Thread by @ChrisMasterjohn

Methylation is about WAY more than B12 and folate. You have to consider at least 26 nutrients and hundreds of different genetic impairments.

A thread 🧵👇

MTHFR’s job is to use riboflavin (in the form of FAD) to take electrons from niacin (in the form of NADPH) to add them to what becomes the methyl group of methylfolate, which then gets passed on to vitamin B12, which then passes it to homocysteine to make methionine.

The NADPH in this reaction comes from glucose in the pentose phosphate pathway. This requires the enzyme lactonase, which requires magnesium or manganese and zinc. It also requires the enzyme transketolase, which requires thiamin.

The carbon atom that makes up the methyl group of methylfolate needs to be present before MTHFR does its thing, and this typically comes from serine or glycine.

Both of these amino acids are found in dietary protein, though on a mixed carbohydrate-inclusive diet, they are primarily synthesized from glucose. The synthesis of serine from glucose requires the enzyme phosphoserine aminotransferase, which requires vitamin B6.

That carbon atom can also come from excess methionine that was buffered by methylating glycine and later harvested from methylated glycine metabolites in the mitochondria to yield formate.

This requires the enzyme glycine N-methyltransferase, whose expression is increased by vitamin A; sarcosine dehydrogenase and dimethylglycine dehydrogenase, which require iron; and mitochondrial formyltetrahydrofolate synthetase, which requires potassium.

The carbon atom can also be gotten from glycine using the glycine cleavage system, which adds lipoic acid and vitamin B5 (as coenzyme A) as cofactors.

If formate is used to supply the carbon atom of the methyl group, MTHFD1 must use ATP to make it happen.

This opens the door to the full suite of nutrients needed for ATP synthesis, which adds biotin (for pyruvate carboxylase to run the citric acid cycle)...

..., copper (for complex IV of the mitochondrial respiratory chain), iodine (to make thyroid hormone, which raises the rate of ATP synthesis), sulfur (for the iron-sulfur complexes of the respiratory chain), sodium (for the transport of many of these components).

The amino acid methionine from dietary protein is always the starting point to provide methyl groups, and MTHFR’s role is to recycle it after it becomes homocysteine.

You can never get the “perfect” amount of methionine to keep this cycle running without a little bit of excess, and that excess will always require molybdenum for its clearance.

Oxidative stress will lead to excessive breakdown of homocysteine and make it unavailable to be recycled by MTHFR. Antioxidant protection adds vitamin C, vitamin E, and selenium to our list.

In addition, MTHFR activity will need to be higher if choline and betaine run low and therefore cannot be used to support methylation through the alternative enzyme betaine homocysteine methyltransferase.

This alone is a list of 26 nutrients.

The role of ATP opens up the door to hundreds of genetic impairments in energy metabolism.

In How I Found My Health “Super Unlock” After 20 Years of Research and 20,000 Genes Tested, I estimated that each person has one to six nutritionally actionable genetic mutations in energy metabolism...

...that are orders of magnitude more important than the other 14 million sites of genetic variation found in everyone.

This means that genuinely drilling down into the stealth contribution to deficient MTHFR activity means running comprehensive screening for energy metabolism.

The energy metabolism screening can reveal needs for nutrients that the nutritional screening will not reveal.

For example, you could have optimal riboflavin status due to a nose-to-tail diet, but you could have a riboflavin-responsive impairment in an enzyme such as ACAD9 that will sap your ATP production...

...unless riboflavin is brought to supraphysiological levels with doses such as 75 milligrams or 400 milligrams per day. The low ATP would hurt MTHFR activity regardless of the presence of MTHFR polymorphisms.

Thus, someone could be homozygous for C667T and also have the ACAD9 mutation.

At 1.5 milligrams per day of riboflavin, the comprehensive nutritional screening shows that their riboflavin status is fine, but they have a 75% genetic hit against their MTHFR.

At 3 milligrams per day of riboflavin, their C677T homozygosity becomes completely irrelevant, but their MTHFR activity is indirectly sapped by low ATP.

At 75 milligrams per day of riboflavin their ACAD9 is optimized, their ATP levels improve, and MTHFR functions normally.

This is just one of hundreds of possible reasons for low ATP, however, thus the importance of the screening, which could reveal hundreds of other such solutions.

The low-hanging fruit of MTHFR is to get dietary riboflavin to 3 milligrams per day.

Track your diet if needed with this help:

chrismasterjohnphd.substack.com/p/how-to-track…

Right above that: my MTHFR Protocol:

chrismasterjohnphd.substack.com/p/the-mthfr-pr…

Next-level: fix any nutrients found in the comprehensive nutritional screening:

chrismasterjohnphd.substack.com/p/comprehensiv…

Highest-level: fix any problems found in the comprehensive screening for energy metabolism:

chrismasterjohnphd.substack.com/p/comprehensiv…

For links and references for all the points made in this thread:

chrismasterjohnphd.substack.com/p/your-mthfr-i…