5,10-methylene-THF

Hypothesis: Possible implication of MTHF level in tics disorder.

Anecdotal evidence:

1. People report that taking Glycine sometimes increase tics (I have similar observations).
2. Personal experience with Serine: apparently it reduces tics, but also can lower energy (and that can be a reason for tics reduction). Serine also being reported by two people to cause negative symptoms in the brain (burning headache, irritability, disinhibition).
3. Carnosine was reported to reduce tics and I saw the same effect.

The common thing between these observations is Serine to Glycine reaction, which is critical for folate metabolism:

“One possible explanation is that high glycine levels limit the number of one-carbon units for nucleotide synthesis, since a glycine overflow can deplete the 5,10-methylene-THF pool by forcing the reversed SHMT reaction” [R1]

“Other amino acids can also fuel the SGOCP. Histidine catabolism can replenish the cytosolic pools of 5,10-methenyl-THF” [R1]

“Thus, although the main one-carbon source for the SGOCP is serine, other sources exist, including the catabolism of glycine, histidine, tryptophan, or threonine, as well as the detoxification of formaldehyde. Diet-derived one-carbons from folate species and vitamins, such as betaine, vitamin B12, and choline, might also be an important exogenous supply of carbon and enzymatic cofactors for the SGOCP” [R2]

“The conversion of serine to glycine by glycine hydroxymethyltransferase (EC2.1.2.1) generates large quantities of 5,10-methylene-THF.” [R2]

It is mainly produced by the reaction of tetrahydrofolate with serine, catalyzed by the enzyme serine hydroxymethyltransferase [R3]

My working theory is that low level of 5,10-meTHF might be implicated in tics.

This would lead to lowered level of 5MTHF and reduced remethylation of homocysteine.

But oral intake of 5MTHF increases tics dramatically that’s why I suspect other roles of 5,10-meTHF than becoming 5MTHF are related to tics.

5MTHF is known as a predominant inhibitor of SHMT, which means that it can inhibit interconversion of glycine <-> serine and THF <-> 5,10-methylene-THF:

“Model simulations also provide evidence that 5-methylTHF (and not 5fTHF) is the predominant physiological binder/inhibitor of SHMT.” (R4)

What is 5,10-methylene-THF (MTHF)

As an intermediate in one-carbon metabolism, MTHF interconverts to 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and methenyltetrahydrofolate. It is substrate for the enzyme MTHFR It is mainly produced by the reaction of tetrahydrofolate with serine, catalyzed by the enzyme serine hydroxymethyltransferase (Wikipedia)

Reactions where MTHF is used

1. As a One-carbon donor for methylation of dUMP to dTMP by Thymidylate Synthase.
2. To produce 5-MTHF from MTHF by MTHFR.
3. In conversion to 5,10-methenyl-THF by MTHFD2 and MTHFD2L (mitochondria).
4. In conversion of Glycine to Serine by SHMT2 in mitochondria.

Reactions where MTHF is produced

1. In conversion of Serine to Glycine by SHMT1
2. Glycine cleavage with simultaneous lipoate reduction by AMT (in mitochondria)
3. in Reversible reaction of 10-formylTHF to form MTHF by trifunctional enzyme MTHFD1 (cytosol)

Open questions

1. Are there known disorders caused by depleted MTHF pool?