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MTHFS defect (folinic acid intolerance) - request for genetic data

nandixon

Senior Member
Messages
1,092
... and secondly, any symptoms which people are currently reporting as being 'folinic acid intolerance' might just as easily be overmethylation (which suggests the dietary folates are being processed just fine and so are contributing to the methylation cycle along with the existing methylfolates?)

I don't think folinic acid would likely be causing over-methylation. It's an inhibitor of SHMT, the enzyme that makes methylene-THF which is the substrate methylenetetrahydrofolate reductase (MTHFR) converts into 5-methyltetrahydrofolate (methylfolate) for use in the methylation cycle. (Less methylene-THF means less methylfolate.)

That's why I was speculating early in this thread that perhaps defects in both MTHFS and SHMT together might possibly cause a folinic acid intolerance problem. (A defective MTHFS causing a buildup of folinic acid that might in turn cause a defective SHMT to be more inhibited than it might otherwise would be.) There are lots of other possibilities for an intolerance, though.

Whilst on this point I just want to clarify my understanding of dietary folates to date because it seems to cause an awful lot of confusion as to how they're processed. DBKita suggests that vegetables contain a bunch of THF's that are packed into polyglutamates.

The "bunch of THF's" apparently include primarily methylfolate and 5-formyltetrahydrofolate (folinic acid) in polyglutamated forms (and I think 10-formyltetrahydrofolate and some others).

Tying this in with Lotus97's input: the SHTM1 related enzyme does the first stage of processing the THF to a DHF and then MTHF677 does the rest through its relation to the DHFR enzyme which converts the Dihidrofolate to methylfolate? Is this correct?

SHMT converts THF to methylene-THF (which is not a DHF) as mentioned above. MTHFR then converts methylene-THF to methylfolate.

I think DHFR primarily comes into play with respect to the synthesis of methylfolate if one is taking the synthetic folate, folic acid.
 
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Journeyman

Senior Member
Messages
193
I don't think folinic acid would likely be causing over-methylation. It's an inhibitor of SHMT, the enzyme that makes methylene-THF which is the substrate methylenetetrahydrofolate reductase (MTHFR) converts into 5-methyltetrahydrofolate (methylfolate) for use in the methylation cycle. (Less methylene-THF means less methylfolate.)

That's why I was speculating early in this thread that perhaps defects in both MTHFS and SHMT together might possibly cause a folinic acid intolerance problem. (A defective MTHFS causing a buildup of folinic acid that might in turn cause a defective SHMT to be more inhibited than it might otherwise would be.) There are lots of other possibilities for an intolerance, though.



The "bunch of THF's" apparently include primarily methylfolate and 5-formyltetrahydrofolate (folinic acid) in polyglutamated forms (and I think 10-formyltetrahydrofolate and some others).



SHMT converts THF to methylene-THF (which is not a DHF) as mentioned above. MTHFR then converts methylene-THF to methylfolate.

I think DHFR primarily comes into play with respect to the synthesis of methylfolate if one is taking the synthetic folate, folic acid.

Thanks for helping clarify my understanding about the dynamics of SHMT1 and MTHFR and MTHFS as they relate to processing dietary folates - that really was important for me so I can understand the 'why' rather than just the 'thats the way it is' ...

I think DHFR primarily comes into play with respect to the synthesis of methylfolate if one is taking the synthetic folate, folic acid.

How then does that reconcile with what seems like accurate information provided by DBKita per this and highlighted in bold:

"Folinic acid is a 5-formyl derivative of THF. The folates in vegetables are not folinic or folic acid (a fully oxidized synthetic folate, i.e. pteroylmonoglutamic acid). This is a notorious misconception in the research community. The folates in food are metabolites of THF packed within polyglutamates. In the intestinal lumen these polyglutmate dietary forms are broken down into monoglutamate variants which can then be converted to DHF and then THF by their respective enzymes. The DHFR enzyme is not present in humans for the synthetic folic acid it is present for processing dietary folates. Folinic acid is readily converted to 5,10 methylene THF without use of DHFR. That being said dietary folates parallel more with folic acid than with folinic acid with one crucial difference ... they can be processed in the intestinal lumen and the liver. Folic acid (I am pretty sure) being fully oxidized must be converted in the liver."

DBKita's post seems accurate to me. Theres no way the human body suddenly evolved the DHFR enzyme in response to the creation of folic acid... its been there for dietary folates since we starting walking upright I'd wager. So I think we can confidently say that DHFR is involved in processing dietary folates, and thus those with the MTHFR677 may by virtue of this mutation alone, have a propensity towards accumulating folinic acid? Now with my understanding about how SHMT1 related enzyme activity is downregulated by the mere presence of 5MTHF or 5FMTHF (formyl) I recognise the importance of somehow preventing SHMT1 downregulation whilst simultaneously creating sufficient healing through the large dosages of MeFol I'm engaging in... How are others achieving this balance? I've read about Yasko's SHMT spray but I doubt I can afford her expensive products, and its not like KFC's secret recipe... I'm sure plenty of people know what makes up the 'DNA' or 'RNA' complexes purported in these sprays....
 

nandixon

Senior Member
Messages
1,092
Thanks for helping clarify my understanding about the dynamics of SHMT1 and MTHFR and MTHFS as they relate to processing dietary folates - that really was important for me so I can understand the 'why' rather than just the 'thats the way it is' ...

How then does that reconcile with what seems like accurate information provided by DBKita per this and highlighted in bold:

"Folinic acid is a 5-formyl derivative of THF. The folates in vegetables are not folinic or folic acid (a fully oxidized synthetic folate, i.e. pteroylmonoglutamic acid). This is a notorious misconception in the research community.

Just to correct this, folinic acid IS found in vegetables. Folic acid is not, of course.

The folates in food are metabolites of THF packed within polyglutamates. In the intestinal lumen these polyglutmate dietary forms are broken down into monoglutamate variants which can then be converted to DHF and then THF by their respective enzymes. The DHFR enzyme is not present in humans for the synthetic folic acid it is present for processing dietary folates.

Of course it's true that DHFR is not present in humans to reduce folic acid, a synthetic substance. And naturally it will reduce any DHF forms present in vegetables to THF. But DHFR's primary critical function is in DNA synthesis. (It also salvages/recycles BH2 to BH4.)

Folinic acid is readily converted to 5,10 methylene THF without use of DHFR.

This needs some clarification. Folinic acid is directly converted to methenyl-THF by MTHFS, not to methylene-THF. Conversion to methylene-THF requires at least one additional step. (I think this is done by a multi-function enzyme, MTHFD1.) It's true that DHFR is not needed.

That being said dietary folates parallel more with folic acid than with folinic acid with one crucial difference ... they can be processed in the intestinal lumen and the liver. Folic acid (I am pretty sure) being fully oxidized must be converted in the liver."

DBKita's post seems accurate to me. Theres no way the human body suddenly evolved the DHFR enzyme in response to the creation of folic acid... its been there for dietary folates since we starting walking upright I'd wager. So I think we can confidently say that DHFR is involved in processing dietary folates,

Again, just to reiterate, that's true, but DHFR's primary function is in DNA synthesis. (My statement, "I think DHFR primarily comes into play with respect to the synthesis of methylfolate if one is taking the synthetic folate, folic acid," was probably a little confusing. :))
 
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Journeyman

Senior Member
Messages
193
Just to correct this, folinic acid IS found in vegetables. Folic acid is not, of course.



Of course it's true that DHFR is not present in humans to reduce folic acid, a synthetic substance. And naturally it will reduce any DHF forms present in vegetables to THF. But DHFR's primary critical function is in DNA synthesis. (It also salvages/recycles BH2 to BH4.)



This needs some clarification. Folinic acid is directly converted to methenyl-THF by MTHFS, not to methylene-THF. Conversion to methylene-THF requires at least one additional step. (I think this is done by a multi-function enzyme, MTHFD1.) It's true that DHFR is not needed.



Again, just to reiterate, that's true, but DHFR's primary function is in DNA synthesis. (My statement, "I think DHFR primarily comes into play with respect to the synthesis of methylfolate if one is taking the synthetic folate, folic acid," was probably a little confusing. :))

Fantastic Nandixon - I think this reply has been of great help to those like me who have been bamboozled by the different types of folate terminology, and then the different ways you can express the same type of folate. For example: Folinic Acid is a different way to say 5 Formyl-tetrahydrofolate (5Formyl-THF) and is the type of folate that makes up about roughly half the total folate content of green vegetables with the remaining half made up by 5-MTHF (L Methylfolate) - learnt this gem thanks to a reply from another knowledgeable person to my other thread specifically about folates from vegetables: http://forums.phoenixrising.me/index.php?threads/folates-from-vegetables.26080/

So: MTHFS relevant enzymes take the 5 Formyl-THF gained from dietary folates and processes them to intermediary folate Methenyl-THF which then undergoes one final step through a 'to be confirmed' enzyme relevant to the MTHFD1 gene? before being made into the 5,10 Methylene-THF which is highlighted in Yasko's diagram here:
http://www.dramyyasko.com/diagrams-listing/

Ps - why does Yasko's diagram show an MTHFR between the 5-MTHF and 5,10 Methylene-THF part of the cycle when we know that 5-MTHF is taken to circumvent the DHFR shortcomings that folk have due to their MTHFR-677 mutation?.

Another point of interest: why if MTHFD1 (or some other key gene) is so critical to the folate cycle, is there no discussion about it in these forums. Is it because theres no known mutations? For myself as a 'normal' MTHFS gene holder it seems that my only cause for concern as it relates to folinic acid intolerance would be whether this MTHFD1 gene is problematic, or through excessive downregulation of thymidine synthesis caused by the SHMT heterozygous I have (+/-) ?

My plan now will be to back off the vegetable intake and stick to my Metafolin (5-MTHF)... Not because of any 'backlog' of folates, but just the fact that the Folinic acid will downregulate the activity of my already problematic SHMT+/- ...
 
Messages
65
Hello all,

Just to keep this thread going, below is my result for MTHFS from mthfrsupport.com, together with some thoughts on its impact following my methylation panel analysis:

** MTHFS - risk allele C - my result CC +/+

Relevant methylation panel relevant results:

** 5-formyl-THF (folinic acid) = 8.30 nmol/l (1.20-11.70)
** 5-L-methyl THF = 16.4 nmol/l (8.4-72.6).

I'm just about to start methylation support, so I'm not responding directly to the issue of folinic acid intolerance, but I think these results show that Rich's hypothesis to Freddd may be accurate. More specifically, I have a homozygous mutation for the MTHFS. This means that I have trouble converting folinic acid to 5,10-methenyl tetrahydrofolate. The failure to achieve this will result in elevated levels of folinic acid, which will inhibit the SHMT reaction of THF to
5,10 methylene tetrahydrofolate, resulting in low levels of methylfolate (as seen in my results). It would seem to follow that, I consume excessive folinic acid (i.e. more than is in vegetables), I may contribute to increased need for methylfolate.

My only confusion is this:
I suspect that in addition, your tetrahydrofolate is probably high, because it is the product of the methionine synthase reaction, and if SHMT is inhibited, that will tend to inhibit the conversion of THF to 5,10 methylene THF, so that THF would probably rise. High THF will likely exert backpressure (product inhibition) on the methionine synthase reaction, so that it is necessary to add more methylfolate to drive it at a normal rate.

My THF level is very low (0.48 nmol/l (0.6-6.8). He did say "probably high", suggesting that it doesn't undermine the hypothesis. Moreover, with the partial block in the methylation cycle, you might expect the level of THF to be low in the absence of B12. Since he was commenting on low THF in Freddd's case, who is already supplying B12, this part of my test may not be very helpful.

Leon
 
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Journeyman

Senior Member
Messages
193
Hello all,

Just to keep this thread going, below is my result for MTHFS from mthfrsupport.com, together with some thoughts on its impact following my methylation panel analysis:

** MTHFS - risk allele C - my result CC +/+

Relevant methylation panel relevant results:

** 5-formyl-THF (folinic acid) = 8.30 nmol/l (1.20-11.70)
** 5-L-methyl THF = 16.4 nmol/l (8.4-72.6).

I'm just about to start methylation support, so I'm not responding directly to the issue of folinic acid intolerance, but I think these results show that Rich's hypothesis to Freddd may be accurate. More specifically, I have a homozygous mutation for the MTHFS. This means that I have trouble converting folinic acid to 5,10-methenyl tetrahydrofolate. The failure to achieve this will result in elevated levels of folinic acid, which will inhibit the SHMT reaction of THF to
5,10 methylene tetrahydrofolate, resulting in low levels of methylfolate (as seen in my results). It would seem to follow that, I consume excessive folinic acid (i.e. more than is in vegetables), I may contribute to increased need for methylfolate.

My only confusion is this:


My THF level is very low (0.48 nmol/l (0.6-6.8). He did say "probably high", suggesting that it doesn't undermine the hypothesis. Moreover, with the partial block in the methylation cycle, you might expect the level of THF to be low in the absence of B12. Since he was commenting on low THF in Freddd's case, who is already supplying B12, this part of my test may not be very helpful.

Leon

I think your observations following a high intake of folinic acid will be of more interest than most given your very clear mutation on the MTHFS gene... I was about to ask whether you noticed any significant symptoms following a large intake of folinic acid but then I read you're new to the methylation protocol, and we don't know your other results. Why don't you add them to your signature - it might allow the more knowledgeable here to piece together the puzzle better and give you more helpful advice... I know it helped for me.

For example, if you were to say you noticed very little after supplementing folinic acid, then that might be because you were grossly deficient in all kinds of folates due to some other genetic mutations on other genes (I don't think the blood tests would be useful for indicating active folates at cellular level btw) If, however, you'd been on the methylation protocol for a week or two and were taking substantial amounts of 5MTHF, and then you took a folinic acid supplement or a huge intake of lightly cooked vegetables, and noticed fatigue feelings, and many of the other issues people describe under 'paradoxical folate deficiency' then I think we'd be able to make some informed judgements.... Look forward to hearing your progress in this respect!
 

nandixon

Senior Member
Messages
1,092
Fantastic Nandixon - I think this reply has been of great help to those like me who have been bamboozled by the different types of folate terminology, and then the different ways you can express the same type of folate. For example: Folinic Acid is a different way to say 5 Formyl-tetrahydrofolate (5Formyl-THF) and is the type of folate that makes up about roughly half the total folate content of green vegetables with the remaining half made up by 5-MTHF (L Methylfolate) - learnt this gem thanks to a reply from another knowledgeable person to my other thread specifically about folates from vegetables: http://forums.phoenixrising.me/index.php?threads/folates-from-vegetables.26080/

So: MTHFS relevant enzymes take the 5 Formyl-THF gained from dietary folates and processes them to intermediary folate Methenyl-THF which then undergoes one final step through a 'to be confirmed' enzyme relevant to the MTHFD1 gene? before being made into the 5,10 Methylene-THF which is highlighted in Yasko's diagram here:
http://www.dramyyasko.com/diagrams-listing/

Ps - why does Yasko's diagram show an MTHFR between the 5-MTHF and 5,10 Methylene-THF part of the cycle when we know that 5-MTHF is taken to circumvent the DHFR shortcomings that folk have due to their MTHFR-677 mutation?

It's correct: MTHFR takes the methylene-THF (made by SHMT from THF) and converts it to methylfolate (5-MTHF).

Like I was trying to say earlier, DHFR doesn't play a significant direct role in the synthesis of methylfolate UNLESS a person is getting their folate from the synthetic form of folate, ie, folic acid (or perhaps if they have some kind of bizarre diet where most of their folate is in the form of dihydrofolates instead of tetrahydrofolates, in which case DHFR would be needed for the DHF to THF conversion; but my understanding is that in a normal human diet, most folate consists of THF forms, and most of that is methylfolate.)

So someone with the MTHFR C677T mutation who was getting most of their folate from folic acid AND who also happened to have a problem in DHFR would be having serious problems. This is how DHFR and MTHFR can be significantly related. But no one should be taking folic acid, so it should be a moot point. (A problem with DHFR could cause other problems, though.)

[For anyone passing this way, note that where Yasko refers to "BH2" in her charts this should actually be "q-BH2" or "qBH2." BH2 is 7,8-dihydrobiopterin, which is recycled by DHFR to BH4. q-BH2, on the other hand, is quinoid 6,7-dihydrobiopterin, which is recycled by DHPR, aka QDPR, to BH4.]

Another point of interest: why if MTHFD1 (or some other key gene) is so critical to the folate cycle, is there no discussion about it in these forums. Is it because theres no known mutations? For myself as a 'normal' MTHFS gene holder it seems that my only cause for concern as it relates to folinic acid intolerance would be whether this MTHFD1 gene is problematic, or through excessive downregulation of thymidine synthesis caused by the SHMT heterozygous I have (+/-) ?

I'm guessing that significant mutations in MTHFD1 may not be very common, but I'm not sure.

My plan now will be to back off the vegetable intake and stick to my Metafolin (5-MTHF)... Not because of any 'backlog' of folates, but just the fact that the Folinic acid will downregulate the activity of my already problematic SHMT+/- ...
 
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nandixon

Senior Member
Messages
1,092
...
** MTHFS - risk allele C - my result CC +/+
...
...I have a homozygous mutation for the MTHFS. This means that I have trouble converting folinic acid to 5,10-methenyl tetrahydrofolate...

Hi Leon,

I think the SNP you're talking about is rs6495446. This is actually probably an up-regulation that increases the activity of MTHFS. The study that found a risk for the C allele is this one here:

Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18522750/

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430944/

In the full text, the authors indicate that rs6495446 probably increases mRNA expression, in which case there would be greater activity for MTHFS in C allele carriers. [But note that the C allele is actually the more common allele by nearly 4 to 1 in the general population (from openSNP), so lab ranges are going to be biased toward results associated with the risk allele.] From the full text:
Interestingly, when we searched a database containing results from a GWAS of global gene expression [37], the association of the rs6495446 C allele with higher expression levels of a MTHFS gene transcript was genome-wide significant (p = 3.3 × 10-10). ...rs6495446 by itself accounted for 13% of the total expression variance of this MTHFS transcript [38].

The authors also strongly indicate that their findings with respect to the C allele being associated with chronic kidney disease need to be replicated. So it doesn't seem certain yet that the likely increased activity is necessarily problematic.
 

Journeyman

Senior Member
Messages
193
It's correct: MTHFR takes the methylene-THF (made by SHMT from THF) and converts it to methylfolate (5-MTHF).

Like I was trying to say earlier, DHFR doesn't play a significant direct role in the synthesis of methylfolate UNLESS a person is getting their folate from the synthetic form of folate, ie, folic acid (or perhaps if they have some kind of bizarre diet where most of their folate is in the form of dihydrofolates instead of tetrahydrofolates, in which case DHFR would be needed for the DHF to THF conversion; but my understanding is that in a normal human diet, most folate consists of THF forms, and most of that is methylfolate.)

So someone with the MTHFR C677T mutation who was getting most of their folate from folic acid AND who also happened to have a problem in DHFR would be having serious problems. This is how DHFR and MTHFR can be significantly related. But no one should be taking folic acid, so it should be a moot point. (A problem with DHFR could cause other problems, though.)

[For anyone passing this way, note that where Yasko refers to "BH2" in her charts this should actually be "q-BH2" or "qBH2." BH2 is 7,8-dihydrobiopterin, which is recycled by DHFR to BH4. q-BH2, on the other hand, is quinoid 6,7-dihydrobiopterin, which is recycled by DHPR, aka QDPR, to BH4.]



I'm guessing that significant mutations in MTHFD1 may not be very common, but I'm not sure.

I'm glad you clarified this again Nandixon because I was looking at this http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-6/ earlier and recalling your comment about folinic acid not being in anyway processed by MTHFR and then Yasko's specific comment "Going from 5 formyl THF to 5 methyl THF requires MTHFR" and starting to query what I now know to be solid advice :)

So for my simple understanding: You eat vegetables you get the broad category of tetradhydrofolates of which most are 5 formyl THF (Folinic acid) and the rest 5MTHF. The folinic acid is first dealt with by SHMT1 to make Methylene THF which then get dealt with by MTHFR to create 5MTHF - the final active form. However I recall reading that we need to ensure SHMT1 is making adequate thymidine for DNA synthesis.... I also recall earlier in this thread something about folinic acid being a downregulator of SHMT1 activity is this correct? Does 5MTHF also act as a downregulator?
How does one like myself who has mutations on both folate strands (1298 and 677) and thus requires copious amounts of folate, do so without upsetting their mutated SHMT1 (+/-) Would it be wisest to simply supplement the Phosphytidal Serine (PS) and Zinc to promote sufficient SHMT?
 
Messages
65
Hi Leon,

I think the SNP you're talking about is rs6495446. This is actually probably an up-regulation that increases the activity of MTHFS. The study that found a risk for the C allele is this one here:

Genome-wide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/18522750/

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2430944/

In the full text, the authors indicate that rs6495446 probably increases mRNA expression, in which case there would be greater activity for MTHFS in C allele carriers. [But note that the C allele is actually the more common allele by nearly 4 to 1 in the general population (from openSNP), so lab ranges are going to be biased toward results associated with the risk allele.] From the full text:


The authors also strongly indicate that their findings with respect to the C allele being associated with chronic kidney disease need to be replicated. So it doesn't seem certain yet that the likely increased activity is necessarily problematic.

Hi Nandixon,

So, in simplistic terms, this particular SNP will mean that I likely tolerate folinic acid - that is, it won't cause SHMT inhibition - unlike other MTHFS genes that one has? This is the only MTHFS gene I have come across in my results. Which one is implicated in SHMT inhibition?

Incidentally, in relation to your earlier post, I have MTHFD1 C105T and G1958A mutations; though I have no idea what these code for, or what the effect of a heterozygous mutation could be.
 

nandixon

Senior Member
Messages
1,092
I'm glad you clarified this again Nandixon because I was looking at this http://www.dramyyasko.com/resources/autism-pathways-to-recovery/chapter-6/ earlier and recalling your comment about folinic acid not being in anyway processed by MTHFR and then Yasko's specific comment "Going from 5 formyl THF to 5 methyl THF requires MTHFR" and starting to query what I now know to be solid advice :)

I never said that. The methylene-THF that results after the sequential action of MTHFS and MTHFD1 on folinic acid could be used by MTHFR to make methylfolate (assuming that that methylene-THF has the same sort of availability to MTHFR that the methylene-THF made by SHMT from THF has; there can be other sources of methylene-THF as well).

So for my simple understanding: You eat vegetables you get the broad category of tetradhydrofolates of which most are 5 formyl THF (Folinic acid) and the rest 5MTHF.

For an omnivorous diet, my understanding is that a person will be getting getting most of their folates in the form of tetrahydrofolates, with methylfolate being in the greatest amount.

The folinic acid is first dealt with by SHMT1 to make Methylene THF which then get dealt with by MTHFR to create 5MTHF - the final active form.

No, MTHFS acts on folinic acid to make methenyl-THF which is acted on by MTHFD1 (I think) to make methylene-THF.

Separately, SHMT acts on THF to also make methylene-THF, i.e., SHMT is recycling the THF produced when MTR uses the methyl group from methylfolate to make methionine from homocysteine.

However I recall reading that we need to ensure SHMT1 is making adequate thymidine for DNA synthesis.... I also recall earlier in this thread something about folinic acid being a downregulator of SHMT1 activity is this correct?

Yes, folinic acid is an inhibitor of SHMT and other enzymes as well.

Does 5MTHF also act as a downregulator?

Methylfolate inhibits a number of different enzymes, including SHMT, as well.

How does one like myself who has mutations on both folate strands (1298 and 677) and thus requires copious amounts of folate, do so without upsetting their mutated SHMT1 (+/-) Would it be wisest to simply supplement the Phosphytidal Serine (PS) and Zinc to promote sufficient SHMT?

It's all a big balancing act that a person usually has to figure out through experimentation. The SNPs can suggest helpful possibilities, but what actually works for someone is another matter. Every single substance a person puts in their body - vitamin, mineral, herb, whatever - is going to have many - dozens or hundreds - of unintended consequences (inhibition of enzymes, inducement of enzymes, increased expression of genes, decreased expression of genes, etc). When a person has a good result from taking a supplement, that just means the combined good effects are outweighing the combined bad effects. That's my take on the whole thing, anyway.
 
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nandixon

Senior Member
Messages
1,092
Hi Nandixon,

So, in simplistic terms, this particular SNP will mean that I likely tolerate folinic acid - that is, it won't cause SHMT inhibition - unlike other MTHFS genes that one has? This is the only MTHFS gene I have come across in my results.

I'm assuming that being homozygous CC for rs6495446 isn't something to be too concerned about because nearly two-thirds of the general population (from openSNP) is also homozygous for that SNP, including me.

Which one is implicated in SHMT inhibition?

We don't know which, if any, of the MTHFS SNPs might cause a decreased function for MTHFS and thereby cause an inhibitory amount of folinic acid to accumulate. That was the purpose of this thread! :)

Incidentally, in relation to your earlier post, I have MTHFD1 C105T and G1958A mutations; though I have no idea what these code for, or what the effect of a heterozygous mutation could be.

Thanks!
 

Journeyman

Senior Member
Messages
193
I never said that. The methylene-THF that results after the sequential action of MTHFS and MTHFD1 on folinic acid could be used by MTHFR to make methylfolate (assuming that that methylene-THF has the same sort of availability to MTHFR that the methylene-THF made by SHMT from THF has; there can be other sources of methylene-THF as well).

Quite right nandixon my apologies!. I've just realised that with the confusion created by the oversimplified Yasko diagram I was of the thinking that there was only one pathway for the creation of the all important 5-methylene THF, and so applied some incorrect assumptions to your earlier explanation.


For an omnivorous diet, my understanding is that a person will be getting getting most of their folates in the form of tetrahydrofolates, with methylfolate being in the greatest amount.



No, MTHFS acts on folinic acid to make methenyl-THF which is acted on by MTHFD1 (I think) to make methylene-THF.

Separately, SHMT acts on THF to also make methylene-THF, i.e., SHMT is recycling the THF produced when MTR uses the methyl group from methylfolate to make methionine from homocysteine.



Yes, folinic acid is an inhibitor of SHMT and other enzymes as well.



Methylfolate inhibits a number of different enzymes, including SHMT, as well.



It's all a big balancing act that a person usually has to figure out through experimentation. The SNPs can suggest helpful possibilities, but what actually works for someone is another matter. Every single substance a person puts in their body - vitamin, mineral, herb, whatever - is going to have many - dozens or hundreds - of unintended consequences (inhibition of enzymes, inducement of enzymes, increased expression of genes, decreased expression of genes, etc). When a person has a good result from taking a supplement, that just means the combined good effects are outweighing the combined bad effects. That's my take on the whole thing, anyway.

Sage advice... this wouldn't be the first time I've employed some health initiatives and then in a few years later (after learning a lot more) looked back and realised why my previous efforts were thwarted.. As I read this I can't help but think about the relevance to other posts I've read recently where glutathione supplementation via NAC has been criticised for its binding effects on B12. This seemed v. confusing at first when taking into account the
Glutathione Depletion-Methylation Cycle Block Pathogenesis Hypothesis proposed by Rich which indicates that a shortage of glutathione is the crux of the problem in many instances. I'm now wondering if the most effective path to recovering both the methylation cycle and the existing damage caused by its malfunction involves exercising both the methylation and detox sides separately. This might practically take the form of using 2 days of methylation supplements and then a day of using NAC and no 5MTHF or Folinic acid to restore SHMT1 activity and increase glutathione before re-commencing the usual methylation protcol for the next 2 days before starting again.... I'd love to hear any thoughts on this...

As for this likely MTHFD1 gene: I've searched it using the 'browse raw data' function of my 23&me to obtain the following:
MTHFD1 Results 23andMe.jpg


Hows that look? am I mutated and if so whats the impact?
 
Messages
21
Location
Clifton Park, NY
MTHFS, ST20-MTHFS 80136129 rs685487 A or G AG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T CT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CT
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AA
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T TT
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CT
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C AC
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AC
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CT
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G GG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T GT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CT
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C AA
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AG
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C CC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T CT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AA
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G AG
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CC
 
Messages
95
I am folinic acid intolerant





MTHFS, ST20-MTHFS 80136129 rs685487 A or G GG
MTHFS, ST20-MTHFS 80136288 rs8033649 A or C CC
MTHFS, ST20-MTHFS 80137560 rs8923 C or T TT
MTHFS, ST20-MTHFS 80138571 rs2733103 C or T CC
MTHFS, ST20-MTHFS 80138745 rs16971427 A or C AA
MTHFS, ST20-MTHFS 80141997 rs655473 A or G AA
MTHFS, ST20-MTHFS 80144197 rs17284990 C or T CC
MTHFS, ST20-MTHFS 80154571 rs16971450 A or G AA
MTHFS, ST20-MTHFS 80154982 rs6495446 C or T CC
MTHFS, ST20-MTHFS 80158042 rs7177659 A or C CC
MTHFS, ST20-MTHFS 80158159 rs6495449 A or G GG
MTHFS, ST20-MTHFS 80162265 rs17285431 A or C AC
MTHFS, ST20-MTHFS 80164053 rs6495451 C or T CT
MTHFS, ST20-MTHFS 80165368 rs2586154 A or G GG
MTHFS, ST20-MTHFS 80168282 rs12899781 G or T GT
MTHFS, ST20-MTHFS 80171971 rs16971478 A or G AA
MTHFS, ST20-MTHFS 80172133 rs2586153 C or T CC
MTHFS, ST20-MTHFS 80174388 rs2562744 A or C AA
MTHFS, ST20-MTHFS 80177687 rs2733106 A or G AA
MTHFS, ST20-MTHFS 80178283 rs12438477 A or C CC
MTHFS, ST20-MTHFS 80182050 rs12898642 C or T CT
MTHFS, ST20-MTHFS 80183766 rs2586182 A or C AA
MTHFS, ST20-MTHFS 80184657 rs2733088 A or G AG
MTHFS, ST20-MTHFS 80186340 rs12440798 C or T CC
 
Messages
95
I would like a list of foods that are high in folinic acid versus other forms of folate if someone has one.
 
Messages
27
Location
Davenport, Iowa
Not sure if anyone is still looking into this but thought I'd add mine in. I do have a really bad reaction to folinic acid supplements and vegetable folates. I was supplementing 800mcg of folinic acid a day after being on methylfolate for 9 months. It was slow but I noticed I was getting more and more hypothyroid and my bp kept going higher. Quit taking it after I put two and two together. Next day took 1500mcgs methylfolate and within 30min my temp went up from 97.8 to 98.6 my high bp dropped to 120/70 and I felt like I had drank a pot of coffee. Next time this happened I had made a big batch of red raspberry leaf tea with nettle known to be high in b vitamins. I drank one cup and went to get my hair dyed within an hour I was so lethargic and my eyes were blood shot and also my tongue felt like it was swelling up. Voice was also super raspy. Realized it was probably a reaction to the folates in the tea and took 1500mcgs methylfolate and symptoms cleared right up.
Rich=1, nandixon=2, Gestalt=3, Anne=4, caledonia=5, geesiddiqui=6, I.R.Baboon=7, Lynn_M=8, merylg=9 snowathlete=10, roxie60=11, drex13=12, Sea=13, Creekee=14, Paula=15, msinnott=16

rs8923 CT (TT) (TT) (TT) (TT) (TT) (TT) (CT) (TT) (TT) (TT) (CT) (TT) (CT) (CT) (CT)
rs2733103 CC (CT) (CC) (CT) (CT) (CT) (CT) (CC) (TT) (CC) (CC) (CT) (CC) (CC) (CT) (CC)
rs16971427 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)x (AA) (AA) (AA) (AA) (AA)
rs655473 AA (AA) (AA) (AA) (AA) (AG) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)
rs17284990 TT (CT) (CT) (TT) (TT) (TT) (TT) (CT) (TT) (TT) (CT) (TT) (TT) (TT) (TT) (TT)
rs16971450 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AG) (AG) x (AA) (AA) (AG) (AG) (AA)
rs6495446 CT (CC) (CC) (CC) (CC) (CC) (CC) (CT) (CC) (CT)(CT) +++ (CT) (CC) (TT) (CT) (CT)
rs7177659 CC (AA) (AA) (AA) (AC) (AA) (AC) (AA) (AA) (CC) (AC)*** (AC) (CC) (AC) (CC) (CC)
rs6495449 GG (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG) (GG)
rs17285431 AC (AA) (AA) (AC) (AA) (AA) (AC) (AA) (AA) (AC)(AA) (AC) (AA) (AA) (AA) (AC)
rs6495451 CT (CC) (CT) (CT) (CC) (CC) (CT) (CT) (CC) (TT) (CT) (CT) (CC) (TT) (TT) (CT)
rs2586154 GG (AG) (AG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (AG) (GG) (GG) (GG) (GG) (GG)
rs12899781 GT (TT) (TT) (GT) (TT) (TT) (GT) (TT) (TT) (GT)(TT) (GT) (TT) (TT) (TT) (GT)
rs16971478 AA (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA) (AA)x (AA) (AA) (AA) (AG) (AA)
rs2586153 CC (CT) (CC) (CT) (CT) (CT) (CC) (CC) (TT) (CC) (CC) (CT) (CC) (CC) (CC) (CC)
rs2562744 AA (AC) (CC) (AC) (AA) (AA) (AA) (AC) (AA) (CC)(CC) (AA) (AA) (CC) (CC) (AA)
rs2733106 AA (AG) (AA) (AG) (AG) (AG) (AA) (AA) (GG) (AA)(AA) (AG) (AA) (AA) (AA) (AA)
rs12438477 CC (CC) (AC) (AC) (CC) (CC) (CC) (AC) (CC) (AA)(AC) (CC) (CC) (AA) (AA) (CC)
rs12898642 CT (TT) (CT) (CT) (TT) (TT) (CT) (CT) (TT) (CC)(CT) (CT) (TT) (CC) (CC) (CT)
rs2586182 AA (AC) (AC) (AA) (AA) (AA) (AA) (AA) (AA) (AA)(AC) (AA) (AA) (AA) (AA) (AA)
rs2733088 AG (AG) (GG) (AG) (AA) (AA) (AG) (AG) (AA) (GG)(GG) (AG) (AA) (GG) (GG) (AG)
rs12440798 CC (CC) (CT) (CC) (CC) (CC) (CC) (CT) (CC) (CC)(CC) (CC) (CC) (CT) (CT) (CC)

MTHFS 2 4 5 6 7 8 9 10 11 14 15 16
rs685487 (GG) (AG) (AG) (AG) (AG) (AG) (GG) (AA)(AG) (AA) (AG) (AA)
rs8033649 (CC) (CC) (CC) (CC) (CC) (CC) (CC) (CC)(CC) (CC) (CC) (CC)

My SHMT C1420T rs1979277 is AG

SHMT 2 RS12319666 GG
RS34095989 AA