Confused about folate differences

[Chiron]

My MTHFR genes are just fine, but I have MTR and MTRR mutations, along with a COMT mutation. So it's been recommended that I take folinic acid and hydroxob12 instead of the methylated forms. I have tried methylfolate before orally and by injection, and I get really messed up.

Normally I have to inject these because my bowels are a wreck -- my terminal ileum does not absorb these vitamins anymore. (I have IBD.)

However it seems that folinic acid by injection is ridiculously expensive. So I'm wondering if I could use folic acid instead? The body converts folic acid to folinic acid anyway, does it not? Or is there a downside I'm not seeing here? Folic acid injections cost peanuts but I am reading a lot of controversial information about them online -- like they cause cancer, linger in the body too long, etc.

If someone could provide clarity I'd appreciate it. I don't want to mess myself up more!

 

[robinhood12345]

bakers yeast is highest food source of folates, and for b12 liver/other organs, oysters/clams/mussels

 

[alicec]

However it seems that folinic acid by injection is ridiculously expensive. So I'm wondering if I could use folic acid instead? The body converts folic acid to folinic acid anyway, does it not? Or is there a downside I'm not seeing here?

Folic acid is processed by the enzyme dihydrofolate reductase (DHFR) which acts on it in two steps. First folic acid is converted to dihydrofolate (DHF), then DHF is converted to tetrahydrofolate (THF). This second reaction is the normal reaction for DHFR - ie DHF is its natural substrate.

THF in turn feeds in to the folate cycle where it is converted to different cofactor forms by the enzymes MTHFD1 and MTHFR. Folinic acid is not an active cofactor but a storage form of folate. It is produced in a side reaction off the main folate pathway.

I've uploaded a diagram which illustrates the essential elements of the folate cycle. Note that folinic is 5 formyl THF. Also note that the diagram implies that folate in vegetables is like DHF but this is not correct. The predominant folates in vegetables are methyl folate and, to a lesser extent, folinic.

So you could say that folic acid is indirectly converted to folinic but the two aren't necessarily interchangeable because different processing steps are involved.

The most significant of these is that while DHFR does recognise folic acid because of structural similarity to its natural substrate, it processes it far more slowly than the natural substrate - 1300 times more slowly. Furthermore there is about a 5 fold natural variation in DHFR, so some people process it extremely slowly. See this paper.

The consequence of this is that, even for those who process folic acid most quickly, even moderate doses of folic acid quickly overwhelm the capacity of DHFR so folic acid accumulates. Excess folic acid inhibits DHFR so DHF accumulates. DHF in turn inhibits several enzymes in the folate cycle, including MTHFD and MTHFR.

So the net effect of anything other than very small doses of folic acid is inhibition of the folate cycle. Slow metabolisers are even more susceptible to this effect.

Injections of folic acid are very likely to be counterproductive.

 

[Chiron]

Folic acid is processed by the enzyme dihydrofolate reductase (DHFR) which acts on it in two steps. First folic acid is converted to dihydrofolate (DHF), then DHF is converted to tetrahydrofolate (THF). This second reaction is the normal reaction for DHFR - ie DHF is its natural substrate.

Brilliant post and demonstration of knowledge. Thank you! This answers all my questions.