New, Inexpensive CBS Ammonia Fix

[nandixon]

I'm not finding any evidence that MTHFR makes BH4 when it runs backwards. Are you sure?

That was sort of my point. Yasko believes this to be true based on the in vitro work of S. Kaufman from 1980:

"Characterization of the dihydropterin reductase activity of pig liver methylenetetrahydrofolate reductase."
http://www.ncbi.nlm.nih.gov/pubmed/6967065

(Kaufman followed up with this 1991 paper: "Some metabolic relationships between biopterin and folate: implications for the 'methyl trap hypothesis'." http://www.ncbi.nlm.nih.gov/pubmed/1784330)

Whether that in vitro reaction described by Kaufman occurs in vivo to any significant extent is debatable. And if it does, note that the substrate for MTHFR in the (in vitro only) reverse direction is quinoid-BH2, not BH2. These are two different isomeric molecules. (q-BH2 is apparently fairly easily converted to BH2, but it's important not to confuse the two.)

As far as I can tell, DHPR and DHFR (a folate enzyme) are the only two enzymes that can make BH2 into BH4.

Again, just to reiterate, DHPR (aka QDPR) uses q-BH2 as its substrate when it forms BH4. DHFR uses the very similar, but different molecule BH2 when it forms BH4. (Yasko confuses q-BH2 with BH2 as well.)

MTHFR can convert q-BH2 into BH4 when running in the reverse direction (as seen in the above linked articles), but this has only been shown in vitro, to my knowledge.

MTHFR cannot convert BH2 into BH4 in any direction.

 

[Kimsie]

Thank you, nadnixon, I took a look at those links.

I have been thinking about it and I think that maybe it doesn't really matter whether MTHFR makes BH4 or not. Taking large amounts of folate didn't help my husband's ammonia issue, taking large amounts of B1 to help make NADPH did. I think it is really an issue with making enough NADPH. NADPH is a currency which can buy ATP and BH4, which you can see in the diagram below. If a person needs to buy a lot of ATP with their NADPH, they won't have enough for BH4, too, unless they can make a lot of NADPH.

To me it appears that when a person is affected by an inability to produce sufficient ATP through the TCA cycle, their body tries to use other pathways for energy production as much as possible, for instance the increase of lactic acid in some people making ATP through glycolysis. Folate is one of those pathways which can make ATP, but at a cost of NADPH and thus BH4, or else at a cost of B6.

My son who has fatigue and depression, was fatigued until he started taking 5 mg of folate a day. The folate relieved his fatigue in 2 hours. I don't think his improvement was from purine synthesis, because purine synthesis takes quite a few ATP. It must have been because he started producing more ATP through these folate pathways.

After about 6 weeks of high folate he started having symptoms of depression. I am pretty sure now that it was because the SHMT enzyme, being used so much, was draining his B6 stores from his body. I have now found that no matter how much B6 I give him, it only gives him a temporary improvement, which I think is because his body adjusts the amount of SHMT enzyme up and since he gets a lot of folate, the extra B6 isn't available for the pathway that causes his depression - the synthesis of heme and catalase and the catalase is needed for dopamine beta-hydroxlase and he doesn't have enough nor-epinephrine so he is depressed (getting depression from low nor-epinephrine appears to also be genetically determined.)

So I am convinced that if a person's pathway to make ATP by the SHMT loop is active enough to significantly contribute to ATP synthesis, it drains B6, at least in susceptible individuals who are affected. Often these people don't have good dream recall.

Of course most likely in most people both of these pathways are working together to make ATP, because the SHMT loop provides NADPH and glycine for the glycine cleavage system loop or for the little purple loop, which I will call the formyltetrahydrofolate dehydrogenase, or FTD loop. In general NADPH would be drained, and in some people B6 would also be drained, and sometimes glycine and/or serine, depending on how well a person was able to make them from the glycolysis pathway or from pyruvate.

So now I am taking my son down to 1 mg of folate a day, and focusing on how to increase his energy production so that he can have enough energy without having to use the folate cycle to produce it. I just started yesterday, so I can't report on my results, yet.

 

[Kimsie]

By the way, Purebulk still has their L-malic acid for sale at 30% off today and tomorrow for Black Friday Sale.

 

[Tunguska]

It might be interesting, if you haven't done it already, to see if taking S-adenosylmethionine (Sam-e) gives you the same negative effect you feel from methylcobalamin (MeCbl)/adenosylcobalamin (AdoCbl), or if it gives you the same positive effect you feel from methylfolate...

I completely forgot. I tried this a second round with large doses of SAMe (1600mg), and still nothing at all. There was a very slight improvement with huge doses of TMG (~5g) but nowhere near methylfolate, though still take some along with methylfolate. I tend to think it's something specific to the folate and not methylating, whether backwards MTHFR or folate cycle as kimsie above or what do I know. Neither do I know what the deal is with B12 so I assume it locks up the folate. It's not bad in smaller doses.

I also don't take malic acid anymore and went back to eating apples, but could not try the liposomal (may later along with lipo vit C, just not thrilled about the lecithin).

 

[aaron_c]

I think that when someone takes a lot of methylfolate it can increase all the folate reactions, including DHFR, which does make BH4, and that might be where the confusion comes from.

I think our bodies tightly regulate the amount of folates in our cells...or at least prevent the levels from going over a certain point. Thus, taking a lot of folates would not necessarily "speed up" all folate reactions. I think this is why taking folinic acid (aka leucovorin) with MTHF usually means you have to take a lot more MTHF--cells will preferentially take up folinic acid before MTHF. Unfortunately, I can't find the exact link that said that when you take a lot of folates the, Reduced Folate Carrier prefers folinic acid to MTHF...but see this imperfect explanation of the two main folate transporters for starters.

On another topic, I have been thinking about what you said regarding CBS regulation. As I see it now, CBS upregulation ala Yasko seems unlikely for most people (see this critique), yet I will give yasko the benefit of the doubt in assuming that she is seeing a pattern in her patients with CBS C699T. Rich Van K also found a pattern of lower homocysteine for people with that snp in his study (he says so in the Sweden videos). So I have been wondering how to reconcile the data.

I wonder if perhaps the issue is B6 availability. Specifically, Rich Van Konynenburg and Amy Yasko are both looking at populations that (I think?) have limited activated B6 (Pyridoxal-5-phosphate, aka P5P, not to be confused with the P5P that is pentose-5-phosphate). In those conditions, someone with a wild-type (aka "normal) CBS would have reduced activity, in effect "sharing" the limited P5P, whereas the CBS enzyme of someone with the C699T mutation might "hog" the P5P. Thus, old people and people and others with Krebs Cycle dysfunction show differences in CBS function depending on the presence of a fairly common SNP, whereas healthy people do not.

 

[Kimsie]

I think our bodies tightly regulate the amount of folates in our cells...or at least prevent the levels from going over a certain point. Thus, taking a lot of folates would not necessarily "speed up" all folate reactions. I think this is why taking folinic acid (aka leucovorin) with MTHF usually means you have to take a lot more MTHF--cells will preferentially take up folinic acid before MTHF. Unfortunately, I can't find the exact link that said that when you take a lot of folates the, Reduced Folate Carrier prefers folinic acid to MTHF...but see this imperfect explanation of the two main folate transporters for starters.

If a person can metabolize folinic acid, why would they need to take MTHF also? If a person can metabolize folinic acid they will change it to MTHF, following an oral dose, and if they can't, they shouldn't take it at all.

I didn't say that taking a lot of folate would speed up all folate reactions, I said it could increase all folate reactions, meaning that it gave the body the opportunity to increase whichever folate reactions it needed to increase, assuming that the needed substrate and cofactors were available, and that there was not inhibition from products. For instance, if the electron transport chain is inhibited and ADP is building up, the body will use large amounts of folate to produce energy, if other factors such as serine are available. Same thing goes for NADPH.

However, this does not mean that we want all these folate reactions to be increased so much, because the cost might not be worth it. For instance, in my son, no matter how much B6 I give him, if I give him a lot of folate, he will not have enough B6 to avoid being depressed, presumably because the B6 is being drawn into the SHMT enzyme, the only folate enzyme which uses B6. Only by limiting his folate and addressing the energy (fatigue) issue in other ways, can he both have enough energy and not be depressed.

 

[aaron_c]

If a person can metabolize folinic acid, why would they need to take MTHF also? If a person can metabolize folinic acid they will change it to MTHF, following an oral dose, and if they can't, they shouldn't take it at all.

I think the major concern there is that some people do not convert 5,10-methylene-THF to 5-MTHF very well. One site I found said that those of us homozygous for MTHFR C677T do so at 10% of the speed of people without this SNP, and people with only one mutation do so at 40% the rate. (If anyone has a link to an actual study, I would be grateful.)

Edit: Thank you @Valentijn.

@aaron_c - MTHFR C677T +/+ means someone is creating methylfolate at 30% of the normal rate, and +/- means they're at about 65% of the normal rate...

It's probably in one of the sources at http://snpedia.com/index.php/Rs1801133

And yes, it says it near the top of the page you linked to. Also, I find the 30% figure for +/+ in "Homocysteine in Health and Disease," page 260.

The two main forms of folate that occur naturally in food are folinic acid and methylfolate, and if we only get it from food, then we have enough transporters for all of it. There are two kinds of folate transporters of which I am aware. The first is the Reduced Folate Carrier (RFC), which is low affinity and high capacity, and therefore becomes more important when we take high doses of folate. The second is the Folate Receptor, which is high affinity, but limited capacity, and only expressed in some cells. Of these, only the RFC will prefer folinic acid, but recall that after the Folate Receptor is filled to capacity--which happens pretty soon, when supplementing folates--it is the RFC that handles all the excess. So when you take a lot of extra folinic acid, you are crowding out the 5-MTHF.

I feel I am on a little shakier ground for this last part, as I have not seen a study formally tracking where individual folates go... And in fact I don't know exactly how the body regulates intracellular folate levels. Is it through selective polyglutamation, or do even polyglutamated folates leak out of cells at a moderate clip? If the second is true, then some of the folinic acid one took as a supplement would also replace some 5-MTHF, which would probably not be transported back into a cell, thus lowering 5-MTHF further.

Also, I believe Rich Van K at first suggested some people try folinic acid...I can't remember why, but I recall that many people did not have a good response. (Probably for reasons explained above?) Of course, if one was experiencing a methyltrap, then one would want the folinic acid to supplant MTHF in the cells, so obviously it depends on what is really going on. Although generally in ME, I would assume one would want to fix a methyltrap by taking B12.

I didn't say that taking a lot of folate would speed up all folate reactions, I said it could increase all folate reactions, meaning that it gave the body the opportunity to increase whichever folate reactions it needed to increase, assuming that the needed substrate and cofactors were available, and that there was not inhibition from products.

I think I see. If one were deficient in folates in general, then yes, taking folates could speed up the rate of folate reactions. But as I said before, I believe the body caps the total amount of folates in a cell. It may be that in adding MTHF in large amounts, our aim is to get a fraction of that into cells and have a fraction of that turn the MTR enzyme before diffusing out because it was not polyglutamated.

Here is an interesting quote from a study:

High-dose prescription folic acid for treating pregnant women to reduce the risk of neural tube defects is between 4 mg and 5 mg. By comparison, the lowest dose of MTHF studied in depression to augment antidepressant treatment is 7.5 mg, roughly equivalent to 52 mg of folic acid.​

Quite asside from whether anyone should be taking 4-5 mg of "folic acid," it seems that we really are supplementing with quite a bit of MTHF.

Best of luck with your son, and I hope you will keep us updated (or perhaps link to where you are keeping people updated on what happens.)

Warmly,

Aaron C

 

[Kimsie]

Hi Aaron, thanks for the comments.

I think the major concern there is that some people do not convert 5,10-methylene-THF to 5-MTHF very well. One site I found said that those of us homozygous for MTHFR C677T do so at 10% of the speed of people without this SNP, and people with only one mutation do so at 40% the rate. (If anyone has a link to an actual study, I would be grateful.) The two main forms of folate that occur naturally in food are folinic acid and methylfolate, and if we only get it from food, then we have enough transporters for all of it. There are two kinds of folate transporters of which I am aware. The first is the Reduced Folate Carrier (RFC), which is low affinity and high capacity, and therefore becomes more important when we take high doses of folate. The second is the Folate Receptor, which is high affinity, but limited capacity, and only expressed in some cells. Of these, only the RFC will prefer folinic acid, but recall that after the Folate Receptor is filled to capacity--which happens pretty soon, when supplementing folates--it is the RFC that handles all the excess. So when you take a lot of extra folinic acid, you are crowding out the 5-MTHF.

I feel I am on a little shakier ground for this last part, as I have not seen a study formally tracking where individual folates go... And in fact I don't know exactly how the body regulates intracellular folate levels. Is it through selective polyglutamation, or do even polyglutamated folates leak out of cells at a moderate clip? If the second is true, then some of the folinic acid one took as a supplement would also replace some 5-MTHF, which would probably not be transported back into a cell, thus lowering 5-MTHF further.

Also, I believe Rich Van K at first suggested some people try folinic acid...I can't remember why, but I recall that many people did not have a good response. (Probably for reasons explained above?) Of course, if one was experiencing a methyltrap, then one would want the folinic acid to supplant MTHF in the cells, so obviously it depends on what is really going on. Although generally in ME, I would assume one would want to fix a methyltrap by taking B12.

I see this type of reasoning all the time but I believe it is based on a misconception of how quickly these reactions are constantly going. Imagine a molecule of folate entering the cell as 5-MTHF. It doesn't stay 5-MTHF for long, less than a second, and it is converted, most likely to THF, unless the person is too low in B12 and has what they call a methyl trap, in which case it might stay 5-MTHF a little longer, or go in the backwards reaction to 5,10-methylene-THF. In a few minutes that molecule of folate will have been transformed 100's or 1000's of times into various forms of folate. So which form of folate you take (5-MTHF or folinic acid, not folic acid) is only important if you have trouble converting that form and it doesn't matter which form is transported into the cell, unless you have trouble converting that form.

Having a mutation can make it so that you need more folate as substrate, in order to have enough of all the forms that you need at all times, because if your enzyme is 10% slow you need about 10% more of the substrate to produce the same amount of product. You probably actually need more than 10% more of the substrate, because the substrate for all the reactions might have to be raised at once, to push one enzyme, but I am just illustrating a point. The 2 mg or 5 mg or 10 mg of folate that a person takes is raising the substrate. The same thing applies to taking SAMe as a supplement - it's a total waste of money because you can accomplish the same thing by taking methionine as long as you have enough folate, B12 and magnesium - it's just raising the amount of substrate.

I think that Rich VanK was suggesting the folinic acid in case some people were having trouble converting one of the other forms.

As an update on my sons, yesterday I forgot to give D the thiamine I have been giving him so I learned that he does indeed have to have a high dose of thiamine - he got both fatigue and depression, but today is feeling really great (I did give him thiamine in the evening yesterday, after I realized that must be why he was feeling worse), we'll see how the rest of the day goes. I think this is either because it helps take a load off of the folate cycle by increasing the NADPH produced by the PPP or because it is helping with the TCA cycle enzymes, of which 2 or 3 use thiamine, depending on if you count pyruvate dehydrogenase as a TCA cycle enzyme. Before we started the D-ribose, the thiamine didn't seem to do anything. He is taking 600-1200 mg a day. I don't know if everyone with these illnesses would need that much, but it is something to try if a person is able to raise it that high. S didn't think the ribose, etc was really important, so he stopped taking it and learned that it is important. These little episodes of taking something out by accident or on purpose are how we find out which things they really have to take.

Kim

 

[Valentijn]

@aaron_c - MTHFR C677T +/+ means someone is creating methylfolate at 30% of the normal rate, and +/- means they're at about 65% of the normal rate. That's according to the actual research which I did read at some point, though I don't have the link handy.

It's probably in one of the sources at http://snpedia.com/index.php/Rs1801133

 

[wastwater]

Anyone know what a G protein is I keep seeing it when I research but don't see it mentioned much http://en.wikipedia.org/wiki/G_protein

 

[Valentijn]

Anyone know what a G protein is I keep seeing it when I research but don't see it mentioned much http://en.wikipedia.org/wiki/G_protein

Basically it's a huge group of things, and it's not known exactly what many of them do. It's a vague description, and it's not possible for us to get anything specific out of a reference to them. However, identifying something as a G protein might be useful for researchers who want to narrow things down and look for more specific characteristics.

If it's only being referred to as G protein, they're basically saying that they found something, but don't really know what yet. It can't be deciphered more than that until more conclusive research has been conducted.

 

[kel88]

I didnt read all message. But i only want to say is that B6 caused CBS Upregulation but P5P is not.

Read this link, they say that you have to avoid B6 but no P5P.

http://metabolichealing.com/metabolic-gateways-cbs-gene-mutations-glutathione/

 

[ahmo]

@kel88 I've been searching for the cause of my high ammonia for several weeks. About 5 days ago my body did not want P5P, which I've been taking at 33mg for about 1.5 years. From the next day I split the capsules, taking only 1/2 per day. After 3 or 4 days I'm no longer coping with so much excess ammonia. I'm also no longer certain that labeling my experience as high ammonia is accurate, it might be high peroxynitrite. In any case, lowering the P5P coincides with a decrease in my high 'ammonia' symptoms, and my need for supporting supplements has dropped considerably.

 

[Gondwanaland]

@ahmo what did you change? Are you taking enzymes?

 

[ahmo]

@Gondwanaland I initially stopped P5P from Jan 17 for 2 days, and then reduced to 1/2. There seems to be a slight decrease in my need for supps a couple days later, and then I began proteolytic enzymes Jan 21, 4 days after I first quit the P5P. The further lessening of symptoms was evident the following day...so either there was a continuing release of the P5P, in the way it took me many days to recover from my B2 experiment, or you might be on to something in the connection with the enzymes. Body still continues to test + for only 1/2 doses of P5P.

 

[kel88]

Ahmo,

Here the same! I doenst understand! Ive got pyrroluria so i have to take B6. I did greet on high dose! But after my prenancy i developped neuropathy...! I didnt know why! Not only from B6 also from P5P! But when i stop taking B6 i get diarrhea ( then i become fructose intolerant without B6 because of the absorption from zinc and you need zinc for that fructose-enzym), and i become depressed because B6/P5P makes neurotransmitters so i cant do without! But now i take a dose wlso from 35mg and i get neuropatic pain when i eat food i think with sulfur! I feel poisend (? Dont know the word in Englisch?)
Maybe also from ammonia ( im homozygoot A1298C) and i always need injections hydroxo B12 10mg twice a week or i get so much brainfog. Now ive got brainfog everyday

I will try molybdenun 1000mcg , and i wilk take yucca 3 times a day by my food when i eat. And i hope that when i go to my doc about 10 days, that i can try to get KUVAN ( BH4) ... I think that would be my treatment!

What are youre symptoms? Do you know if you got high urine sulfur? And what are you doinig about ammonia?

I did post a link this day , something about sulfur, maybe thats also interesting for you? You have to look in my postings!

 

[Gondwanaland]

you might be on to something in the connection with the enzymes

You are now getting more from the food you eat... Remember the protease rage, which causes the same symptom I get from supplementing mB12... It is not the protease that cause the symptom, rather the B12 absorption

And what are you doinig about ammonia?

If you do a search for the word ammonia here in the boards, you will find a lot of information:
http://forums.phoenixrising.me/index.php?search/18069494/&q=ammonia&o=date&c[title_only]=1

I will try molybdenun 1000mcg , and i wilk take yucca 3 times a day

It is always best to start one supplement at a time at lower doses and increase slowly. You never know how your body will react. All supplements have side effects!

 

[ahmo]

This conversation has made me very curious. What was it that made me suddenly so sensitive to the P5P? I first became aware of my high background levels of ammonia/peroxy following my high dose B2 experiment. Later it was clearly in-the-world oxidative stress. Now, linked to P5P. I'm wondering if it's possible that the malic acid has actually made something more efficient, so that I need less of the B vits? And thus the higher amounts become something I need to get rid of?

@Gondwanaland I'm taking the enzyme away from food, so don't know about better absorption. The gola with the enzyme away from foods is to cleanse organs.

@kel88 I've now been taking 1200 molybd daily, 1/2 AM/PM. It's been several weeks since I went to this high dose. When I was suffering from the 'ammonia' symptoms, my body asked for additional 150mcg AM/PM.

When I tested w/ sulfate strips, I was always next to lowest rating. Even though I had symptoms. I'm no longer using them. My symptoms: something like headachey, more like a pressure inside head, squinty eyes, something approaching breathlessness, restlessness...the feelings together have the warning, This is the feeling of heading toward a Crash.

I had used yucca, then switched to ornithine, + arginine, citrulline, lysine. But I replace all of that with malic acid. And now from my going deeper into Pall's work with peroxynitrite, I've added many of his recommendations for oxidative stress (his list starts with Mfolate): Reseveratrol, ALCAR, higher doses of astaxanthine, watermelon, carrots. You'll find a list of his suggestions here:
http://www.thetenthparadigm.org/cfsweb.htm

 

[kel88]

Gondwanaland you are right! I think i should try the moly first ... My multi contain already 100mcg. I think i wil try a caps of 500mcg en higher up to 1000mcg + multi 100 mcg.

And later Yucca! It would be great if the yucca kills a the bad bacteria.

AHMO huh thats weird... Did you got low sulfur in youre urine? But you are also homo for a CBS mutation right? How that possible? Maybe i first have to try sullfur strips also! Because it looks like ive got the same as you! Other symptoms maybe but also react to P5P .. Do you got also the A1298c homo? Maybe thats the difference ? In very curiouse...

Can you let us know how youre treatment is going? I also use astaxtantine and eat every day carrots so thats a good thing right ... But can you test if its peroxynitrite ?I would really love to know if its that or ammonia of sulfur that i react to but how do i know that? In our country i cant find something like sulfur strips... Maybe i can do a ammonia bloodtest or something...

 

[brenda]

Hi

I am ++CBS and have low urine sulphate 744 ug (690-2,988) on the OAT test.