Glycine

Dietary intake of glycine is important

Our own ability to make Glycine from Serine is limited by the rate of folate cycle:

the capability to synthesize glycine from serine is constrained by the stoichiometry of the glycine hydroxymethyltransferase reaction, which limits the amount of glycine produced to be no more than equimolar with the amount of C 1 units produced.

This constraint predicts a shortage of available glycine if there are no adequate compensating processes.

Here, we test this prediction by comparing all reported fluxes for the production and consumption of glycine in a human adult.

Detailed assessment of all possible sources of glycine shows that synthesis from serine accounts for more than 85% of the total, and that the amount of glycine available from synthesis, about 3 g/day, together with that available from the diet, in the range 1.5–3.0 g/day, may fall significantly short of the amount needed for all metabolic uses, including collagen synthesis by about 10 g per day for a 70 kg human.

This result supports earlier suggestions in the literature that glycine is a semi-essential amino acid and that it should be taken as a nutritional supplement to guarantee a healthy metabolism." (R1)

This is one more cause of developing lowered GSH while we age. And one more blocker for getting out of GSH depletion in high oxidative stress patients.

And amounts are quite large, comparing to other nutrients.

Dependency on 1C units utilisation

Same authors suggested that glycine synthesis depends on utilisation of one-carbon units:

A critical weak link is created in glycine biosynthesis by the stoichiometry of the reaction catalyzed by glycine hydroxymethyltransferase (EC 2.1.2.1), which converts serine into glycine plus one C1 unit: this produces an absolute dependence of the glycine production flux on the utilization of C1 units for other metabolic pathways that do not work coordinately with glycine use. It may not be possible, therefore, to ensure that glycine is always synthesized in sufficient quantities to meet optimal metabolic requirements. (R2)

What is interesting here, is that use of 1C units is not synchronised with use of glycine and that could be an issue according to the authors.

That means, that the product of SHMT - 5,10-methylene-THF should be considered as inhibitor-or-switch of SHMT activity. Perhaps it’s the level of 5,10-methylene-THF that tells in which direction of reversible reaction should the enzyme work?

Folinic acid and 5MTHF are inhibitors of SHMT

Both Folinic acid (5fTHF) and 5MTHF inhibit SHMT, so taking high doses of those forms of folate is not recommended under high oxidative stress conditions when methionine cycle is slowed down due to oxidation of methylcobalamin cofactor.

The SHMT- and MTHFS-catalyzed “futile cycle” may serve regulatory functions by controlling 5fTHF concentrations. The primary metabolic function of SHMT is to reversibly interconvert serine and THF to glycine and 5,10-methyleneTHF (CH2F). 5fTHF is a feedback inhibitor of SHMT, and also binds to and inhibits AICARFT, but the purpose of the 5fTHF futile cycle in regulating SHMT and FOCM remains unresolved. This is due in part because 5mTHF, which is more abundant than 5fTHF, also serves as a potent inhibitor of SHMT. (R3)

Explanation: mitigation of high oxidative stress requires increased amounts of glutathione, which is made from cysteine, glycine and glutamic acid.

Taking high doses of 5-MTHF will inhibit synthesis of glycine, making it harder for the cells to make GSH, which is also required for preparation of methylcobalamin (from any orally taken form).

Insufficient supply of intracellular methylcobalamin leads to accumulation of 5-MTHF, which inhibits glycine synthesis further, creating a vicious cycle.