMT.

    I first heard this idea of GNMT being a key player in methylation on Chris Masterjohn's podcast episode called Living with MTHFR. I scratched the surface with my summary above, but I think GNMT is the main point that differs from most other information that's available on methylation. If this seems interesting, I'd highly recommend listening to that episode because he goes into a lot more detail on how this all works.

    I should also mention that supplementing creatine and increasing choline intake are only parts of his advice. He has a short video summarizing the rest of his recommendations on Youtube:


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