Ammonia and BH4 - is this a myth or something?

[Kimsie]

Would you say that it's a good idea to increase even folate when increasing B3? I am wondering which ratio between B3 and folate is optimal. How much folate would you need to take when taking, say 500mg B3?

I would say that it isn't so much a ratio as what amount of folate is optimal for an individual. We have found that over 1 mg of folate draws too much B6 into the SHMT enzyme, at least that is what I think is happening. This decreases B6 availability for other reactions, even when the person takes 100 mg of P5P a day. The amount of B3 doesn't seem to have any effect on this. So for us, we limit folate to 1 mg, but that might not be true for people who have more problems in the folate cycle. My sons each have either one copy of C677T (depression) or one copy of A1298C (schizophrenia), but I don't think their mutations have any direct effect on their illnesses. Double mutations might do more.

I just experimented with higher folate yesterday, 1.6 mg extra over the 1 mg, and it caused a return of depressive symptoms in my son who has depression. This doesn't mean that someone else will get depression from folate, it just means that B6 is being used excessively by folate, and the SHMT enzyme is the only folate enzyme that uses B6. It would be pretty complicated to tell you how I came to that conclusion, but if you want to know I can tell you in another post.

So in answer to your question, I would say that 1 mg of folate might be the right amount, but it depends on if that works for you. We use that amount even with higher amounts of niacinamide.

 

[Kimsie]

This article here:

5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels: Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling
http://circ.ahajournals.org/content/114/11/1193.long

This is the main article that I was examining yesterday, but today I took a closer look at it and I see that they do show that 5-MTHF is a peroxynitrite scavenger. That's nice.

I still think there is a problem with high dose folate for many people with ME/CFS, meaning doses much over 1 mg, because of the SHMT enzyme effect on the availability of B6, and the ammonia production from glycine decarboylase, which are hard to avoid if the person is using the folate cycle for ATP production. It might be that some people with CFS are not able to use the folate cycle for energy, and those people might benefit the most from 5-MTHF. (Those people would have to rely more on the glycolysis pathway for alternative energy production.)

It seems that the glycolysis pathway might have a relationship with PEM because of the lactic acid buildup, so maybe the glycolysis pathway is the primary alternative pathway used by people with ME/CFS. (My son who has schizophrenia was found to be low in lactic acid, so I guess he doesn't use that pathway, but only the folate pathway.)

 

[pemone]

I know that you have seen my folate cycle illustration but I put it here for those reading this thread who have not seen it to show what I am talking about.
View attachment 9329In someone who is low on ATP and NADPH these pathways will be pulled more towards the directions I have in the red arrows.

Can someone explain the difference between MTHFR and MTHFD on this diagram? I have never seen MTHFD on one of these diagrams before.

 

[alicec]

the difference between MTHFR and MTHFD

They are two different enzymes. MTHFR catalyses the transformation of 5,10 methylene THF into 5 methyl THF. This is a one-way reaction.

The MTHFD1 enzyme has three separate functions in one protein and catalyses a series of reactions in the folate cycle. As shown in the diagram, it transforms 5,10 methylene THF into 5,10 methenylTHF, then transforms this product into 10 formylTHF, then transforms this product into THF. All three of these reactions are reversible.

I've uploaded an alternative diagram showing the two-way possibilities for the MTHFD1 reactions.