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SHMT and Related Pathways

Discussion in 'Genetic Testing and SNPs' started by LaurieL, Jul 4, 2013.

  1. LaurieL

    LaurieL Senior Member

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    I honestly do not have any idea of where to start with this. I have so much info and have done so many things with my studies here, its difficult for me to go back to the beginning. I began looking at this SNP as there really is very little information about it. I have also been mucking around with arginine lately, as recommended by my toxicologist years ago. Back then I did not have methylation in place, and I certainly didn't have any reaction to it like I do now. I have read posts here mentioning arginine, and the reactivation of viruses, but honestly, I haven't had that. In fact, I have had some startling reactions in my cognitive function, energy, and .....my skin. Yeah, I know....weird. At least I thought so until I started looking at SHMT more closely. So forgive me, I will just jump in and take the plunge.

    Please, by no means, if you do not have this SNP, there are other implications when this pathway is strained despite mutation or not. If you do have this mutation, it is a down regulation of its function and besides the MTHFR mutation, will also lead to insufficient THF. A situation in which this pathway may be strained is glycine based detoxification, upregulated to exposure, in which places a strain on the serine hydroxymethyltransferase enzyme pathway. It is this pathway that is mainly responsible for glycine biosynthesis. It is also this pathway that leads to pyruvate, so again, bear with me through all this information.

    As a side note, you ever wonder why Dr. Yasko puts SHMT first of the first priority mutations? I did, but couldn't find her reasoning, at least not specific enough for me. I now have my own, and I offer to you all in the hopes it will help someone else.

    Her definition goes like this....SHMT shifts methylation away from the long and short routes and goes into a side reaction that leads to thymidine production. The thiamine discussion taking place right now pertains also to this enzyme pathway. The long and short routes are those of the folate pathway.

    There are two isoforms of SHMT, 1) cSHMT, and 2) mSHMT. cSHMT is found in the cytosol, of which the 1420CC genotype can equate to higher Hcy levels and significantly lower RBC and plasma folate levels. Imagine combining this one with a MTHFR mutation? The CT genotype is associated with a shift in the distribution of folate derivatives. Specifically what shift has yet to be elucidated to me. mSHMT is found in the mitochondria.

    Onwards...

    SHMT is a member of the PLP or P5P (B6) enzyme class. P5P is needed by both mSHMT and cSHMT at all times to activate this enzyme. Upregulation would then lead to low levels of B6 for the many other umpteen reactions in the body, and could also be considered a contributor to low levels being found in some. I think this enzyme would be first priority because of its function, so diversion of cofactors would keep this running, eventually lower levels of cofactors ensue, and the SHMT will become strained amongst others. A downregulation mutation leading to some significant problems.

    Its functions more specifically....SHMT uses serine to synthesize glycine. P5P is a cofactor in certain enzymes that deal with transamination reactions required for the synthesis and catabolization of amino acids (AA). I place heavy emphasis on catabolism here.

    Transamination reactions are the process in which an AA and an alpha-keto acid react. In this process the amino groups are removed from the AA, leaving an alpha-keto acid. This alpha-keto acid is then converted by numerous co-factors including P5P, into the corresponding AA in protein chains. This is potentially huge for us, as so many of us experience the catabolic state.

    More functions...and probably one of the most important. SHMT is essential for the acquisition of one carbon units for subsequent transfer reactions. 5, 10 methyleneTHF is used by thiamidate synthase to convert dUMP to dTMP.

    Many diseases are currently thought to be linked to the improper or lack of function of the SHMT function. Why don't we hear much about this? This pathway has many implications in the ME/CFS circles, mutation or not. I digress...

    Back to dUMP and dTMP. What they are currently finding is that the incorporation of dUMP into DNA instead of the preferred dTMP, is that dUMP results in DNA strand breaks because dUMP is not being methylated to dTMP. o_O

    This effect has been shown to be present in patients with Leukemia whose DNA does not repair itself and causes deletions in DNA segments and also the translocation of chromosomes. Although our condition is not Leukemia by any means, I used it as an example because so many of the effects I have experienced with ME/CFS have been quite similar, and that this effect is quite possible with those diseases being correlated to SHMT.

    Back to catabolism. This concept is related to ATP, all of which we are all too familar with, but I rarely see it said as to why, chemically. Why dont we have any energy? Why are some losing body mass, muscle wasting. SHMT leads to pyruvate of which then leads to the citric acid cycle. Little SHMT, little energy. We lose muscle mass in the catabolic state and we can't recover from it because we dont have the proper DNA to heal the damage. Catecholamines, infections, stress/trauma, and cytokines are the main contributors to the catabolic state. Food for thought anyways.

    Anyone lose their sense of taste when they got this? Incidently, ATP is associated with the ability to taste?

    So if the transmination process is compromised, we then lack the ability to break down amino acids to be incorporated into proteins, so we lack functional proteins and of which we then see a need to increase protein intake due to the catabolic state. But the intake from diet isn't enough, or is just enough to get us through a resting state, anything more and we go into a more severe catabolic state in which we cannot recover from the extra activity.

    Going to watch the fireworks.....finish later with an edit.

    LaurieL
    Jarod and helen1 like this.
  2. LaurieL

    LaurieL Senior Member

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  3. HealthyCat

    HealthyCat

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    Good post. How did/do you address SHMT? What folinic acid do you use?
  4. greenshots

    greenshots Senior Member

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    yasko puts SHMT first because it is a dead end pathway. If this is blocked, it takes your folate and holds it there so you won't get it converted into folinic or 5MTF. This means it steals this from the rest of the cycle. Then if you have other problems, its even worse. As I know it, folate goes from SHMT and is changed to folinic, then goes to MTHFR and is changed to 5MTF and then goes to MTR/MTRR.
  5. frenchmoxie

    frenchmoxie

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    So are we supposed to be treating for SHMT with just folinic acid? Or are there other things as well? I've read the information Yasko offers on SHMT, but it's not much. Thanks!
  6. Critterina

    Critterina Senior Member

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    Thank you for making this post, frenchmoxie. It led me to read LaurieL's post at the top, which I've printed out because I need to figure out all that biochemistry enough to follow it.

    I'm cSHMT +/+, so I know my folinic acid is compromised (is it a 100% shutdown that direction?) but I'm also MTHFR A1298C +/-, so I'm making less of it that way, too. I was always very strong with very good stamina, until an infection, Dec 2011, started everything southward. I've since had trouble with muscle wasting, food sensitivities, blood sugar regulation, body hair falling out, changed sweat patterns, hormones taking a deep dive toward zero, etc. I'm also MTRR +/+ and MTR +/-, so greenshots, I am starting to understand what you mean by "other" things wrong in the folate cycle.

    Yasko says folinic acid, AMRI says folinic acid and MTHF. I don't know what anyone else said. There's a post about MTHFS and folinic acid intolerance. Here's one of my posts there: http://forums.phoenixrising.me/inde...est-for-genetic-data.19168/page-5#post-376671. It says what I added to help me tolerate folinic acid. They are the things recommended for energy support when you treat CBS on the AMRI website.

    Folinic acid also got me temporarily out of Level 1 "paradoxical folate deficiency" after 4 days when on a low-sulfur diet that I started at the same time.. I say temporarily because symptoms returned when at day 7 I (1) substituted an additional mg MTHF for the 800 mcg folinic acid I was taking and (2) stopped the low sulfur diet I was on. I have since added back in the folinic acid, and symptoms are improving more slowly, except maybe my gut which seems to be getting worse (and now I'm on antibiotics again for sinuses, so this will be a long road.)
  7. Critterina

    Critterina Senior Member

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    I just saw this post, http://forums.phoenixrising.me/inde...what-folinic-acid-for-shmt.24143/#post-371585 about lactoferrin and rosemary, and a product called SHMT spray. I looked up the spray and the portions of some of the ingredients are proprietary.
  8. Critterina

    Critterina Senior Member

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    LaurieL,

    Thanks again for starting this thread. I am definitely SHMT1 +/+, but some of my lab result don't quite line up. I have lab results before being put on a protocol, and then after 3 months, and then after 5-6 months. Instead of absolute values and reference ranges, I convert everything to percent of reference range.

    I did have muscle wasting, which has stopped since starting my protocol, although I don't seem to have added muscle. I was also taking inactive B6 prior, and amino acid levels indicated B6 deficiency, so I switched to P5P when I started the protocol.

    RBC (may be low): 39% - 19% - 28% - it took a dive when I started supplementing with MTHF and MB12.
    folate levels - not tested
    Glycine (probably compromised) - 96% - 54% - 55% (Just edited this, also found there are two other paths to synthesize glycine, so I must be making it with serine glyoxyl transaminase or with glycine synthase enzymes) - so glycine initially high, then dropped.
    Hcy (probably elevated) - only tested after 3 months, was 19% of range. At that time my methionine was also below normal, so that probably had an effect

    I guess what I'm trying to understand is why the Glycine was so high. I must be making it (however slowly with my +/+) but wasn't using it until I started with the MTHF and other stuff on my protocol. Perhaps I have other mutations that make the first SHMT reaction work better than the second one that makes folinic acid?

    Can you tell me more about "glycine-based detoxification, upregulated to exposure" - is this something one would instigate with supplements? Does upregulated to exposure mean until you start feeling some effects of having depleted the glycine, and how would one know?
  9. frenchmoxie

    frenchmoxie

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    Critterina: I just purchased the SHMT spray, along with the SHMT/AHCY Iron-Related Bacterial Issues supplement (which also contains Lactoferrin), and the Ultimate B-Complex. I had been looking for a product that contained both Adenosyl and Hydroxo- B12 forms, and Ultimate B-Complex fits the bill.

    You and I seem to have similar mutations (but I am hetero for SHMT).
    I am also +/+ for MTRR A66G
    +/- for CBS 699T & A360A, MTHFR A1298C, MTRR A664A, MAO-A R297R, COMT V158M, COMT H62H, VDR Bsm, VDR Taq, BHMT-04, BHMT-08, SHMT1 C1420T

    I am just beginning my methylation journey, and just received my results one week ago. I will be following your posts on here, seeing as how some of our mutations are similar. Have you used any of the supplements for methylation on Yasko/Holistic Health's website?
  10. Critterina

    Critterina Senior Member

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    frenchmoxie,

    Hi! I just received the SHMT spray yesterday.

    EDIT POST: I tried one spray and in 10 minutes my nose was stopped. In 12 hours, I was reaching for my albuterol. I test negative for milk allergies (both skin and serum tests), but it really seems to mess with me. It will probably be 3 days before I'm back to being me. But, lesson learned, it's probably the lactoferrin I'm reacting to. I thought maybe it was the casein. Thanks for mentioning in your post that it's in the SHMT RNA product.

    I'm going to try to return the SHMT spray, but not sure how successful I'll be. If you find it helps you, I may have some to give away. :)

    I called customer service, spoke to a supervisor, and got permission to return the product, but I didn't get around to it right away. Meanwhile, I had the same reaction after drinking some kombucha (a fermented tea - I do continuous brew method). Then I realized that just before I used the spray, I'd had some kombucha. Then I read about histamine intolerance - and to avoid fermented foods. I was feeling really clear today, so I tried the spray again, one spray. No issues for 15 minutes, so I tried 2 sprays. Guess I have to throw out my kombucha culture. END EDIT.

    I'm impressed you figured out how to follow someone so soon! Congrats and thanks. I'll return the follow.

    To answer your question, no, I haven't tried any more of the Holistic Health International line of products. Given my response to this one, I'm not sure that I'll be trying any more, but let me know how you do.
  11. Critterina

    Critterina Senior Member

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  12. frenchmoxie

    frenchmoxie

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    Well that's great! I'm glad that the SHMT spray turned out to not be the culprit, and hopefully will be able to help you. For what it's worth, I cannot tolerate fermented foods. I do have an intolerance to yeast, based on food allergy testing and just generally feeling like crap anytime I had fermented foods. At least you figured it out, sorry you have to say goodbye to your kombucha though : (
    Critterina likes this.
  13. Critterina

    Critterina Senior Member

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    Yes, I felt I needed to fix that post to set the record straight. I love kombucha, but maybe it was the histamine reaction that I was feeling (like a little drunk in my arms and legs) when I drank it. I'm thinking to put the kombucha mother culture to sleep to see if once I fix my copper deficiency (which will improve the function of my DAO and HNMT enzymes which metabolize histamine) I can add back in the histamine-rich foods that I always tolerated before taking 30 days of copper-binding Levaquin, which is when this problem started.
    I'm actually thinking I should post my genetics and get some input, since it's obvious that some of the people here have a lot more experience than any of my healthcare providers. Now to find the right place...
    frenchmoxie likes this.

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