Help and experiences with MTR++/MTRR++ please
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First check what your SNPs actually do from a source other than Yasko and her derivatives. Some of her claims are just not reliable.
Here and here are a couple of threads which identify which SNPs actually do something.
In general methylB12 supplementation may be helpful but as the discussion on the TMG thread shows, many others factors feed in also. In the end you may need to supply all these elements.
Here and here are a couple of threads which identify which SNPs actually do something.
In general methylB12 supplementation may be helpful but as the discussion on the TMG thread shows, many others factors feed in also. In the end you may need to supply all these elements.
Thank you yes I actually prefer Heartfixer to Yasko's explanations but there is generally less info out there on these 2 compared with mthfr.
Thanks for those links, bit simpler to comprehend.
From them I deduce that MTR & MTRR homo means overall there's likely chronicly low methionine > low SAMe > poor methylation. & SAMe supplementation potentially necessary despite providing mfolate & mb12.
Hetero SNPs perhaps clog up other parts as well exacerbating (mthfr1298, BHMT, MTHFS, CBS).
I am wondering what knock on effect there may be from MTR/MTRR to BH4 production but brain bout to explode from this mornings chemistry lesson
Thanks for those links, bit simpler to comprehend.
From them I deduce that MTR & MTRR homo means overall there's likely chronicly low methionine > low SAMe > poor methylation. & SAMe supplementation potentially necessary despite providing mfolate & mb12.
Hetero SNPs perhaps clog up other parts as well exacerbating (mthfr1298, BHMT, MTHFS, CBS).
I am wondering what knock on effect there may be from MTR/MTRR to BH4 production but brain bout to explode from this mornings chemistry lesson
Be careful - Heartfixer repeats Yasko's errors.
Less info out there might be a good thing - most of the claims about MTHFR which proliferate on the internet are nonsense.
MTHFR 1298, BHMT and CBS have little or no effect, even +/+, so I wouldn't worry about them.
Can't remember MTHFS but I'd be surprised if +/- was anything to worry about.
I can't think of anything in particular, it would have to be something indirect. Is there some particular aspect you have in mind?
Disregard what Yasko and Heartfixer say about BH4. This is one of Yasko's most egregious mistakes and Heartfixer just repeats it.
As I mentioned in the TMG thread, severe brain fog is my worst sx. By trial and error it seems to be high ammonia. Clinical liver disease isn't apparent so I am left with hypotheses from my SNPs. I have treated and am managing my gut health for infections and overgrowth. Because I struggle to believe my MTHFR or CBS SNPs are behind this, I wondered if MTR/MTRR could be indirectly affecting my ability to keep ammonia (& to a lesser degree, sulphur) under control. According to some source I can't recall if was HF, BH4 is prioritized to ammonia over neurotransmitters. I always get depression & anxiety with these severe fog/vertigo days & weeks.
Of course there could be something else entirely happening but the fog improves with 2x daily lactulose when it hits.
It first started in 2012 when I had a severe relapse after general anesthetic but I'd also used whey for years and that year decided to try NAC thinking it was a good idea. Not sure if the trigger was surgery/antibx or NAC or both.
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You are right - they are not.
BH4 has nothing to do with ammonia. I don't know where Yasko got this idea but I suspect she simply misread metabolic diagrams which show the NOS (which uses BH4) and urea cycle (which uses ammonia) pathways side by side because they share arginine and citrulline as reactants. She somehow conflated the two independent pathways.
NOS converts arginine to citrulline plus nitric oxide (NO). It uses BH4 as a cofactor (5 cofactors in total - a complicated enzyme). Ammonia has no part in this reaction.
Ammonia is processed in the urea cycle. This is a more complicated cycle of interconversion which includes arginine and citrulline (though in a different sequence) along with other intermediates. Ammonia is incorporated into the cycle and the less toxic waste product urea is produced as a by-product.
While on the subject of BH4, Yasko's claims that methylfolate/MTHFR regenerates BH4 is also incorrect.
Suggesting the ammonia source is the gut. This need not be anything pathological, just a preponderance of microbes which can ferment amino acids, in turn releasing ammonia as a by-product (for example - there could be other explanations).
How to fix this? I've been treated for dientamoeba twice, with metronidazole then doxycyline. This was post-2012. No sxs of dientamoeba now but still get the fog. Herbalist has put me through 2mths of wormwood Treatment, first week I thought I was dying (the 'ammonia' sx I assumed from dead microbes). Have done body ecology, gaps, low FODMAPS. My gut issues preceded ME, really don't know the answer. Take probiotics, am a mess without them, but I'm convinced no one really knows which and how many strains are best!
I wondered if it (poor gut flora) goes back to poor immune function that in part is affected by methylation and/or toxicity. That parasite apparently does not normally become pathogenic in healthy adults. Obviously not many of us here are healthy!
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Existing probiotics are pretty inadequate. They don't reflect the species that are present in the gut and don't change the gut microflora.
They do have some benefits as they transit through the gut, influence the host immune response and help crowd out more sinister things from taking up residence.
Working on feeding the flora well is the best thing I can think of but effecting real change can take a long time.
Dientamoeba was the likely cause of my son's ME/CFS.
Even though the bug has now been treated, the brain fog was there until we had B12 and B2 and other nutrient levels built up enough (thanks to PR and the b12 oils guy).
Comments about diagnosis
You need a PCR test with the word 'dientamoeba' and 'PCR' on the pathology request. We had one false negative after the first round of treatment. You need to wait at least 6 weeks after ceasing treatment to avoid a false negative (we had waited only 4). The collection centre also made a difference.
Comments about treatment
You might then need more treatment - oral antibiotics can be ineffective. See these two sites and more details of our experience below:
We think my son might have had the little critters for up to a decade before them being tested for and diagnosed early last year.
Metronidazole and doxycyline are not always effective. If you are experiencing a reaction to wormwood, then something is obviously still there.
We had three rounds of treatment.
1st treatment - oral doxycycline: This worked on my husband (infected but asymptomatic), but my son's health slid further down into the pit after a very brief recovery. This was where the false negative came in.
2nd treatment: A double oral treatment of metronidazole and doxycyline, which was totally ineffective.
3rd treatment: A triple dose of very strong antibiotics administered via colonic irrigation, followed up with 10 days of oral antibiotic (also very strong). The CDC in Sydney administered the treatment.
This third treatment worked: no more gut symptoms, but he is still recovering from possibly a decade of malnutrition, as we call it.
Probiotics: We had to resort to D-lactate free probiotics. In the end, one brand of sheep's milk yoghurt was the best thing. I suspect it was fermented for long enough to consume all the lactose. (The scd diet website talks about this.)
Finally, we stumbled across this website. Who knows if it the ideas actually work, but we found the propolis helped heal the gut and the royal jelly helped with other issues. We never got to try the bee pollen because the triple antibiotic therapy came along first.
Even though the bug has now been treated, the brain fog was there until we had B12 and B2 and other nutrient levels built up enough (thanks to PR and the b12 oils guy).
Comments about diagnosis
You need a PCR test with the word 'dientamoeba' and 'PCR' on the pathology request. We had one false negative after the first round of treatment. You need to wait at least 6 weeks after ceasing treatment to avoid a false negative (we had waited only 4). The collection centre also made a difference.
Comments about treatment
You might then need more treatment - oral antibiotics can be ineffective. See these two sites and more details of our experience below:
- the Parasites page on the Centre for Digestive Diseases website (Sydney, Australia)
- the BadBugs website for lots of horror stories about how hard these things are to treat.
We think my son might have had the little critters for up to a decade before them being tested for and diagnosed early last year.
Metronidazole and doxycyline are not always effective. If you are experiencing a reaction to wormwood, then something is obviously still there.
We had three rounds of treatment.
1st treatment - oral doxycycline: This worked on my husband (infected but asymptomatic), but my son's health slid further down into the pit after a very brief recovery. This was where the false negative came in.
2nd treatment: A double oral treatment of metronidazole and doxycyline, which was totally ineffective.
3rd treatment: A triple dose of very strong antibiotics administered via colonic irrigation, followed up with 10 days of oral antibiotic (also very strong). The CDC in Sydney administered the treatment.
This third treatment worked: no more gut symptoms, but he is still recovering from possibly a decade of malnutrition, as we call it.
Probiotics: We had to resort to D-lactate free probiotics. In the end, one brand of sheep's milk yoghurt was the best thing. I suspect it was fermented for long enough to consume all the lactose. (The scd diet website talks about this.)
Finally, we stumbled across this website. Who knows if it the ideas actually work, but we found the propolis helped heal the gut and the royal jelly helped with other issues. We never got to try the bee pollen because the triple antibiotic therapy came along first.
Thank you yes I found myself on those websites after the metronidazole didn't work (also near killed me, horrible drug I feel for you guys taking double & triple combos).
I really believed the doxycyline was effective but now I'm running over the last few months again with a dientamoeba lense.
In 2012 the severe brain fog started but I didn't have gut issues & malaise from it like the parasite caused in 2014 (it was quite particular, it'd hit late afternoon with fever when with ME/CFS that's my best time usually plus pretty dramatic gut issues). So I don't think my gut was symptomatic from dientamoeba until 2yrs after the initial severe brain fog.
2012 I was working 24hrs a week (10yrs after 1st ME/CFS dx) until I had minor surgery under general & wound up in bed for 6mths. I didn't think it was just ammonia from dientamoeba when I didn't have the dientamoeba gut sxs then. When I had the bad gut sxs I didn't have the bad brain fog. They didn't occur together. Guess I reason if I knew what went wrong I'd know where to try fixing it and its how I ended up down the methylation rabbit hole.
I really believed the doxycyline was effective but now I'm running over the last few months again with a dientamoeba lense.
In 2012 the severe brain fog started but I didn't have gut issues & malaise from it like the parasite caused in 2014 (it was quite particular, it'd hit late afternoon with fever when with ME/CFS that's my best time usually plus pretty dramatic gut issues). So I don't think my gut was symptomatic from dientamoeba until 2yrs after the initial severe brain fog.
2012 I was working 24hrs a week (10yrs after 1st ME/CFS dx) until I had minor surgery under general & wound up in bed for 6mths. I didn't think it was just ammonia from dientamoeba when I didn't have the dientamoeba gut sxs then. When I had the bad gut sxs I didn't have the bad brain fog. They didn't occur together. Guess I reason if I knew what went wrong I'd know where to try fixing it and its how I ended up down the methylation rabbit hole.
The gut issues for us were minor. A bit of constipation and some cramping. With a school-aged child, it we just thought 'this child is not robust'. It was the ongoing and increasing fatigue and brain fog that made us follow up more aggressively.
The triple combo was the most difficult. The post-treatment oral antibiotic caused severe nausea.
It's so hard to track all this down.
The triple combo was the most difficult. The post-treatment oral antibiotic caused severe nausea.
It's so hard to track all this down.
I don't have anything meaningful to add, most things I know have been mentioned.
But maybe a quick recap might help:
That would mean digestion and absorption of proteins would be less than optimal since the bacteria get a chance to do it instead.
Having a positive response to taking SAMe would also exclude methylation from your ammonia problems I think, since, if Homocysteine would be draining via the transsulfuration pathway (Homocysteine -> Cystathionine -> Ammonia) taking SAMe would lead to an increase and a worsening of your ammonia problems.
From what I've read so far having sufficient bile (and stomach acid) is also important to control gut bacteria (ties in in what I said above).
Boron helps, vitamin D is important (probably related to boron's effect). But I haven't done a lot of digging in this category.
In the end everything comes back to that damned (and wonderful) liver.
But maybe a quick recap might help:
- MTRR is the enzyme that 'fixes' inactive, protein bonded cobalamin for the MTR enzyme. If MTRR would have a meaningful impact it would be that more (Methyl)cobalamin is wasted and thus more Methylcobalamin is needed.
- MTR is the enzyme that does the heavy lifting in recycling Methylfolate to THF, forming Methylcobalamin and converting Homocysteine back to Methionine (cfr. the TMG thread). I guess more of all these things would be wasted in case it would be working less efficiently. Again, assuming if + SNPs have an impact.
That would mean digestion and absorption of proteins would be less than optimal since the bacteria get a chance to do it instead.
Having a positive response to taking SAMe would also exclude methylation from your ammonia problems I think, since, if Homocysteine would be draining via the transsulfuration pathway (Homocysteine -> Cystathionine -> Ammonia) taking SAMe would lead to an increase and a worsening of your ammonia problems.
From what I've read so far having sufficient bile (and stomach acid) is also important to control gut bacteria (ties in in what I said above).
Boron helps, vitamin D is important (probably related to boron's effect). But I haven't done a lot of digging in this category.
In the end everything comes back to that damned (and wonderful) liver.
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This paper/article seems to contain the answer: http://www.altmedrev.com/publications/13/3/216.pdf
Note that it does come from Thorne research. But a quick look at some of the things that are mentioned seem to confirm what is said.
Etc.
From a quick look at it folate metabolism is very important to maintain BH4 levels via several mechanisms. Although I question the Methylfolate <-> BH4 substitution he poses.
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There are links between folate and BH4 but some of that article is not correct.
The links are :-
1) Structural similarities, both being pteridine derivatives
2) The enzyme dihydrofolate reductase (DHFR) plays a role in both folate and BH4 related pathways
3) MeTHF is a peroxynitrile scavenger and so has BH4 sparing properties.
The article illustrates some of this correctly.
Fig 5 shows the structural similarities.
When BH4 acts as a cofactor in neurotransmitter synthesis (as shown in Fig 3 in the paper), it is oxidised to qBH2 (quinoid BH2).
qBH2 is regenerated to BH4 by the enzyme dihydropteridine reductase (DHPR; as shown on the left hand side of Fig 4b in the paper).
qBH2 can convert to BH2 (very closely related but not identical). BH2 can be regenerated to BH4 by the enzyme DHFR, as shown in Fig 4 b and 5.
DHFR is best known for its role in the folate cycle, where it reduces dihydrofolates (DHF) from, for example, vegetables, to tetrahydrofolate (THF), which then feeds into various folate pathways.
The broad specificity of the enzyme means it can also recognise folic acid, even though this compound is unknown in nature.
The same broad specificity means that it recognises BH2, reducing it by the same mechanism used for DHF.
So the same enzyme is used in two, independent metabolic pathways, a not uncommon situation.
Reference 37 in the article is about the peroxynitrile scavenging properites of MeTHF but the article seems to miss this completely and claims it as something else (more below).
As well as this midunderstanding, here are the things that are misleading in the article.
It (and Yasko) claims that there is another link between the pathways through MTHFR and that MeTHF regenerates BH4. This is shown in Fig 4a, the right hand side of Fig 4b and the left-hand side of Fig 6.
This is the idea that MTHFR runs backwards, directly regenerating BH4 (the reaction supposedly adversely affected by the SNP A1298C).
(Yasko says the reaction converts BH2 to BH4. The paper says it converts qBH2 to BH4).
Way back, I read a number of original papers trying to get to the bottom of this, since it contradicted textbooks and every scientific study I looked at. There was one exception.
That was an in vitro study which used qBH2 and various other reactants under conditions which forced the enzyme to run backwards. (The author was interested in the mechanism of action of the reaction). qBH2 was converted to BH4.
So the claim is not entirely baseless (though the SNP claim seems to be - I could find nothing whatsoever about that). Since 1980, however, when that single study was done, no other studies have followed so it doesn't appear to be of any significance.
The enzyme has never been shown to run backwards in vivo and the diagrams in the article are really fanciful.
The article also talks about the link between folate and BH4 via NOS, saying
I read both those references. The first one (37) doesn't say what the article says it does (and illustrates later with another version of MTHFR running backwards). The study actually shows that MeTHF protects BH4 in the NOS reaction by scavenging peroxynitrile. This is something which others studies have shown also.
As for the substitution claim which you are sceptical about @MacGyver, reference 38 provides in vitro and theoretical (computer modelling of the two substances in the enzymic binding site) evidence to support this, though none that it happens in vivo. So it is possible, but needs more study to confirm.
I am not sure the ammonia source is restricted to the gut as I am also affected by sulphur, lactulose can lower ammonia of hepatic origin, and my sxs can be exacerbated quite rapidly by particular supplements (like MSM) which suggests to me a metabolic component not just microbes.
@MacGyver I stopped the ALCAR, my body temperature is better and so are my emotions. This has effects on thyroid function and I am sensitive to that. It is plausible it was also generating a greater need for other nutrients in short supply. Maybe it is an occasional adjunct rather than a habitual one for me.
I hear what you're saying with SAMe and worsening my sxs I think. Do you mean instead of hcy cycling round to MTRR for conversion back to methionine it'll drain out via CBS and aggravate the sulphur/ammonia issues?
Is frustrating when the things you need make you worse for other reasons.
I have a couple of +/- CBS SNPs plus 1 BHMT +/- but this alone doesn't seem enough to explain it. Could slow a jam at MTR/MTRR cause hcy to back up and spill down CBS? Perhaps there's other genes and enzymes involved. I've had elevated liver enzymes before and generally react very poorly to pharmaceuticals, my liver is probably my saddest organ.
I have SAMe on its way from iherb, I'm going to increase my mfolate from 400 to 800 as per Freddd's protocol & see how that sits then try the SAMe and see how I respond. I was told by my ND (she's still learning too) to be careful of too much folate as I didn't need it (but did want me to try SAMe) so I was not concerned taking food based folate alongside mfolate but last few days I've separated them by several hours and I feel good after the mfolate dose then crash about 3 or 4hrs later.
@MacGyver I stopped the ALCAR, my body temperature is better and so are my emotions. This has effects on thyroid function and I am sensitive to that. It is plausible it was also generating a greater need for other nutrients in short supply. Maybe it is an occasional adjunct rather than a habitual one for me.
I hear what you're saying with SAMe and worsening my sxs I think. Do you mean instead of hcy cycling round to MTRR for conversion back to methionine it'll drain out via CBS and aggravate the sulphur/ammonia issues?
Is frustrating when the things you need make you worse for other reasons.
I have a couple of +/- CBS SNPs plus 1 BHMT +/- but this alone doesn't seem enough to explain it. Could slow a jam at MTR/MTRR cause hcy to back up and spill down CBS? Perhaps there's other genes and enzymes involved. I've had elevated liver enzymes before and generally react very poorly to pharmaceuticals, my liver is probably my saddest organ.
I have SAMe on its way from iherb, I'm going to increase my mfolate from 400 to 800 as per Freddd's protocol & see how that sits then try the SAMe and see how I respond. I was told by my ND (she's still learning too) to be careful of too much folate as I didn't need it (but did want me to try SAMe) so I was not concerned taking food based folate alongside mfolate but last few days I've separated them by several hours and I feel good after the mfolate dose then crash about 3 or 4hrs later.
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sb4
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Is it possible that high dose 5MTHF will "free up" more of DHFR so that is can recycle more BH4 instead of generating 5MTHF?
sb4
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Thanks, that totally make sense.
I wonder if the follow scenario could work out though. If you had an excessive need for both BH4 and 5MTHF thanks to peroxynitrite, virus dna methylation, or whatever then lets say that DHFR works at max rate on BH4 recyling @ 50 reactions per second and the same for 5MTHF. Now lets say that the need for BH4 is 100 and the same for 5MTHF. Then:
Need for BH4 (100) + need for 5MTHF (100) = 200;
Enzyme rate = 100;
Agonistic Signal = 200 - 100 = +100;
So in this scenario the enzyme would be running at max capacity and also being signaled to produce 100 more.
Now we give ample 5MTHF:
Need for BH4 (100) + need for 5MTHF (0) = 0;
Enzyme rate = 100;
Agonist signal = 0;
So in this scenario the agonist signal and inhibition signal would equal each other out so there would be no slowing of the enzyme. Plus due to the high concentration of 5MTHF and low concentration of BH4, all the enzyme activity would be recycling BH4.
I know I have pulled these numbers out of the air and I'm sorry if the question seems a bit pedantic. I am just trying to wrap my head around how enzymes operate.
I'm not sure what you mean by "and the same for 5MTHF". DHFR doesn't produce MeTHF, it produces THF. The latter does feed into the folate cycle, one product of which is MeTHF, but there are several steps in between and several different enzyme systems operating, each of which have their own set of rate determining parameters.
Need for MeTHF doesn't impact on DHFR, it mainly impacts on MTHFR.
Also, DHFR doesn't only recycle BH4, it also converts DHF (produced by the TYMS reaction) to THF. Demands from each of these reactions will vary depending on what else is going on in the cell.
You seem to be oversimplifying, though maybe I don't really understand your question.
sb4
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Thanks. Yeah I'm oversimplifying it because I don't understand it that well.
In this case, as the concentration of THF would be high, then DHFR should be more inclined to recycle BH4 (if the concentration of that is low). I was thinking, in this case, the inhibition provided by high THF wouldn't matter as the lack of BH4 would be agonistic (is this the correct word?) to the enzyme and the two would balance out. In this way MeTHF, not only by quenching peroxynitrite but also by causing excess THF (sparing DHFR) would help BH4 levels.
If you don't understand my question don't worry about it. It is clumsily written.
I was assuming that if MeTHF was in excess then also THF would be, and in that case DHFR would be inhibited by the THF as you say. Of course I didn't realise that THF could be used for things beside making MeTHF. However assuming that you took enough MeTHF, enough would recycle back to THF then go down those pathways until they have enough THF and say we don't need anymore and inhibit DHFR.
In this case, as the concentration of THF would be high, then DHFR should be more inclined to recycle BH4 (if the concentration of that is low). I was thinking, in this case, the inhibition provided by high THF wouldn't matter as the lack of BH4 would be agonistic (is this the correct word?) to the enzyme and the two would balance out. In this way MeTHF, not only by quenching peroxynitrite but also by causing excess THF (sparing DHFR) would help BH4 levels.
If you don't understand my question don't worry about it. It is clumsily written.