I was wondering what other effects folate might have, beside methylation, since I always have different reactions to methylfolate and methylcobalamin supplements.
In addition to 5-MTHF, there are multiple other folate forms with different functions and 5-MTHF can be converted into these forms.
10-formyl-tetrahydrofolate is a cofactor in the synthesis of purines. Purines are important in the DNA and AMP (adenosylmonophosphate, precursor of ATP) and GMP have functions in the metabolism as ATP and GTP. ATP is an important energy unit, GTP activates G proteins. Detailed information on the biosynthesis of purines here: https://en.wikipedia.org/wiki/Purine_metabolism#Biosynthesis.
So obviously this makes 10-formyl-THF relevant for ATP production from AMP in the oxidative phosphorylation. But even if the energy metabolism is inhibited and ATP cannot be formed, AMP has individual metabolic functions.
AMP activates the 5’AMP-activated protein kinase/ AMPK. This enzyme is responsible for reacting to low energy levels in the body. When ATP levels are low and AMP or ADP levels are high, it activates the fatty acid oxidation in liver and muscles, increases the production of ketone bodies and inhibits the cholesterol and fatty acid synthesis. AMPK also affects glucose metabolism by stimulating glucose transport into the cell and glycolysis and inhibiting gluconeogenesis and glycogen-synthesis.
AMPK reduces pathways that use up energy and increases energy production by stimulating glucose and fatty acid breakdown. This makes it an important response of the body to low energy levels. It is hypothized that AMPK activation plays a role in exercise and adapts the muscles etc and energy metabolism to increased energy requirements during bodily exertion.
I think, folate status might be relevant in AMPK activation, because the folate form 10-formyl-THF is a cofactor for synthesizing AMP via purine biosynthesis.
This post on phoenixrising is about findings of low AMPK activity in ME/CFS patients.
At the moment I have trouble judging, how important the interaction of folate and the purine synthesis and AMPK activation is for ME/CFS. Also, I’m unsure, if improving MTHFR function by supplying its cofactor vitamin B2 is sufficient or if there is an additional need for supplementing folate.