Is Molybdenum necessary for methylation?

[outdamnspot]

I'm sorry to hear that. Do you have the money to get some testing done? Possibly a methylation panel? It might shorten the guessing game.

I'm not sure what a methylation panel is, but I had a standard MTHFR gene test done by my doctor. I can't recall the details but she said there are two branches involved in methylation and I had both (which correlated with greater symptom severity).

Again, I hope he doesn't mind me posting the response here, but this is what Greg said about sublingual B2:

I worked in buccal and sublingual delivery. Basically, whilst you may have receptors for insulin uptake in the mouth, you don't have them for B12, folate, B2, etc. You also have a very high level of alkaline phosphatases and several other enzymes in saliva that clip the "so-called" active B2 and just leave you with straight riboflavin, B2. IT is a big con. The way sublinguals basically work is by slowly trickling material into the stomach and thereby giving you prolonged uptake. The problem is that everything is also exposed to proteolysis, alkaline phospatase, lysozyme, and many other enzymes in saliva. Also it maximizes binding of B12 to hpatocorrin, which is massively secreted in the salivary glands. If you gut is not working properly you won't even cleave the B12 off haptocorrin.

DIgestion and uptake happen for a good reason in the intestine, you have a football field sized uptake system. Compare that to about a hankerchief size in the mouth. Further, most of the receptors for uptake are on the villi in the small intestine. Basic biology I am afraid, but hey, the supplement guys won't tell you that. They want you to believe their fairy-tale.
I have worked in oral delivery for about 30 years now, and have broken many a paradigm as far as uptake, have performed uptake studies in so many different experimental animals and I can tell you they are all pretty much the same, but of course differ in size.

So, I guess my options are:

1. Try the standard methylation protocol, i.e. B12, methylfolate etc. However, I have already experimented with methyl-b12 and couldn't tolerate it.

2. Try the active B2 (as sublingual) and hope it does work, in spite of what Greg says.

3. Follow what Greg says and try the Iodine, Selenium (which caused crashes) etc.

or:

4. Forget methylation for now and try to treat the gut overgrowth (Strep).

 

[alicec]

So taking the sublingual FMN should circumvent that problem?

Yes, though I don't think there has been a lot of study of how much of the dose is actually absorbed. Still I noticed a difference in potency between equivalent doses swallowed and used sublingually (well actually between upper gum and cheek where it dissolves more slowly than under the tongue).

 

[outdamnspot]

That domain in described in other publications as a molybdopterin binding domain (molybdopterin is the prosthetic group that the molybdenum metal is complexed to in molybdenum-requiring enzymes).

As to the functional status of the domain, I found this recent paper which suggests that it does have activity - FAD hydrolase activity. This would convert FAD back to FMN.

I don't have the energy to follow this up at the moment but the Wikipedia entry on FAD hydrolase indicates that it is an important part of riboflavin metabolism.

It seems not a lot is known about the human enzyme. Delving into the bacterial enzyme (where the two steps are contained in a single enzyme, unlike the two separate enzymes in human) might reveal more but there is certainly nothing terribly obvious about the Mo requirement that Greg insists on.

I agree that Greg is a generalist with a great interest in B12 deficiency, but not necessarily really appreciative of the problems of people with CFS/ME.

I've always been happy to put his ideas to the test and have gotten some benefit from them (and love his B12 oil products) but the more I have tried to understand B12 metabolism and why so many people with CFS/ME seemed to be helped by it to at least some extent, the more I realise that too much is just unknown.

Just to double-check, alice, I was reading in another thread that you said you did have more success using the sublingual B2, is that correct? So you don't necessarily agree with Greg that it's useless without the cofactors like Selenium etc.?

 

[outdamnspot]

Yes, though I don't think there has been a lot of study of how much of the dose is actually absorbed. Still I noticed a difference in potency between equivalent doses swallowed and used sublingually (well actually between upper gum and cheek where it dissolves more slowly than under the tongue).

Woops, I wrote my last message just after you had replied. So do you take Selenium with the active B2? Greg said the process won't work without Moly -- though you guys mentioned it probably isn't a necessity. My hesitation is messing around with stuff like Selenium etc. and enduring crashes that might not improve; just three days of MB12 has set me back significantly.

So in theory the sublingual B2 could bypass the need for thyroid support? I am wondering if I could possibly just see what happens with active B2 + B12 together.

 

[alicec]

you said you did have more success using the sublingual B2, is that correct? So you don't necessarily agree with Greg that it's useless without the cofactors like Selenium etc.?

The SL FMN did seem to be more potent.

I have read studies of active B6 which showed there are two routes for absorption, one as described by Greg where the phosphate group is clipped off before it is absorbed across the intestinal wall. This if you like is the classical route. However there was evidence also for direct uptake (without clipping of the phosphate), probably by endocytosis, but not much was known about it.

I have assumed that similar mechanisms apply to active B2.

How any individual responds to different forms of the active vitamins might depend on how active the direct uptake mechanism is. The classical mechanism depends on clipping off and adding back the phosphate and maybe this doesn't work well in some and they need the direct uptake.

Getting even a little of the active vitamin this way may be enough to get poorly function pathways going.

You do indeed need things like the selenium, iodine etc for the normal route from riboflavin so it makes sense to try to supply everything if possible, though theoretically, the SL FMN should at least in part get around this requirement.

Much of what Greg says is correct - eventually we should be able to make the active vitamins ourselves, but empirically, the SL FMN has seemed like a good stop gap to me. It was definitely different from riboflavin.

I haven't yet done the experiment of going back to riboflavin though I intend to do this soon.

As for your plan with B12 and FMN, all I can say is try it and see what happens.

 

[aaron_c]

A methylation panel would be something like this: https://www.doctorsdata.com/methylation-profile-plasma/

It sounds like you are willing to experiment, and I think you are working with a lot of the right pieces. I'll keep my fingers crossed for you.

On the off-chance that you continue to encounter unreasonable difficulty with supplements that are normally helpful for people with ME/CFS, you might consider testing for mercury poisoning. Here is my thinking:

Your reaction to selenium seems weird. Increased metabolism should give you energy--not that I have ever heard of selenium causing hyperthyroidism. You also seem to be having difficulties with methylation supplements above and beyond what most of us deal with. Rich Van Konynenburg mentions in the Sweden lectures that some of the people in his study who didn't respond well to methylation supplements had mercury poisoning, and he thought the mercury poisoning was responsible for their poor response. (Granted, I don't know the details of what you tried and it is also possible that you just haven't experimented enough.) According to Dr. Myhill, selenium chelates mercury, but without sufficient sulfur-containing amino acids it won't get excreted. The bit about "sulfur-containing amino acids" sounds like an over-generalization to me, but it at least suggests the possibility that dysfunction in your transulfuration pathway might cause the selenium to mobilize--but not excrete--mercury. This might crash you.

The above paragraph is mostly speculation, and I only mention it because it might be an issue--and it is something you can test for. I am a fan of testing for mercury by using Andrew Cutler's special counting rules on a hair mineral analysis, but the more classic way to test for chronic mercury is a provoked urine analysis.

 

[outdamnspot]

As for your plan with B12 and FMN, all I can say is try it and see what happens.

Thanks, will do -- I've put in an order for both. I'm sorry if this is the sort of thing that's been covered here a lot -- I just feel too fatigued to do extensive research -- but are PWME's better off avoiding multivitamins? I was eyeing up something like this http://au.iherb.com/Life-Extension-...ivitamin-Mineral-Supplement-120-Tablets/67025, which would meet the Selenium, Moly etc. requirements. I always have this (maybe false?) assumption that taking the nutrients in concert might help ease negative reactions. Only problem I guess is the Methylfolate content, which I guess could cause problems if B12 isn't being taken yet.

 

[outdamnspot]

As for your plan with B12 and FMN, all I can say is try it and see what happens.

Would you agree with Greg that L-selenomethionine is the wrong form? He said that's why you can't use Brazil Nuts as a source, and you would need methylselenocysteine instead.

 

[taniaaust1]

Woops, I wrote my last message just after you had replied. So do you take Selenium with the active B2? Greg said the process won't work without Moly -- though you guys mentioned it probably isn't a necessity. My hesitation is messing around with stuff like Selenium etc. and enduring crashes that might not improve; just three days of MB12 has set me back significantly.

i had gene testing done which showed I probably had issues with Molybdenum and hair testing done which vertified I had almost nil and was very deficient So for myself I definately needed the Moly (I actually noticed an improvement after 5 days of taking it). Hair testing showed that I was low in Selenium. Taking both those things helped me in some way which was noticable.

I tend to go by my test results as otherwise its like stabbing around in the dark and wasting lots of money on things which may not do a thing (and worst which could cause more issues if you didnt need). I randomly tried things and did that for years and I think only about one in every 25-30 things I trialed was helpful, till I started to using test results to guide me and now most of the things I try are helpful at least some.

 

[taniaaust1]

Main thing I'm missing is magnesium, which I can't tolerate, but I try to get that from diet too, and green smoothies for folate.

I reactly badly to magnesium supplements until I tried Thompson's Organic Magnesium.

 

[Eastman]

I am on a pretty restricted Keto diet...

I'd love to believe that but everything I seem to try makes me worse :-/ It makes getting anywhere nigh-impossible...

If you keep getting problems with everything you try, you might want to consider the possibility that a ketogenic diet may not be for you.

Did you see my reply to a post of yours on the Resistant Starch thread?

 

[alicec]

I always have this (maybe false?) assumption that taking the nutrients in concert might help ease negative reactions

Many nutrients act in concert and I agree it is a good idea to provide the whole gamut - eg all the B vitamins, not just a couple, all the trace minerals etc.

Whether this helps with negative reactions I don't know but it helps ensures other things don't become limiting when we start increasing some particular nutrient.

In the short term taking a few isolated nutrients may not be a problem but may become so in the long term.

 

[alicec]

Would you agree with Greg that L-selenomethionine is the wrong form? He said that's why you can't use Brazil Nuts as a source, and you would need methylselenocysteine instead.

No I don't agree - I have posted about that previously.

 

[outdamnspot]

Well, I was feeling frustrated today and took about 10mg of Methyl-B12 sublingually in split doses.

I crashed, but what's interesting is that the crash was really no worse than that provoked by 500mcg. I think I remember Freddd saying something about how the initial intake will always have the strongest effect, and that B12 doses aren't exponential in terms of side-effects.

I notice my brain feels 'smother' and aspects of my depression lift.

The downside is that it makes me extremely hungry (not sure if that's related to a crash), and also worsens my balance problems (again, something I experience when I crash, but I also thought it might be due to 'nerves awakening', as described by Freddd).

I am staying on top of Potassium via lite-salt.

 

[outdamnspot]

No I don't agree - I have posted about that previously.

Just out of curiosity, do you have a science background?

 

[outdamnspot]

No I don't agree - I have posted about that previously.

This was Greg's comment re: Selenium ..

"You need to find something with selenocysteine, or selenite. Selomethionine is not the right form and in fact there are publications showing it doesn't work. You don't have the enzymes to cleave the selenium off. There is a specific triplet codon for selenocysteine, no such thing for selenomethionine, so it is inserted more or less randomly into any protein and so does nothing, but it could raise you risk of autoimmune reactions."

 

[outdamnspot]

A methylation panel would be something like this: https://www.doctorsdata.com/methylation-profile-plasma/

It sounds like you are willing to experiment, and I think you are working with a lot of the right pieces. I'll keep my fingers crossed for you.

On the off-chance that you continue to encounter unreasonable difficulty with supplements that are normally helpful for people with ME/CFS, you might consider testing for mercury poisoning. Here is my thinking:

Your reaction to selenium seems weird. Increased metabolism should give you energy--not that I have ever heard of selenium causing hyperthyroidism. You also seem to be having difficulties with methylation supplements above and beyond what most of us deal with. Rich Van Konynenburg mentions in the Sweden lectures that some of the people in his study who didn't respond well to methylation supplements had mercury poisoning, and he thought the mercury poisoning was responsible for their poor response. (Granted, I don't know the details of what you tried and it is also possible that you just haven't experimented enough.) According to Dr. Myhill, selenium chelates mercury, but without sufficient sulfur-containing amino acids it won't get excreted. The bit about "sulfur-containing amino acids" sounds like an over-generalization to me, but it at least suggests the possibility that dysfunction in your transulfuration pathway might cause the selenium to mobilize--but not excrete--mercury. This might crash you.

The above paragraph is mostly speculation, and I only mention it because it might be an issue--and it is something you can test for. I am a fan of testing for mercury by using Andrew Cutler's special counting rules on a hair mineral analysis, but the more classic way to test for chronic mercury is a provoked urine analysis.

I don't think I have a mercury issue because I've never had fillings. If the adrenals were weak, then couldn't speeding up the metabolism or boosting the thyroid cause a crash? I found NDT completely intolerable. Also, doesn't Selenium have some effect on detoxing the liver?

 

[alicec]

do you have a science background

Yes in biochemistry - spent all my working life in medical research.

 

[alicec]

there are publications showing it doesn't work.

I haven't come across these though it is some time since I have looked. Everything I have read says that most of the selenomethionine (and all of the selenocysteine) that is ingested is broken down and the liberated selenium is incorporated into newly synthesised selenocysteine as it is incorporated into proteins.

Any selenomethionine that is not metabolised is indeed randomly incorporated into proteins where it plays no special role. The selenium becomes available for incorporation into selenocysteine when the protein is broken down.

I'll look for the studies showing that selenomethionine is not broken down. Maybe these are new - they contradict everything I have seen.

 

[alicec]

I have done a quick search on google scholar for studies on selenium metabolism in humans.

I didn't find anything recent, and nothing to support Greg's claim that selenomethione is not broken down and so does not become available for incorporation into selenocysteine.

I did find something I didn't know. In this relatively recent review (most studies are quite old), they discuss how selenomethionine is converted to selenocysteine by the normal methylation and transsulfuration pathways that produce cysteine from methionine.

This is apparently a major processing pathway.

They also emphasise that the incorporation of selenomethionine into general proteins is an important storage mechanism for selenium in the body.

I have uploaded a figure from the review which illustrates the interconversion of various forms of selenium.