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Folic acid-this is weird. Methylation experts please.

folate methylfolate dopamine

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#1 experimenting

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Posted 18 January 2019 - 10:10 PM


I'm COMT -/- ie warrior. I'm great under stress, but generally useless in real life and rarely feel pleasure. Additional issues with weight gain and pain despite OK lab work.

So narrowed it down to neurotransmitters. Vit D megadose helped but hypercalcemia is a real problem. If I Co megadose K, the effects are lost.

So one of my SNPs apparently leads to low BH4, hence low neurotransmitters. But I do horribly on methyl donors because they speed up COMT which is already a problem.

So, enter good old folic acid. Took 1.2g and feeling strong dopaminergic effects. Is it placebo? Will it wear off? What's going on here? I'm confused and need help. What else should I stack with?

#2 experimenting

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Posted 18 January 2019 - 10:14 PM

I should add my methylation SNPs

A1298C; GG
C677T: GG

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#3 AceNZ

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Posted 18 January 2019 - 11:01 PM

The biochemistry here is relevant and important (too bad we can't post images....).

 

BH4 is a co-factor for the production of Tyrosine, L-DOPA (Dopamine precursors), 5-HTP (Serotonin precursor) and Nitric Oxide (NO). In the process of those reactions, BH4 is transformed into BH2. BH2 is then recycled back to BH4 using Methylfolate and SAMe.

 

In addition, BH4 is inhibited by Reactive Oxygen Species (ROS). The enzyme that converts BH2 to BH4 (DHPR) is inhibited by Aluminum, and the enzyme that converts Arginine to NO is inhibited by Lead.

 

COMT is responsible for breaking down Dopamine and Norepinephrine.

 

COMT -/- is the "normal" state, so I would be surprised if it's playing a significant role here (not impossible, just unlikely, IMO).

 

That high-dose Folic Acid helps suggests a possible issue with BH2 to BH4 recycling.

 

If BH4 is a problem, the typical stack would be:

 

1. Methylfolate (supports BH2 to BH4) -- *not* Folic Acid, which can create havoc with methylation-related metabolism

2. Methyl-B12 (supports methylation-related metabolism). Some people need different forms of B12 at first, but most do OK on the Methyl version.

3. Magnesium citrate (helps drive the Methionine cycle to indirectly provide SAMe; better than taking SAMe directly for most people)

4. A strong anti-oxidant or two to drive-down ROS, anything *except* Vit C -- a mix of Vit E, CoQ10, Vit A and similar is generally fine

 

I would add them one at a time with a day or two in between each, in the order above, rather than all at once.

 

If you don't make enough progress with those, the next step would be to try adding Tyrosine and/or 5-HTP.

 

I would also suggest an RBC Mineral test, to check for high Aluminum and Lead.

 



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#4 experimenting

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Posted 18 January 2019 - 11:19 PM

The biochemistry here is relevant and important (too bad we can't post images....).

BH4 is a co-factor for the production of Tyrosine, L-DOPA (Dopamine precursors), 5-HTP (Serotonin precursor) and Nitric Oxide (NO). In the process of those reactions, BH4 is transformed into BH2. BH2 is then recycled back to BH4 using Methylfolate and SAMe.

In addition, BH4 is inhibited by Reactive Oxygen Species (ROS). The enzyme that converts BH2 to BH4 (DHPR) is inhibited by Aluminum, and the enzyme that converts Arginine to NO is inhibited by Lead.

COMT is responsible for breaking down Dopamine and Norepinephrine.

COMT -/- is the "normal" state, so I would be surprised if it's playing a significant role here (not impossible, just unlikely, IMO).

That high-dose Folic Acid helps suggests a possible issue with BH2 to BH4 recycling.

If BH4 is a problem, the typical stack would be:

1. Methylfolate (supports BH2 to BH4) -- *not* Folic Acid, which can create havoc with methylation-related metabolism
2. Methyl-B12 (supports methylation-related metabolism). Some people need different forms of B12 at first, but most do OK on the Methyl version.
3. Magnesium citrate (helps drive the Methionine cycle to indirectly provide SAMe; better than taking SAMe directly for most people)
4. A strong anti-oxidant or two to drive-down ROS, anything *except* Vit C -- a mix of Vit E, CoQ10, Vit A and similar is generally fine

I would add them one at a time with a day or two in between each, in the order above, rather than all at once.

If you don't make enough progress with those, the next step would be to try adding Tyrosine and/or 5-HTP.

I would also suggest an RBC Mineral test, to check for high Aluminum and Lead.


Nice one, thanks. But as I said-I have serious issues with methyl donors. Methyl folate flattens me out completely (think it's norepinephrine related) and b12 just makes me feel weird (blood level is also 650 so no issues there).

You mentioned that folic acid wreaks havoc with the cycle, why's that? Also, isnt COMT +/- normal?

Thanks again.

#5 AceNZ

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Posted 18 January 2019 - 11:42 PM

Nice one, thanks. But as I said-I have serious issues with methyl donors. Methyl folate flattens me out completely (think it's norepinephrine related) and b12 just makes me feel weird (blood level is also 650 so no issues there).

You mentioned that folic acid wreaks havoc with the cycle, why's that? Also, isnt COMT +/- normal?

Thanks again.

 

Your user name here is appropriate: you may have to do some self-experimentation to find the right combination.

 

Since you have trouble with Methylfolate and since regular B12 makes you feel wierd, you may need to start with one of the alternative forms of B12:

 

Hydroxo-B12 is good when you have elevated ROS and elevated NO. It helps lower NO. Don't use Methylfolate while on Hydroxo-B12.

 

Adenosyl-B12 is good with elevated MMA or SNPs in CBL genes. Can use with Methyfolate if NO isn't elevated.

 

Measured blood levels of B12 may or may not be meaningful, depending on the status of your MTHFR and related enzymes/SNPs. If you have 23andMe data, you can get a free analysis at Genetic Genie: https://geneticgenie...ation-analysis/

 

BTW, Vit D is also an anti-oxidant, so it may be that the reason megadoses helped is because it drove down ROS. You might try other anti-oxidants to see if they have a similar effect.

 

The reason for avoiding Vit C in my antioxidant step is because it breaks down Norephinephrine. However, if you're experiencing high Nor levels, then Vit C may actually be a good choice. (Keep in mind that at very high doses, Vit C is actually an oxidant, not an antioxidant).

 

The "-" in SNP markers means that you don't have an uncommon allele; a "+" means you do have an uncommon allele. So "-/-" means common allele on both strands of DNA. Usually, but not always, a "+" is associated with an underactive enzyme, with "-/+" being a little underactive, and "+/+" being very underactive.

 

Folic Acid isn't found in nature. It's a synthetic compound. As such, it isn't metabolized cleanly, and the byproducts can interfere with the associated metabolism. It's a bad, bad compound that should be purged from all foods and supplements. Methylfolate the best form to supplement.

 

In addition to the items you supplement, you may also need to experiment with dosing. Sometimes, a small / micro dose is all that's needed.



#6 experimenting

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Posted 19 January 2019 - 12:54 AM

Your user name here is appropriate: you may have to do some self-experimentation to find the right combination.

Since you have trouble with Methylfolate and since regular B12 makes you feel wierd, you may need to start with one of the alternative forms of B12:

Hydroxo-B12 is good when you have elevated ROS and elevated NO. It helps lower NO. Don't use Methylfolate while on Hydroxo-B12.

Adenosyl-B12 is good with elevated MMA or SNPs in CBL genes. Can use with Methyfolate if NO isn't elevated.

Measured blood levels of B12 may or may not be meaningful, depending on the status of your MTHFR and related enzymes/SNPs. If you have 23andMe data, you can get a free analysis at Genetic Genie: https://geneticgenie...ation-analysis/

BTW, Vit D is also an anti-oxidant, so it may be that the reason megadoses helped is because it drove down ROS. You might try other anti-oxidants to see if they have a similar effect.

The reason for avoiding Vit C in my antioxidant step is because it breaks down Norephinephrine. However, if you're experiencing high Nor levels, then Vit C may actually be a good choice. (Keep in mind that at very high doses, Vit C is actually an oxidant, not an antioxidant).

The "-" in SNP markers means that you don't have an uncommon allele; a "+" means you do have an uncommon allele. So "-/-" means common allele on both strands of DNA. Usually, but not always, a "+" is associated with an underactive enzyme, with "-/+" being a little underactive, and "+/+" being very underactive.

Folic Acid isn't found in nature. It's a synthetic compound. As such, it isn't metabolized cleanly, and the byproducts can interfere with the associated metabolism. It's a bad, bad compound that should be purged from all foods and supplements. Methylfolate the best form to supplement.

In addition to the items you supplement, you may also need to experiment with dosing. Sometimes, a small / micro dose is all that's needed.


So basically my goal seems to be to rev up BH4. Folate does this, no? How does b12 help me at all? Not sure what else will do this that isn't a methyl donor.

#7 AceNZ

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Posted 19 January 2019 - 02:12 AM

So basically my goal seems to be to rev up BH4. Folate does this, no? How does b12 help me at all? Not sure what else will do this that isn't a methyl donor.

 

To rev-up BH4, you need three things: Methylfolate, SAMe, and low ROS. Two of those are methyl donors. You may only need to supplement or fix one or two of the three, depending on your particular biochemistry.

 

Methylfolate can be taken as a supplement. ROS can be decreased with antioxidants.

 

You need the B12 to produce SAMe.

 

For SAMe, it's best to not take it as a supplement, and instead create it endogenously. SAMe is made is by metabolizing Methionine, through a step that requires Magnesium, as part of the Methionine cycle.

 

Methionine, in turn, can be obtained in the diet, but it's mostly made by metabolizing Homocysteine, through a step that requires Oxygen, Zinc, B2, B3, B12 and Methylfolate -- with B12 and Methylfolate being the limiting factors for most people.

 

I should add that your trouble with Methylfolate isn't uncommon. The usual recommendation there is to start with Methyl-B12. Since you can't tolerate that either, then start with the Hydroxo (most likely) or Adenosyl form. Take it for four to six weeks, at a relatively high dose (at least 5000 mcg). This should help normalize your methylation-related metabolism. After that, try Methyl-B12 again. When you can tolerate that, then add a small dose of Methylfolate (say 400 mcg or even less), and see how you do.



#8 experimenting

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Posted 19 January 2019 - 02:18 AM

To rev-up BH4, you need three things: Methylfolate, SAMe, and low ROS. Two of those are methyl donors. You may only need to supplement or fix one or two of the three, depending on your particular biochemistry.

Methylfolate can be taken as a supplement. ROS can be decreased with antioxidants.

You need the B12 to produce SAMe.

For SAMe, it's best to not take it as a supplement, and instead create it endogenously. SAMe is made is by metabolizing Methionine, through a step that requires Magnesium, as part of the Methionine cycle.

Methionine, in turn, can be obtained in the diet, but it's mostly made by metabolizing Homocysteine, through a step that requires Oxygen, Zinc, B2, B3, B12 and Methylfolate -- with B12 and Methylfolate being the limiting factors for most people.

I should add that your trouble with Methylfolate isn't uncommon. The usual recommendation there is to start with Methyl-B12. Since you can't tolerate that either, then start with the Hydroxo (most likely) or Adenosyl form. Take it for four to six weeks, at a relatively high dose (at least 5000 mcg). This should help normalize your methylation-related metabolism. After that, try Methyl-B12 again. When you can tolerate that, then add a small dose of Methylfolate (say 400 mcg or even less), and see how you do.


Here's an interesting theory. I need more BH4, but I also have overactive COMT. COMT requires methyl groups. If I take folic acid, I deplete methyl groups, reducing COMT. AND eventually I get BH4. This seems to be what I'm feeling. This possible?

I tried SAM-E and just felt jittery. And I'm just now remembering how horrible I felt on 5MTHF, just this awful dysphoria, so I'm a bit scared of trying it again (in fairness I started at 1mg, so perhaps the thing to do was scale down the dose).

But maybe cheap folic acid is a crude way of getting to the end goal?

#9 AceNZ

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Posted 19 January 2019 - 02:55 AM

Here's an interesting theory. I need more BH4, but I also have overactive COMT. COMT requires methyl groups. If I take folic acid, I deplete methyl groups, reducing COMT. AND eventually I get BH4. This seems to be what I'm feeling. This possible?

I tried SAM-E and just felt jittery. And I'm just now remembering how horrible I felt on 5MTHF, just this awful dysphoria, so I'm a bit scared of trying it again (in fairness I started at 1mg, so perhaps the thing to do was scale down the dose).

But maybe cheap folic acid is a crude way of getting to the end goal?

 

High Folic Acid would act something like Methotrexate, so, yes, it would reduce methylation. However, low methylation would impair BH4, not improve it.

 

COMT specifically works with SAMe, the same material needed for BH4.

 

Feeling jittery after taking SAMe suggests high levels of norepinephrine, which in turn suggests normal or even slow COMT, not overactive.

 

I understand being reluctant to try things that have produced bad experiences in the past -- totally reasonable. Since you're having trouble on the methylation side, you may want to start by attacking ROS with antioxidants, as I said earlier.

 

Good luck!



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#10 experimenting

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Posted 19 January 2019 - 04:07 AM

High Folic Acid would act something like Methotrexate, so, yes, it would reduce methylation. However, low methylation would impair BH4, not improve it.

COMT specifically works with SAMe, the same material needed for BH4.

Feeling jittery after taking SAMe suggests high levels of norepinephrine, which in turn suggests normal or even slow COMT, not overactive.

I understand being reluctant to try things that have produced bad experiences in the past -- totally reasonable. Since you're having trouble on the methylation side, you may want to start by attacking ROS with antioxidants, as I said earlier.

Good luck!


Thanks.

I'm looking through my SNPs and of the routes you've described I think the folate avenue is the one to start with.

Going to retry 5MTHF-but since you mentioned it, what are the specific dangers of folic acid?

#11 AceNZ

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Posted 19 January 2019 - 04:20 AM

Going to retry 5MTHF-but since you mentioned it, what are the specific dangers of folic acid?

 

Probably an increased cancer risk, especially at higher doses.

 

More info at the link:

 

https://www.drfuhrma...-not-folic-acid



#12 Furniture

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Posted 26 January 2019 - 12:36 AM

Your user name here is appropriate: you may have to do some self-experimentation to find the right combination.

 

Since you have trouble with Methylfolate and since regular B12 makes you feel wierd, you may need to start with one of the alternative forms of B12:

 

Hydroxo-B12 is good when you have elevated ROS and elevated NO. It helps lower NO. Don't use Methylfolate while on Hydroxo-B12.

 

Adenosyl-B12 is good with elevated MMA or SNPs in CBL genes. Can use with Methyfolate if NO isn't elevated.

 

Measured blood levels of B12 may or may not be meaningful, depending on the status of your MTHFR and related enzymes/SNPs. If you have 23andMe data, you can get a free analysis at Genetic Genie: https://geneticgenie...ation-analysis/

 

BTW, Vit D is also an anti-oxidant, so it may be that the reason megadoses helped is because it drove down ROS. You might try other anti-oxidants to see if they have a similar effect.

 

The reason for avoiding Vit C in my antioxidant step is because it breaks down Norephinephrine. However, if you're experiencing high Nor levels, then Vit C may actually be a good choice. (Keep in mind that at very high doses, Vit C is actually an oxidant, not an antioxidant).

 

The "-" in SNP markers means that you don't have an uncommon allele; a "+" means you do have an uncommon allele. So "-/-" means common allele on both strands of DNA. Usually, but not always, a "+" is associated with an underactive enzyme, with "-/+" being a little underactive, and "+/+" being very underactive.

 

Folic Acid isn't found in nature. It's a synthetic compound. As such, it isn't metabolized cleanly, and the byproducts can interfere with the associated metabolism. It's a bad, bad compound that should be purged from all foods and supplements. Methylfolate the best form to supplement.

 

In addition to the items you supplement, you may also need to experiment with dosing. Sometimes, a small / micro dose is all that's needed.

 

Isn't Vitamin C is a cofactor in Norepinephrine synthesis from dopamine? not it's breakdown into epinephrine

 

https://www.ncbi.nlm...les/PMC3527656/

"Ascorbic acid enhances synthesis of norepinephrine from dopamine in adrenal chromaffin cells by serving as a co-factor for chromaffin granule dopamine β-hydroxylase (DβH). However, there is controversy regarding in situ kinetics of the ascorbate effect in chromaffin cells, as well as whether they apply to neuronal cells. In this study we evaluated the stimulation of norepinephrine synthesis from dopamine in cultured SH-SY5Y neuroblastoma cells. These cells contained neither ascorbate nor norepinephrine in culture, but when provided with dopamine, they generated intracellular norepinephrine at rates that were stimulated several fold by intracellular ascorbate. Ascorbate-induced increases in norepinephrine synthesis in dopamine-treated cells were linear over 60 minutes, despite saturation of intracellular ascorbate. Norepinephrine accumulation after 60 minutes of incubation with 100 μM dopamine was half-maximal at intracellular ascorbate concentrations of 0.2 – 0.5 mM, which fits well with the literature Km for ascorbate of DβH using dopamine as a substrate. Moreover, these ascorbate concentrations were generated by initial extracellular ascorbate concentrations of less than 25 μM due to concentrative accumulation by the ascorbate transporter. Treatment with 100 μM dopamine acutely increased cellular superoxide generation, which was prevented by ascorbate loading, but associated with a decrease in intracellular ascorbate when the latter was present at concentrations under 1 mM. These results show that ascorbate promptly enhances norepinephrine synthesis from dopamine by neuronal cells, that it does so at physiologic intracellular concentrations in accord with the kinetics of DβH, and that it both protects cells from superoxide and by providing electrons to DβH."

 

 



#13 AceNZ

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Posted 26 January 2019 - 01:02 AM

Isn't Vitamin C is a cofactor in Norepinephrine synthesis from dopamine? not it's breakdown into epinephrine

 

https://www.ncbi.nlm...les/PMC3527656/

"Ascorbic acid enhances synthesis of norepinephrine from dopamine in adrenal chromaffin cells by serving as a co-factor for chromaffin granule dopamine β-hydroxylase (DβH)."

 

Sorry, typo.

 

I meant to say the reason to avoid Vit C in my antioxidant step is that it helps breaks down / speeds the conversion of Dopamine into Norepinephrine (aka "enhances synthesis of norepinephrine from dopamine"). If one of your goals is to increase Dopamine, Vit C works against that. Similarly, the second part after that should say "high Dop or low Nor," not "high Nor."



#14 Furniture

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Posted 26 January 2019 - 04:58 AM

I should add my methylation SNPs

A1298C; GG
C677T: GG

 

Since you have no SNP in your MTHFR genes and you seem to react positively to Folic Acid, I would suggest making sure you get adequate Vitamin B6 and B2 in your diet (or supplementing if this is not sufficient). Both B6 and B2 are required in the pathway to produce MethylFolate from Folic Acid.

 

folic-acid-metabolism.png

 

Additionally, have you tried using Folinic Acid (AKA 5-Formyl-THF)? It's found naturally in foods and is more downstream than Folic Acid so it would therefore be more active than Folic Acid. Many people who are sensitive to methyl- groups (which you say you are) use Folinic Acid supplements with success


Edited by Furniture, 26 January 2019 - 05:04 AM.


#15 gamesguru

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Posted 26 January 2019 - 06:26 AM

I would wager the opposite.. low dopamine and high norepinephrine.

 

Avoid calcium, supplement magnesium.. experiment with ginseng, green tea, and COMT-inhibiting flavonoids.



#16 experimenting

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Posted 26 January 2019 - 05:51 PM

Since you have no SNP in your MTHFR genes and you seem to react positively to Folic Acid, I would suggest making sure you get adequate Vitamin B6 and B2 in your diet (or supplementing if this is not sufficient). Both B6 and B2 are required in the pathway to produce MethylFolate from Folic Acid.

folic-acid-metabolism.png

Additionally, have you tried using Folinic Acid (AKA 5-Formyl-THF)? It's found naturally in foods and is more downstream than Folic Acid so it would therefore be more active than Folic Acid. Many people who are sensitive to methyl- groups (which you say you are) use Folinic Acid supplements with success


Going to give it a try-will report back. Basically I like the concept of downstream folates, minus the methyl group. Let's see.

#17 experimenting

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Posted 26 January 2019 - 06:12 PM

Since you have no SNP in your MTHFR genes and you seem to react positively to Folic Acid, I would suggest making sure you get adequate Vitamin B6 and B2 in your diet (or supplementing if this is not sufficient). Both B6 and B2 are required in the pathway to produce MethylFolate from Folic Acid.

folic-acid-metabolism.png

Additionally, have you tried using Folinic Acid (AKA 5-Formyl-THF)? It's found naturally in foods and is more downstream than Folic Acid so it would therefore be more active than Folic Acid. Many people who are sensitive to methyl- groups (which you say you are) use Folinic Acid supplements with success


I think the SNP I have is the rarer A1298C which means my body doesn't convert METHYLFOLATE well. But I also have overactive COMT. So one idea would be to significantly overload with methylfolate but avoid adding extra methyl groups- hence the folate.

#18 Furniture

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Posted 26 January 2019 - 07:00 PM

I think the SNP I have is the rarer A1298C which means my body doesn't convert METHYLFOLATE well. But I also have overactive COMT. So one idea would be to significantly overload with methylfolate but avoid adding extra methyl groups- hence the folate.

 

Ahhh my mistake. You are homozygous for A1298C and normal (wild type) for C677T
 



#19 experimenting

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Posted 26 January 2019 - 07:07 PM

Ahhh my mistake. You are homozygous for A1298C and normal (wild type) for C677T

Yep exactly. So can't convert 5MTHF. Hence the generally flat affect. Is ramming my body with more folates a solution? Basically I think I suffer from low BH4.

Edited by experimenting, 26 January 2019 - 07:07 PM.


#20 Furniture

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Posted 26 January 2019 - 07:25 PM

Yep exactly. So can't convert 5MTHF. Hence the generally flat affect. Is ramming my body with more folates a solution? Basically I think I suffer from low BH4.

 

I'm not sure. It seems that A1298C mutations aren't as much of an issue as C677T. What I've read is that A1298C SNP's don't slow the conversion to Methylfolate greatly unless combined with at least 1 mutation at C677T (compound homo- or hetereozygous).

 

For now I would try supplementing with Folinic Acid (and possibly cofactors like B2 and B6) and see how you react. I don't think this will be available in store, but amazon.com and iherb.com carry a few brands.

 

Additionally, make sure you are getting adequate Potassium and Magnesium. It seems that pushing on your methylation and folate cycles in any manner, usually through B-vitamins, can have a mopping effect on K and Mg leading to deficiency. Some people mistake anxiety, tremors, depression, and other psychologically effects to methyl- groups but are really experiencing a rapid loss of electrolytes.

http://mthfr.net/pre...cts/2014/11/26/

https://forums.phoen...angerous.14410/

 

Also, how do you react to plain old Tyrosine or Phenylalanine?


Edited by Furniture, 26 January 2019 - 07:28 PM.


#21 experimenting

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Posted 26 January 2019 - 08:08 PM

I'm not sure. It seems that A1298C mutations aren't as much of an issue as C677T. What I've read is that A1298C SNP's don't slow the conversion to Methylfolate greatly unless combined with at least 1 mutation at C677T (compound homo- or hetereozygous).

For now I would try supplementing with Folinic Acid (and possibly cofactors like B2 and B6) and see how you react. I don't think this will be available in store, but amazon.com and iherb.com carry a few brands.

Additionally, make sure you are getting adequate Potassium and Magnesium. It seems that pushing on your methylation and folate cycles in any manner, usually through B-vitamins, can have a mopping effect on K and Mg leading to deficiency. Some people mistake anxiety, tremors, depression, and other psychologically effects to methyl- groups but are really experiencing a rapid loss of electrolytes.
http://mthfr.net/pre...cts/2014/11/26/
https://forums.phoen...angerous.14410/

Also, how do you react to plain old Tyrosine or Phenylalanine?


Headaches from tyrosine. I think it skews my neurotransmitters too much.

My flat affect "feels" like low bh4, whatever that means. Crucially, A1298C doesn't affect MTFHR. It affects conversation of MTFHR into BH4. So I'm not sure how exactly to drive more of this conversion, more folate or not. Why do you suggest b2 and b6?

#22 Furniture

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Posted 26 January 2019 - 09:34 PM

Headaches from tyrosine. I think it skews my neurotransmitters too much.

My flat affect "feels" like low bh4, whatever that means. Crucially, A1298C doesn't affect MTFHR. It affects conversation of MTFHR into BH4. So I'm not sure how exactly to drive more of this conversion, more folate or not. Why do you suggest b2 and b6?

 

A1298C does affect MTHFR:

 

https://genesight.co...c-polymorphism/

 

Table 1: The Effect of the MTHFR C677T and A1298C Polymorphisms on MTHFR Enzyme Activity

Genotype 677CC 677CT 677TT 1298 AA 100% 51-73%2-4 22-32%2-4 1298 AC 60-92%2-4 36-60%2-4 N/A 1298 CC 52-60%2-4 N/A N/A

*Percentages denote MTHFR enzyme activity. Ranges are included to reflect different values reported in the literature.

 

(ok this is supposed to be a table, click on the link for the right format)

 

 

And MTHFR doesn't convert BH4, do you mean DHFR? DHFR (dihydrofolate reductase) converts DHF to THF but also BH2 to BH4, and I don't think this happens concurrently, I think they compete for the enzyme. Here's why I think that:

 

The-interlinked-folate-and-methionine-cy

 

It seems that in the normal folate cycle, 5,10-MTHF converts to 5-MTHF (by way of the MTHFR enzyme) which would eventually lead to THF and back to 5,10,-MTHF again.

 

But with a A1298C polymorphism (less MTHFR activity or a Vitamin B2 deficiency) the conversion is slowed and 5,10-MTHF gets backed up. Instead, 5,10-MTHF converts to DHF (by the enzyme Thymidylate Synthase (TS) which uses deoxyuridine monophosphate (dUMP) as a cofactor). Then, DHF has to convert to THF to re-enter the normal folate cycle. In order to do that, it uses the DHFR enzyme and competes with BH2. It might be that DHFR has a higher affinity for DHF than it does for BH2 so less BH4 is synthesized in order to prioritize making THF needed in the folate cycle. And this is why low BH4 levels may be a thing.

 

I searched online and found what you said, that A1298C is not so much implicated with high homocysteine levels and is more implicated in cases of low BH4 levels, but they don't give an explanation how or why. I couldn't find information that A1298C is directly involved in BH4 recycling over C677T, only that it seems to be implicated, maybe by clinical or anecdotal evidence?? From my understanding, both C677T and A1298C mutations should lower BH4 levels since they both are components of the MTHFR gene (which converts 5,10-MTHF to 5-MTHF)

 

Also I'm totally making the assumption that DHF and BH2 are competitive for one another as a substrate for DHFR, not that they are both required for that one reaction, as the arrows might appear to indicate. I got that from this:

 

https://www.mygenefo...n-bh4-can-make/

"As mentioned above, several studies have shown that DHFR can recycle BH4 from BH2. This study by Xu et al (R) investigates its role in detail, trying to understand how QDPR and DHFR interact. Using mice completely lacking the QDPR gene, the authors discovered that DHFR was able to step in and replace its activity. However, there are a couple of caveats that go with the study. Firstly, the affinity of DHFR for BH2 is much lower than for DHF, so the authors propose that the recycling activity of DHFR only kicks in when levels of BH2 are high. Secondly, the authors also state that the affinity of mouse DHFR for BH2 is much higher than that of the human form. So, whilst DHFR may be able to step in to assist BH2 to BH4 processing its importance might be much lower. Finally, the authors show that high levels of BH2 also lead to a reduction in the availability of THF. The logical explanation for this would be that DHF. THF activity is reduced as DHFR is converting BH2 > BH4. However, this doesn’t seem to be the case. The authors were unable to exactly pinpoint how these were linked but hypothesized that excess BH2 may impact on the activity of other enzymes such as MTHFR."

 

Figure-3.png


Edited by Furniture, 26 January 2019 - 09:39 PM.


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#23 Furniture

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Posted 26 January 2019 - 09:44 PM

Yea L-Tyrosine makes me really irritable if I use it twice in a row or more.

 

I've learned that amino acid precursors for neurotransmitters is only for short-term relief and is not the right way to tackle the root cause to a problem, because the body is pretty efficient at regulating when there are excess precursors or recycling when there's a lack of them.



#24 Furniture

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Posted 26 January 2019 - 09:46 PM

Also, did you get your MTR, MTRR, BHMT, or CBS genes tested?



#25 experimenting

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Posted 27 January 2019 - 12:25 AM

Also, did you get your MTR, MTRR, BHMT, or CBS genes tested?


MTRR A66G: GG ++
MTRR K350A: AA--
MTRR R415T: CC--

CBS C699T: GG--

No idea what those mean or what to do now...confused. All I think is that my combination of COMT and MTFHR means I should take folate, but not methylfolate. Any ideas? Maybe Niacin?

#26 Furniture

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Posted 29 January 2019 - 06:12 AM

MTRR and MTR are both involved in creating Methionine Synthase (MS), to be specific:

MTRR is the gene instruction for Methionine Synthase Reductase: which is required to produce Methionine Synthase (MS)

MTR is the gene instruction for Methione Synthase (MS) which regenerates methionine from homocysteine

 

Methionine Synthase is what connects the Folate Cycle to the Methionine Cycle, it uses Vitamin B2, B12 and 5-MTHF (AKA B9) and converts Homocysteine to Methionine.

 

I'm not sure about the sub-parts of the MTRR gene you listed, I will look into it and get back to you.

 

Sorry I cant be of further assistance. I'm trying to understand all of this myself.



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#27 experimenting

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Posted 29 January 2019 - 10:33 PM

Thanks. I'm quite confused too. More research required.





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