New, Inexpensive CBS Ammonia Fix

[Lou]

@aaron_

How kind of you for posting that information on mthfr 1298c, thanks! Unfortunately, I no longer possess a Lymeless brain and working out the details of what you presented, albeit simple for you, is for me much like learning the Icelandic language, or something-- not going to be pretty.

Actually, whether from mthfr 1298c or some other problem, I do have excess ammonia buildup. I know this from the symptoms and especially from an experience about a month ago; think I'll relate that experience in case anyone else is not familiar with the saccharin/ammonia connection. I surely wasn't, until this happened:

I've drank coffee all my adult life, a cup or two in the morning and a cup right after work. For past ten years or so have used saccharin instead of sugar because I like it better. Okay, so about a month ago I decided maybe the saccharin wasn't so benign and I'd quit it, which I did.

The result --at first, anyway-- was subtle and I didn't put two and two together. However, approximately a week or little longer later I could barely function mentally at all. It was awful, and I seriously considered possibility that I'd had a mini stroke or that maybe even a brain tumor was at bottom the cause for this overwhelming brain fog.

Then something reminded me of stopping the saccharin and gradually getting worse from that point. I googled saccharin/ammonia and sure enough the little sweet stuff mops it up. And for me it worked like a charm, took extra amount in coffee that evening and next morning and by noon my mental functioning, such as it is, was greatly improved. Like night and day from when things were worst.

Am back off the saccharin, replacing it with yucca and activated charcoal. So, think I'll order the BH4 and try it. If sometimes, even if it's just a hunch or complete shot in dark, you'd like to suggest something that might help it work for mthfr 1298c problem, please, feel free. Thanks, again, Aaron.

 

[Adlyfrost]

Sorry no time to read all this thread- just quick comment: I was using citrulline malate a few years ago- thought I found the cure until it starting making me extremely hyper and nervous to the point of a nervous breakdown and had to stop. I think it activated something autoimmune, not sure. Used it for ammonia detox.

Thinking about going to malic acid. Never had a problem with it in sugar-free candies. Will post back if it works for energy.

Be careful ya'll with citrulline.

 

[Adlyfrost]

Also, anyone ever try methionine? I have and it seemed to have a calming effect but read something about how it was dangerous. It is also a good ammonia detox. Any thoughts?

 

[Adlyfrost]

@aaron_c : awesome explanation in your first post! Interesting, before I knew I had CFS, thought I had porphyria and is why I took citrulline. I probably just have a defective ammonia detox gene (thank God no porpyria).

Thanks also for instructions in making liposomal stuff.

 

[ahmo]

@aaron_c I've just re-read your original post w/ diagram for the umpteenth time. Re your comments about oxaloacetate. I wonder if this answers a puzzle for me. There have been times when I've been detoxxing when my body wants high oxalate. Not each time. But definitely following some of my coffee enemas, when I need extra supps for ammonia, my body also wants high ox: parsley, nuts and tahini when I was still eating them, or tea, which I've added to my footbaths.I searched several times, but never found the connection. I think you've nailed it.

 

[Critterina]

In particular I am unsure about Critterina's comment about the forward reaction of MTHFR using up BH4. Where did you get that from @Critterina?

Basic biochemistry, really. If the reaction is reversible, as it is described in lots of places, the 5,10-methylenetetrahydrofolate to 5-methyltetrahydrafolate conversion performed by the MTHFR enzyme adds two hydrogen atoms to the molecule, breaking a carbon-nitrogen bond. When the reaction goes backward, the two hydrogens get tacked on to the dihydrobiopterin molecule, making it into tetrahydrobiopterin. So, if the reaction is reversible, all parts are reversible, and the two hydrogens that made the 5,10-methylenetetrahydrofolate had to come from the tetrahydrobiopterin, leaving dihydrobiopterin as the result of the reaction.
Did I make a mistake here?
(P.S. I thought maybe I got it from my Lehninger textbook on Biochemistry, but nope, they only talk about 5,10-methylenetetrahydrofolate in terms of purine synthesis.)

 

[aaron_c]

Ok, Tunguska, thanks. I have a better idea where you are coming from. And you do have chronic fatigue, right? Just being...careful, I guess.

I hadn't seen anything indicating xanthine would convert to XMP (in that direction). I guess this does it? https://en.wikipedia.org/wiki/Xanthine_phosphoribosyltransferase Couldn't find a reference to the enzyme they wrote on the xanthine-XMP link in the figure from that book.

I agree, it must be the same enzyme with a different name. It does the exact same thing, with as far as I can tell the exact same cofactors. Also, the wikipedia name makes more sense.

With 250mg UMP sublingual, when it works, produces a strong increase in focus, alertness and motivation in what seems like the front of the brain. Along the lines of the first time I took tyrosine but stronger and more focused. Basically dopamine, exactly where it needs to be. Upping to 500mg sublingual it became a bit robotic. It doesn't seem to be fading but I can't reproduce it 100% consistently yet although some patterns/cofactors are obvious.

I do believe I will try some UMP.

I took a ton of glutamine for gut reasons over months

Oh glutamine...sorry, I misread your post as saying glutamate. Ergh. So disregard that bit where I said you don't respond that way to glutamate.

I'm hetero for one CBS gene, A1298C, and all the BHMTs, but my issue is with ammonia specifically. I've eaten high protein for an extended period because of serious skeletal problems. I don't want to cut back on it (much, except maybe in the morning), but there's a trade-off with it having noticeably affected mental function. I suspect the BH4 is eaten up because a high dose of methylfolate is a requirement for the focus.

Interesting, because when I have serious BH4 issues I become very very depressed. Motivation and concentration suffer too, but it's not the main thing. But high dose methylfolate fixes the focus issue? Or it just needs to be there, along with ____? Is it CBS C699T you are hetero for? I am curious, because when I hear you say that you eat lots of protein, have a CBS defect, and notice the protein effecting your ability to focus, I think molybdenum (Mo) deficiency problem causing excessive sulfites. As you may know, "[Sulfite toxicity caused by Mo deficiency] can result in the impairment of the synthesis of Dopamine and the conversion of Dopamine to Noradrenaline, which can lead to neurological fatigue." Sorry if this is all review for you.

I also tried CDP-choline but it was nowhere near UMP in strength. What I read was that citocoline was broken down into choline and cytidine in the stomach (https://en.wikipedia.org/wiki/Citicoline#Medical_uses), and cytidine converted to uridine, so it should be similar to taking a bit of UMP and a choline source. For me too much choline seems to produce a depressant effect too though I don't think CDP-choline had enough to be noticeable. However many months ago I tried a TAU (triacetyluridine) version of uridine and it produced some fatigue at first, so who knows.

Although this might not have been a question...it seems like you are not the only person for whom choline produces a depressant effect. Here is Rich Van K on acetylcholine (from choline):

it serves as the neurotransmitter between the nerves and the muscle cells, and it serves as the neurotransmitter for the parasympathetic nervous system in general.

In chronic fatigue syndrome, it is my current hypothesis that choline, phosphatidylcholine, and acetylcholine are depleted...

I think that low acetylcholine would explain the results of blood flow studies in the forearm reported by Vance Spence's group at the U. of Dundee a few years ago. I think it can also help to explain why the ratio of sympathetic to parasympathetic nervous system activity in CFS is higher than normal, as shown in heart rate variation studies.

Check out the link for the rest of his excellent take on choline metabolism in ME/CFS.

I am really glad that you brought uridine to my attention--I have ordered some, so fingers crossed. I'm posting my thoughts on it on your pyrimidine thread. But I will ask here as well: Does anyone know about nucleotide levels in people with ME/CFS?

What a pleasure looking into this with you (and everyone else),

Warmly,

Aaron C

 

[aaron_c]

@aaron_cdefinitely following some of my coffee enemas, when I need extra supps for ammonia, my body also wants high ox: parsley, nuts and tahini when I was still eating them, or tea, which I've added to my footbaths.I searched several times, but never found the connection. I think you've nailed it.

I am glad malic acid seems to be working for you. And it really is great to find another piece in our puzzles, eh?

I didn't know that coffee enemas could increase ammonia. Do you know how that works?

The very best to you,

Aaron C

 

[Tunguska]

I have to make an addendum to my earlier post: I wrote that sardines and beans were involved but it seems that muscle meats are having a better or more reliable effect, notably well-done chicken breast (of course with some molybdenum, R5P and others).

Coincidentally it might lend credence to @aaron_c 's post http://forums.phoenixrising.me/index.php?threads/new-inexpensive-cbs-ammonia-fix.31835/#post-496986 . While the sardines were high in guanine and xanthine, according to http://eurekamag.com/research/001/069/001069639.php the chicken breast is high in... hypoxanthine:

Young, L. L., 1983: Effect of stewing on purine content of broiler tissues. Journal of Food Science 48(1): 315-316

Breast meat of broilers contained adenine 21.1, guanine 26.5 and hypoxanthine 130.8 mg/100 g. Corresponding values were thigh 19.9, 24.6 and 99.0, and skin 13.0, 18.8 and 27.1. Boiling the chickens to an internal temperature of 80 deg C increased...

130.8 mg/100 g is suspiciously much higher than the hypoxanthine numbers found in http://jn.nutrition.org/content/106/3/435.full.pdf for other foods. Frustratingly I can't find another good reference to confirm it.

Then it takes another turn: http://books.google.ca/books?id=gRS...KKETTj&focus=viewport&dq=chicken+hypoxanthine

Most abundant in chicken muscle is inosinic acid which degrades to inosine and hypoxanthine.

Suggests straight inosine or IMP might also be a factor. In fact there are threads about inosine as a supplement: http://forums.phoenixrising.me/index.php?threads/inosine-reaction.18758/ I do intend to try it.

I can't figure out what else that would be in chicken breast that wouldn't be as prevalent in sardines/herring, salmon, whey, kidney beans, split peas, or all the common supplements.

 

[Tunguska]

Ok, Tunguska, thanks. I have a better idea where you are coming from. And you do have chronic fatigue, right?

Most certainly chronic fatigue, and my neurotransmitters are bust (most obvious: memory problems). I may have CFS/ME at least was diagnosed in Canada with what I forgot was the wording and exercise does cause problems etc., but it's not the focus here.

Oh glutamine...sorry, I misread your post as saying glutamate. Ergh. So disregard that bit where I said you don't respond that way to glutamate.

I heed it anyway because from what I understood it can contribute to glutamate levels.

Interesting, because when I have serious BH4 issues I become very very depressed. Motivation and concentration suffer too, but it's not the main thing. But high dose methylfolate fixes the focus issue? Or it just needs to be there, along with ____? Is it CBS C699T you are hetero for? I am curious, because when I hear you say that you eat lots of protein, have a CBS defect, and notice the protein effecting your ability to focus, I think molybdenum (Mo) deficiency problem causing excessive sulfites. As you may know, "[Sulfite toxicity caused by Mo deficiency] can result in the impairment of the synthesis of Dopamine and the conversion of Dopamine to Noradrenaline, which can lead to neurological fatigue." Sorry if this is all review for you.

I'm hetero for the other CBS, whatever it is again. I don't seem to have too many damning individual genes but visibly have genetic issues. Maybe I have a few less efficient genes that combine. Methylfolate seems to be next most important after R5P and whatever is in the meat - and molybdenum - but again I haven't nailed down everything. Single dose of methylfolate between 800-2400mcg definitely has an effect (BUT it's tricky because the folate - and uridine - do coincide with worsening of some skeletal problems).

I hadn't seen that quote about molybdenum specifically affecting dopamine through sulfites so that it is good to know, thanks. I may need to look into it sooner. It's quite possible I have sulfite problems (I've had to put off these concerns due to skeletal problems requiring protein - and sulfate-containing supplements and sulfate itself).

Although this might not have been a question...it seems like you are not the only person for whom choline produces a depressant effect. Here is Rich Van K on acetylcholine (from choline):
Check out the link for the rest of his excellent take on choline metabolism in ME/CFS.

Very interesting... I read that but didn't remember (oh god help). I'll have to go over it again.

Funny he mentioned creatine. Coincidentally I made a thread about it in the SNP section.

I don't know about nucleotide levels so I would ask the same question. As for uridine, it's part of a popular nootropic stack along with choline and omega-3 (DHA). Hopefully it has some effect for you, but if CDP-choline helped I'd suspect it would too. I had a strong effect the very first day but you may need to experiment.

 

[Gondwanaland]

I am sorry this biochemistry is way over my head... Still, I have some scattered comments I would like to make and a question to pose.

@Tunguska regarding sulfate intolerance:

If ammonia is high, it will block the elimination of sulfate.

Regarding inosine, it increases uric acid, which I have experienced has an exacerbating effect on intolerances.

After supplementing quercetin, bromelain and malic acid I found out I am salicylate sensitive (high uric acid plays a role here which I don't yet understand). Soaking in the bathtub with sodium bicarbonate and supplementing magnesium oxide help to reverse [hi sal] food intolerances by alkalinizing the body and neutralizing and/or excreting excess uric acid. My question is would someone who is salicylate sensitiv tolerate magnesium malate? Does anyone know the answer?

izzy

 

[aaron_c]

Hi @Lou

Best of luck with the BH4. I am quite interested in your comment about saccharine and ammonia, but when I googled them all I came up with was how ammonia was involved in the industrial synthesis of saccharine. Do you have that link, by any chance?

Aaron C

 

[Lou]

Hi @Lou

Best of luck with the BH4. I am quite interested in your comment about saccharine and ammonia, but when I googled them all I came up with was how ammonia was involved in the synthesis of saccharine. Do you have that link, by any chance?

Aaron C

You're right, I got nothing, either. So, I must have gotten something I read in one of my alternative health books mixed up with it, thinking I'd googled it. Sorry.

The likeliest is a huge book written by a medical doctor and his wife, the name of which now slips my mind, but I'll try to find where I came up with that notion (other than the fact it 'seems' certainly to work for me. It may take awhile.

My BH4 was supposed to ship yesterday, and I've gotten 5 Htp, nadh, malic acid, and oligomeric proanthocyanidins already delivered, see if I can trial and error combinations for better result.

 

[aaron_c]

@Lou

You may know this already, but be careful with the malic acid and nadh--malic acid will recycle nadh, so they should stimulate you in the same way, which may not be helpful.

Best of luck

 

[Lou]

@aaron_c

You may know this already, but be careful with the malic acid and nadh--malic acid will recycle nadh, so they should stimulate you in the same way, which may not be helpful.

Best of luck[/quote

No, didn't know that, my approach has gotten too similar to a blind man in a pharmacy thinking: 'hmm, that bottle feels about right'.

Thanks very much, Aaron.

 

[nandixon]

Basic biochemistry, really. If the reaction is reversible, as it is described in lots of places, the 5,10-methylenetetrahydrofolate to 5-methyltetrahydrafolate conversion performed by the MTHFR enzyme adds two hydrogen atoms to the molecule, breaking a carbon-nitrogen bond. When the reaction goes backward, the two hydrogens get tacked on to the dihydrobiopterin molecule, making it into tetrahydrobiopterin. So, if the reaction is reversible, all parts are reversible, and the two hydrogens that made the 5,10-methylenetetrahydrofolate had to come from the tetrahydrobiopterin, leaving dihydrobiopterin as the result of the reaction.
Did I make a mistake here?
(P.S. I thought maybe I got it from my Lehninger textbook on Biochemistry, but nope, they only talk about 5,10-methylenetetrahydrofolate in terms of purine synthesis.)

Here is some clarification:

In the forward reaction, MTHFR takes 5,10-methylenetetrahydrofolate and converts it to 5-methyltetrahydrofolate ("methylfolate") using NADPH as the reducing agent. (FAD/vitamin B2 is also present.)

Tetrahydrobiopterin (BH4) is not involved in the forward reaction. And this forward reaction is not reversible with respect to this particular combination of reactants and products.

When Yasko refers to a "reverse" reaction of MTHFR, she is referring to the enzyme running in the opposite direction to what I first described but using a different combination of reactants and products:

In Yasko's reverse direction, MTHFR takes quinoid-dihydrobiopterin (q-BH2) and converts it to BH4. In this reverse direction, methylfolate is used as the reducing agent (producing 5,10-methylenetetrahydrofolate in the process). NADPH can also act as the reducing agent.

However, this reverse reaction has only ever been shown to occur under in vitro conditions - according to the research articles Yasko cites in the pdf reference @aaron_c linked to in an earlier post. The extent to which this reverse reaction occurs under normal physiological conditions in the human body is probably debatable.

This reverse reaction happening in the body seems to just be a theory. Certainly there seem to be no publications showing that A1298C has a greater ability to impair this theoretical in vivo reverse reaction than C677T.*

More importantly, note that in this reverse reaction, MTHFR would be performing the identical transformation of q-BH2 into BH4 that another enzyme in the body already does, i.e., dihydropteridine reductase (DHPR). (Not to be confused with DHFR. The gene that makes DHPR is QDPR.)

If MTHFR running in reverse were significant in vivo, then in cases of DHPR deficiency, methylfolate should be an effective treatment to produce the needed BH4. But it's not. Methylfolate, being a powerful antioxidant, certainly can have a sparing effect on BH4, but that does little good for someone who can't make it in the first place.

I think the only proven effect of A1298C is its increased worsening of the effect of C677T, when that latter SNP is also present. And this is with respect to MTHFR running in the forward direction, of course.

*(Note that until 2002, in order to measure the activities of the MTHFR enzyme, and including the C677T and A1298C defects, it was actually necessary that the enzyme always be run in reverse - using non-physiological substrates, e.g., menadione as the oxidizing agent, to convert methylfolate into 5,10-methylenetetrahydrofolate. Because, as mentioned above, the reaction does not run in reverse with the physiological substrates. In 2002, a method was developed for measuring the reaction in the forward direction using the physiologically correct substrates.)

 

[Tunguska]

Here is some clarification:

In the forward reaction, MTHFR takes 5,10-methylenetetrahydrofolate and converts it to 5-methyltetrahydrofolate ("methylfolate") using NADPH as the reducing agent. (FAD/vitamin B2 is also present.)

Tetrahydrobiopterin (BH4) is not involved in the forward reaction. And this forward reaction is not reversible with respect to this particular combination of reactants and products.

When Yasko refers to a "reverse" reaction of MTHFR, she is referring to the enzyme running in the opposite direction to what I first described but using a different combination of reactants and products:

In Yasko's reverse direction, MTHFR takes quinoid-dihydrobiopterin (q-BH2) and converts it to BH4. In this reverse direction, methylfolate is used as the reducing agent (producing 5,10-methylenetetrahydrofolate in the process). NADPH can also act as the reducing agent.

However, this reverse reaction has only ever been shown to occur under in vitro conditions - according to the research articles Yasko cites in the pdf reference @aaron_c linked to in an earlier post. The extent to which this reverse reaction occurs under normal physiological conditions in the human body is probably debatable.

This reverse reaction happening in the body seems to just be a theory. Certainly there seem to be no publications showing that A1298C has a greater ability to impair this theoretical in vivo reverse reaction than C677T.*

More importantly, note that in this reverse reaction, MTHFR would be performing the identical transformation of q-BH2 into BH4 that another enzyme in the body already does, i.e., dihydropteridine reductase (DHPR). (Not to be confused with DHFR. The gene that makes DHPR is QDPR.)

If MTHFR running in reverse were significant in vivo, then in cases of DHPR deficiency, methylfolate should be an effective treatment to produce the needed BH4. But it's not. Methylfolate, being a powerful antioxidant, certainly can have a sparing effect on BH4, but that does little good for someone who can't make it in the first place.

I think the only proven effect of A1298C is its increased worsening of the effect of C677T, when that latter SNP is also present. And this is with respect to MTHFR running in the forward direction, of course.

*(Note that until 2002, in order to measure the activities of the MTHFR enzyme, and including the C677T and A1298C defects, it was actually necessary that the enzyme always be run in reverse - using non-physiological substrates, e.g., menadione as the oxidizing agent, to convert methylfolate into 5,10-methylenetetrahydrofolate. Because, as mentioned above, the reaction does not run in reverse with the physiological substrates. In 2002, a method was developed for measuring the reaction in the forward direction using the physiologically correct substrates.)

This is interesting but confusing. Personally high-dose methylfolate (1600+mcg in one go) is what helps me achieve a dopamine-boosting effect. I assumed it was related to generating or recycling BH4 since I understood it's required by tyrosine hydroxylase, and the reverse reaction thing. If not it would be nice to know how methylfolate helps since it's a big factor, outside Krebs. Then again nobody can tell me exactly what riboflavin does either.

Note this is in spite of B12. Adb/methylB12 has the opposite effect as folate and seems to cancel out the folate and depress. I have to take them separately or else less dopamine. I am A1298C +/- but didn't put much stock in it (my SNPs aren't terribly exciting).

 

[aaron_c]

@nandixon

Thank you for the very informative post.

Do you know how to account for Bottiglieri et al's correlation between folate levels and BH4 levels? It seems like the MTHFR-BH4 thing was their first attempt to explain it. I have also found that taking a lot of 5MTHF only spares BH4 so much for me. So what is the connection between folate and BH4?

The bit about DHFR and DHPR is also enlightening. I actually just spent some time going to the local medical school library to get some articles, including the one with the diagram for BH4 recycling using MTHFR and DHFR (not DHPR). I don't have anything to add to what you wrote, just that the article is from 1992. Just shows me what we have learned since 1992, I guess.

 

[nandixon]

This is interesting but confusing. Personally high-dose methylfolate (1600+mcg in one go) is what helps me achieve a dopamine-boosting effect. I assumed it was related to generating or recycling BH4 since I understood it's required by tyrosine hydroxylase, and the reverse reaction thing. If not it would be nice to know how methylfolate helps since it's a big factor, outside Krebs. Then again nobody can tell me exactly what riboflavin does either.

Note this is in spite of B12. Adb/methylB12 has the opposite effect as folate and seems to cancel out the folate and depress. I have to take them separately or else less dopamine. I am A1298C +/- but didn't put much stock in it (my SNPs aren't terribly exciting).

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...

There are many theories for why taking methylfolate might improve things relative to tetrahydrobiopterin (BH4) - besides the theory of having an enzyme (MTHFR) run in reverse to perform the same function another enzyme (DHPR/QDPR) already does. For example:

It may have a sparing effect on BH4; it may have a stabilizing effect on BH4; it may act as a substitute (mimic) for BH4; etc.

And this is in addition, of course, to any effects methylfolate may have from providing extra 1-carbon building blocks. Lots of other possibilities too.

 

[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...

There are many theories for why taking methylfolate might improve things relative to tetrahydrobiopterin (BH4) - besides the theory of having an enzyme (MTHFR) run in reverse to perform the same function another enzyme (DHPR/QDPR) already does. For example:

It may have a sparing effect on BH4; it may have a stabilizing effect on BH4; it may act as a substitute (mimic) for BH4; etc.

And this is in addition, of course, to any effects methylfolate may have from providing extra 1-carbon building blocks. Lots of other possibilities too.

I tried SAMe months ago, 200-600 at once on empty stomach. The first days it had a slight energizing effect somewhat like high dose ubiquinol I guess, but not reminiscent of dopamine. I think it helped joints too (which, folate seems to worsen). Then it stopped having any effect. Since it was expensive I didn't intend on buying it again. Things have changed slightly since then so maybe it would be worth attempting. I don't have much bearing on the state of my methylation.