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Do we really need folate that is methylated? Methylation cycle thoughts...

Discussion in 'Genetic Testing and SNPs' started by Kimsie, Nov 5, 2013.

  1. Kimsie

    Kimsie Senior Member

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    Here are some thoughts I have. If anyone can show me if and where they are either right or wrong, that would be great.

    Folate is recycled many times through the methylation cycle, so if you take methyl folate, each molecule only contributes one methyl group to the production of SAMe and then it has to be remethylated before it can be used for that purpose again. I think that the reason taking methyl folate helps has little to do with the fact that it is methylated. I have a theory to propose that I believe applies to other areas in the methylation cycle and could be very helpful.

    Theory: If the product of an enzyme is lower than needed in the body, then a higher amount of either the substrate (the thing the enzyme works upon, or one or more cofactors is needed. (I am using cofactors loosely to mean anything that the enzyme needs to do its job, even if the thing is a part of the enzyme, such as zinc is a part of methionine synthase).

    If this is the case then the advantage of taking 5mg of methylfolate for someone who has the MTHFR C677T gene mutation is that because the enzyme is weak, it needs more substrate to work upon, assuming that there are enough methyl groups in the pool to draw from, and folate is the substrate of MTHFR, so giving 5 mg of methylfolate gives a person a lot of folate. I don't see why it makes any difference if the folate is in the form of folinic acid, the form of folate usually found in food, or methylfolate. The tiny amount of methyl groups in 5 mg of methylfolate isn't going to be enough to methylate grams of homocysteine.

    Where does the pool of methyl groups come from? I have heard that it comes from stomach acid, so you may need to take swedish bitters or something to increase your stomach acid, but I am really not too knowledgeable here.

    So according to my theory if a person does not have enough SAMe, they need to look at their level of the substrate, homocysteine, and the levels of the cofactors of the methionine cycle. The cofactors here are: folate, zinc, B12, and in some cases perhaps the levels of their methyl pool in the form of stomach acid. I believe that when people take SAMe in large amounts and find that it helps their symptoms of depression or whatever, it is not the SAMe itself that is helping them, but the fact that if you take, say, 1000 mg of SAMe each day, you are adding one gram of the substrate of the methionine cycle. They could get the same effect by taking 1 gram of methionine each day for a lot less money. You may ask: Why would a person be low on this substrate? It could be because they have gut dysbiosis and they no longer are able to digest and absorb the methionine. Or they could have a higher need for SAMe for a variety of reasons, than they can get from their diet. If a person is low on the substrate, taking a large amount of the cofactors can sometimes draw more of the substrate into the cycle, but only temporarily. This is why sometimes taking methylfolate or B12 has a dramatic effect at first, but then stops working as well. If that is the case, you need to get more of the substrate, which for SAMe is methionine.

    What about people who are sensitive to methyl groups? Why are some people sensitive, and others not? I think this has something to do with COMT and niacin, especially niacin. I will use my son who has schizophrenia as an example. This relates to depression, also.

    I believe that often low SAMe levels are a result of histamine in the body. High histamine can be caused by allergies or by gut bacteria. My observation is that histamine depresses the levels of dopamine and norepinephrine because high histamine MUST be balanced with epinephrine and the dopamine and norepinephrine levels are drained to be made into epinephrine. High epinephrine also causes a feedback loop to lower the amount of the enzyme that produces dopamine leading to constant low dopamine and norepinephrine. The higher the histamine levels the lower the dopamine and norepinephrine, even enough to cause deep depression in the cases where a person does not have enough tyrosine. Taking tyrosine supplements will help a lot for the deep depression, but the levels of dopamine and norepinephrine will be somewhat low even with lots of tyrosine as long as the epinephrine levels are high because of the feedback loop. I am speaking from experience here. Normally epinephrine levels are high only very briefly, but stress or histamine can keep them high on a continual basis. Since histamine is degraded by SAMe, when the person raises SAMe levels the histamine levels will return to normal and the levels of dopamine and norepinephrine will rise.

    The COMT enzyme must have SAMe and niacin to work. When we take cofactors and substrates such as folate and B12 to help our methylation cycle we raise the level of SAMe. But even if a person does not have COMT mutations, they will not be able to get rid of dopamine and norepinephrine effectively if they don't have enough niacin. My son who has schizophrenia gets symptoms of overmethylation when he takes folate and B12. He has taken large amount of niacin in the past with no results, but I didn't know at that time that he probably has a mutation that makes it hard for him to absorb folate, so that was probably lowering his SAMe. He even tested low in folate at that time, but we thought that just supplementing the “normal” amount would be sufficient. In order for him to get rid of his excess dopamine (which is believed to be a great problem in schizophrenia) he has to have sufficient levels of both SAMe and niacin, at the same time. I think that what is commonly called overmethylation is really underniacinization; the person for some reason needs more niacin than other people to regulate their levels of catacholamines or they just don't have enough niacin. So with my son what we are trying to do is learn the correct amounts of all the supplements he needs to take to have enough SAMe and enough niacin to keep his dopamine levels in the correct range. It is too early to tell, but it seems to be helping him. You don't want to take huge amounts of niacin, because that will lower your SAMe levels too much because it is a methyl sponge.

    So for people who are called overmethylators, perhaps the answer is to take whatever amount of folate and B12 and perhaps methionine they need along with some niacin in whatever amount keeps the overmethylation symptoms away.

    If you try this I would sure like some feedback on how well it works and what amounts of different substrates and cofactors you find works for you.
     
    helen1 likes this.
  2. Critterina

    Critterina Senior Member

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    @Kimsie,
    I think you're doing the right thing testing your understanding by writing this. I'm only going to address a little because I need to get to sleep.
    I agree with you. You can sometimes increase the substrate to make a reaction go. There will be a rate-limiting substance, and if you increase it, you can make more of whatever you're trying to.

    Now here I disagree with you. If you have MTHFR C677T, you can not make methylfolate efficiently. If you take folinic acid, yes you have more substrate, so you may make some more, but the enzyme itself to make the conversion is defective, so more substrate is of limited use. If, instead, you take the methylfolate, it's in the form that can be used directly; the availability isn't slowed down by needing to be converted by a defective enzyme. If you have MTHFR A1298C, the conversion of folinic acid to methylfolate is fine; if you have MTHFR C677T it's not. And 5 mg of methylfolate isn't what I'd call a small amount, but "small" - that's all a matter of opinion.

    There's another step in getting the methylfolate to give it's methyl group to the homocysteine to make methionine. That's where the MTR and MTRR enzymes and methylB12 come in. The reaction uses up a methylfolate and a methylB12. MTR does the reaction. The common SNP in MTR is an "always on" condition, so it is more efficient at the reaction than "normal". The MTRR is what creates the methylB12 and the common SNP, the A66G is a down-regulation, so it's not as efficient. Therefore, if you supplement with methylfolate, you still may not be good at converting homocysteine to methionine because you're short of methylB12. If you have this mutation, you can supplement with hydroxyB12 or cyanoB12 and increase the substrate (sort of like taking folinic acid when you have MTHFR C677T) or you can go around the defective MTRR by taking methylB12.

    OK, that's all from me for tonight! If anyone sees holes in my thinking, please speak up. Maybe someone smarter or less sleepy than me can address your other paragraphs.

    Peace to you and your son.
     
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  3. Kimsie

    Kimsie Senior Member

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    More substrate is not of limited use. This is a chemical reaction, and increasing the substrate increases the product.

    "The rate of a chemical reaction is affected by the total number of enzymes as well as the concentration of substrates."

    If your MTHFR 677 gene is functioning at 60% (which is equal to the number of enzymes being less) then you probably need nearly twice as much folate (the substrate) to make the same amount of methylfolate, assuming that you have enough methyl groups in the available. If you have a double and you function at 10% then you probably need ten times as much folate and if you have a mutation that makes it hard to absorb folate then you need even more. Since the RDA for folate is set at 400mcg, then a person with a double would probably need at least 4 mg of folate a day, maybe more, to compensate.

    I think you got your information about how MTRR works from Amy Yasko; a lot of people do. What she says isn't exactly wrong if you read it carefully, but it gives people the wrong idea about what MTRR does. The MTR reaction does not use up a methyl B12, it used the B12 as a tranfer point for the methyl group. Methionine synthase (MTR) has a B12 molecule in it. The MTR takes the methyl group from methylfolate and puts it onto its molecule of b12, then it takes that methyl group and put it onto a molecule of homocysteine. After it does this 200 to 2000 times the B12 molecule in the molecule of methionine synthase gets changed to an inactive form, and MTRR changes that form back to the active form, giving a longer life to each molecule of methionine synthase. If you have the MTRR mutations, then your methionine synthase will have to be replaced more often, calling for more B12. Since each B12 molecule is used maybe 1000 times to transfer a methyl group, even if you didn't have any MTRR enzyme activity at all, the one methyl group attached to the molecule of B12 isn't going to be significant unless you have trouble making the first methylated molecule, and I don't know what enzyme does that. My observation of my son leads me to believe that a molecule of methionine synthase lasts a very short time at his rate of use - maybe 2 hours max, so many thousands of these methyl groups must be transferred every hour of the day. You must have to have tens or hundreds of thousands of reactions recycling methionine each day, at least, in which case 5 mg of methylfolate isn't going to contribute a significant number of methyl groups.

    I hope this helps!
     
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  4. Critterina

    Critterina Senior Member

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    I don't know who you're quoting, but as a former chemistry teacher and researcher in physical chemistry, I know that if the substrate is not the rate-limiting factor, increasing the substrate is not going to increase the rate of the reaction.

    I have never systematically read Yasko. Her explanations run into too many unsubstantiated claims, my questions are not answered, and I lose interest.

    is exactly the kind of explanation that I can't get my head around. What makes it work a number of times and then stop? How does MTRR "change it back"? Why would having an MTRR mutation make me replace the MTR more often? Sorry, but none of this makes sense.
     
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  5. Kimsie

    Kimsie Senior Member

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    That particular quote is from the University of Tennessee. http://www.tiem.utk.edu/~gross/bioed/webmodules/enzymes.htm

    Here is another one:
    "...Enzymes reaction rate is dependable on several factors: pH, temperature, and concentration of both the enzyme and substrate." http://en.wikibooks.org/wiki/Principles_of_Biochemistry/Enzymes

    My explanation about MTRR isn't very complete. There is a much better explanation here:
    http://en.wikipedia.org/wiki/Methionine_synthase
    There is a chart labeled Scavenger Pathway of Methionine Synthase Reductase to Recover Inactivated Methionine Synthase with an explanation next to it.

    Only a few sites on the web carry the correct information about MTRR, most sites have gotten their information either directly or indirectly from Amy Yasko, as I said before, what she says isn't really wrong, but people interpret it to mean something that isn't right. Here is a quote from her book "The function of methionine synthase reductase (MTRR) is to regenerate methyl B12 for methionine synthase to utilize" People take this to mean that MTRR remethylates B12 when she actually says that it regenerates B12, so this has gotten all over the internet. But here is a quote from the govenment site about MTRR: After a period of being turned on (active), methionine synthase turns off (becomes inactive). Methionine synthase reductase reactivates methionine synthase so the enzyme can continue to produce methionine.

    My ideas about how many times the reactions occur an hour are entirely out of my own head based on observing my son and may very well be completely wrong.

    I can tell that you must be like I am...I have to understand why things work the way they do.
     

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