Is Molybdenum necessary for methylation?

[pemone]

There are two steps in converting riboflavin to the active vitamin - first to FMN, then to FAD. Molybdenum is used in the second step. Thyroid hormone is used in the first step hence the need for iodine and selenium.

FMN (also known as riboflavin 5 phosphate) is available as a supplement but not FAD.

Note also that swallowed FMN is largely processed before it is absorbed from the intestine. This involves clipping off the added phosphate group which negates the point of taking the active vitamin. There does appear to be a second route of direct uptake but this is not well understood.

Sublingual FMN should be directly absorbed.

Right. The metabolic pathway is from the inactive riboflavin to FMN (aka R5P), and then to FAD. If you ingest FMN or FAD, they convert to riboflavin and absorb from the gut as riboflavin. So the attempt to sell you FMN or FAD as a pill you swallow is an incredibly cynical things for as supplement company to do. I read that there may be another pathway for absorption in the gut, but it is not well studied and not well defined.

Sublingual FMN should work, but sublingual FAD would be much better if that were available. FAD is the form of the active flavin that gets used in most enzymes. Can someone summarize the sublingual forms that are available now?

 

[pemone]

I am somewhat concerned with his strategy of taking iodine, selenium, b2 and molybdenum until symptoms appear, then backing off and ramping up. While high doses of iodine might be helpful for some people--maybe even people with Hashimoto's--people at risk for Hashimoto's should be aware of the risk it poses as well. Some minerals do not signal immediately when you take them in excess, allowing toxic amounts to build up over time. I am concerned that selenium is one of them. Very high doses of b2 can deplete one of boron, and very high doses of molybdenum can deplete one of copper.

Just some add-ons to your comments.

I share your concern about selenium toxicity, as the range between too-low and too-high selenium is very narrow. The symptoms of too-low and too-high selenium are very similar, so symptoms might be tricky for a non-expert to assess. What is worse is that different parts of the US have MASSIVELY different amounts of selenium in the soil. In some areas, you get an overdose just from eating food. If you are going to play with selenium, you need to run a plasma selenium test periodically to make sure you are not raising your plasma level too high. Actually, it is a good health practice to watch selenium no matter what. Chris Masterjohn recommends keeping plasma selenium around 120 ug/L.

Regarding the molybdenum depleting copper, note that this was based on studies in ruminants, and humans do not have the same digestive processes that cause the copper depletion. The copper concern starts at 2000 mcg per day for a 70 kg human, and the RDA is 45 mcg. So there is a very very large safety margin for molybdenum supplementation, and if you are staying under 1 gram (1000 mcg) per day you look pretty safe.

 

[pemone]

With so many things to delve into and limited brain capacity I have never followed up Greg's claims about the requirement for molybdenum in forming FAD.
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.

So my brief research on this in PubMed suggests a few things:

1) We do not understand the function of the FAD synthase enzyme that converts FMN to FAD very well.

2) We do not understand the FAD hydrolase function of FAD synthase, which may require molybdenum for proper function. FAD hydrolase helps to convert FAD back to FMN.

3) When you read about FAD hydrolase, you realize that it is very important in the metabolism of flavoproteins. These are critical in energy generation in the electron transport chain.

So to have a "hypothesis" that a molybdenum deficiency might cause a problem in FAD hydrolase that then sabotages riboflavin's role in energy production in some important way, would probably not be a crazy theory. There is no experimental evidence to prove it is true, but it an interesting idea. And if you get a profound positive response from the more bioavailable forms of molybdenum that Greg recommends - such as sodium molybdate - then this might be the mechanism.

 

[pemone]

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.

It was not covered in this thread up to the point of your post, but the form of molybdenum seems to matter, for reasons I cannot get explained. I was taking 1 mg (1000 mcg) against the RDA of 45 mcg of molybdenum glycinate. It did nothing for me, and in fact my RBC test for molybdenum was below the low end of normal. The more bioavailable form is sodium molybdate, which almost immediately started to show positive effects for me, mainly by blunting the brain fog that I get two hours after eating a meal. In my case, I definitely have some problems around sulfite metabolism, as I have extremely low plasma sulfate and a high cysteine/sulfate ratio that might suggest a sulfite accumulation problem. The molybdenum in molybdate form seems to be helping that.

 

[pemone]

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.

While not useless, hair testing of selenium is the wrong way to test it. Use plasma selenium.

 

[pemone]

I am on a pretty restricted Keto diet, I don't think I would be getting much Molybdenum looking at the list.

Have you had a glucose + insulin tolerance test to determine your insulin sensitivity? What was the result of that?

Unless you are profoundly overweight and have a tolerance test that quantifies a high degree of insulin resistance, I would be extremely wary about using a ketogenic diet. This is what started my chronic fatigue illness. I went into a state of profound muscular fatigue, and when I tried to (incorrectly) reverse the diet, I was unable to reverse the symptoms.

It turns out I had polymorphisms of one of my genes of fatty acid oxidation that is pathological in conditions of extreme catabolic stress...such as a ketogenic diet. Once I corrected the diet with sufficient carbohydrate, all of my muscular fatigue vanished, but it took me 2.5 years to get to that point.

Unfortunately, the long period of extremely low energy created neurological issues and problems around my sulfur metabolism that I am still resolving.

Ketogenic diet works for people with the required metabolic flexibility. But the fatty acid oxidation pathways are incredibly complex biochemically and rely on a very large number of enzymes to perform their job. You only need to accumulate a few key polymorphisms along that pathway and your ability to use fat for energy becomes sub-optimal. You will never notice this on a normal diet, but once you cut out carbs you will slowly descend into a sheer living hell. And in my case the long-term effects of that hell have yet to be completely resolved.

 

[pemone]

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

Potassium chloride is a bad idea. Published research shows that it can cause ulcerations in the small intestine that give no symptoms until they become life-threatening perforations that then require bowel resection surgery, itself a life-altering operation.

The right form of potassium is potassium citrate. The citrate does not cause ulcerations, and it is one of the two forms of potassium that alkalizes the urine and in published research spares bone mass loss. Potassium chloride does NOT spare bone loss in the published research.

 

[pemone]

Yes, getting B12 pathways working can increase need for folate. Some of the unpleasant symptoms that arise are simply due to insufficient folate. People often think that the folate is causing problems and reduce dose, but actually they need more.

The phenomenon seems to be related to refeeding syndrome.

Greg from B12 oils would say that ongoing need for large amounts of folate reflects a problem with making active B2 since this is needed by the MTHFR enzyme to recycle folate. This seems to be a fair claim though in my own case, while attention to all the things needed to make active B2 has enabled me to reduce my folate intake considerably, I still seem to need a relatively high dose. Something else is going on but I don't know what.

When Greg talks about "paradoxical folate deficiency" I do not think he is talking about the rate of folate utilization. He is talking about a condition where you have very highly elevated plasma folate, and in spite of that you actually have a functional folate deficiency. His reasoning for that is that you have a functional B12 deficiency, and this is preventing your body from using folate inside the cell. So your dietary folate accumulates and never metabolizes away.

I have no idea whether this theory makes any biochemical sense or not. But that seems to be the way that Greg reasons about this issue.

 

[pemone]

Do you think Folate should not be started before B12? My doctor's original advice was to start with Methylfolate (200mcg, then raise each week); I asked her if this could lead to methyl-trapping if I wasn't taking B12, but she didn't know what I was referring to.

The conventional medical thinking is that folate supplementation without B12 can mask the symptoms of a B12 deficiency, and can in fact provoke some of them. One way it can do this is by hiding the megaloblastic anemia associated with B12 deficiency. Megaloblastic anemia is characterized by red blood cells that are larger than normal. As a result, there are not enough red blood cells. This anemia is known as vitamin B-12 or folate deficiency anemia, or macrocytic anemia, as well. Taking folate can prevent the anemia from fully showing up on your blood tests, and as a result, your B12 deficiency can be extremely severe and remain undiagnosed. This can result in irreversible brain damage, in the case of an extreme B12 deficiency with neurological impacts.

 

[pemone]

As I've said previously, taking a few isolated b vitamins is not likely to be a problem in the short term but is likely to be in the longer term. You may find that any positive response to B12 and folate quickly peters out as you deplete other needed B vitamins.

Which B vitamins do B12 and folate deplete?