The Folate Cycle

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The starting point of methylation is the folate cycle. Folate (vitamin B9) from foods is the base substance of the process, and the folate cycle breaks it down and, via a number of enzymatic steps, reduces and transforms it into it the hydrogen-rich 5-MTHF (methyl folate). 5-MTHF is then passed onto either to the methionine cycle to make SAMe or to the biopterin cycle to facilitate synthesis of certain neurotransmitters and hormones. Along the way, purines and thymidine are made and form the basis of DNA, and therefore cellular growth and repair. This is the basic process in a nutshell!

Keeping it simple, any issues with this pathway in the Lifecode Gx®️ Methylation Report (presence of any red SNPs on the pathway diagram, or several ambers), could indicate reduced function and synthesis of 5-MTHF. Consider also whether the client has a low folate diet, if there are any gut or digestive issues that would affect nutrient digestion and absorption, and if there is extra need for 5-MTHF - for example, high stress, pregnancy or trying to conceive. In this context, you can suggest some fundamentals that may help - stress reduction, rest to optimise recovery and repair, increase folates in the diet, support digestion, and potentially a supplement of methyl folate.

The advantage of methyl folate is that it cuts out all the preceding steps and can be used directly as an 'active' form, simplifying the whole process biochemically. Folinic acid is also an option, but note that it is a synthetic form that enters the cycle at the 'Formyl-THF' stage around the middle of the pathway, and, although it may help with purine and pyrimidine synthesis, it still requires processing by MTHFD1 and MTHFR to form 5-MTHF, so is not a complete solution for all. It is also worth noting that it is considered a medicine in UK and some other countries, so may not available for everyone to prescribe. Using methyl folate will also promote purine and pyrimidine synthesis, as long as there is sufficient B12, as it will be recycled into the folate cycle as THF (more on this in the Methionine Cycle article).

Now let's look at the detail of the folate cycle, the meaning of each SNP, and any further specific recommendations for support.

FOLH1

The first process in the folate cycle relies on digestion, as most dietary folate is in 'polyglutamyl' form in plants, which is quite hard to break down. Folate Hydrolase enzyme, aka Glutamate Carboxypeptidase II, produced by the villi, hydrolyses polyglutamyls, resulting in monoglutamyl folate forms. SNPs in FOLH1 gene can reduce its activity, compounded by gut dysfunction such as inflammation, coeliac disease, surgery etc. Alcohol is also a specific inhibitor. To support FOLH1, increase food folates, while supporting gut epithelial health, and avoiding alcohol. Zinc is also a cofactor for the enzyme, so enrich the diet with zinc, or consider a supplement.

Incidentally, the synthetic folic acid form of folate is a monoglutamyl and has an advantage in that it skips this step, but has other disadvantages later on in the process. We can also get 5-MTHF directly from diet in animal foods, although not much, so it may not be a reliable source. 

RFC1

The next step involves transporting the folate into cells via RFC1 (Reduced Folate Carrier 1, aka SLC19A1).  RFC1 SNPs are associated with reduced ability to take up, retain, and metabolise folates. We can support RFC1 as per FOLH1, optimising folate intake to increase supply. As with all aspects of the folate cycle, using methyl folate as a supplement bypasses FOLH1, RFC1 and other steps.

DHFR

There are then a series of conversion steps that transform folate, moving it closer to the 5-MTHF form. Dihydrofolate (DHF) is reduced to tetrahydrofolate (THF), using the DHFR enzyme (Dihydrofolate reductase) and vitamin B3 (NADH) as cofactor, effectively doubling the hydrogens. The variant on DHFR is actually a deletion (19-bp deletion) and results in increased activity. While this sounds like it might be positive for 5-MTHF, in fact it seems to accelerate use of folate into the thymidine pathway via TYMS (see later) at the expense of 5-MTHF production. Think of it as it pushing folate down the pathway so fast, it’s too fast, and it wastes folate, rather like water disappearing down a plughole. 

DHFR is particularly influenced by higher dose folic acid, in supplements or fortified foods. Amounts higher than 500 mcg can result in high circulating, un-metabolised folic acid levels in blood, and this can potentially block the activity of the more useful 5-MTHF.

DHFR SNPs can be supported by optimising MTHFR function further down the cycle, to make sure more 5,10-methylenetetrahydrofolate (5,10 methylene THF) is used for 5-MTHF, and by avoiding any folic acid. Of course, use of methyl folate bypasses DHFR.

DNA Building/TYMS

At this point in the cycle (and later), we have an important offshoot function that facilitates cell replication and repair. This is especially important for pregnancy and fertility, but also tissue health, and immune activity when we are injured or inflamed.

The 10-Formyl THF form of folate can be directly used for synthesis of purines (a source of the bases guanine and adenosine). Then, when further converted into 5,10-Methylene THF, this is used to form the base thymine from thymidine via the TYMS enzyme (thymidylate synthase). The bases are then used as the building blocks for DNA replication. TYMS SNPs may impact DNA stability, increasing the risk of certain cancers.

SHMT

THF to 5,10-Methylene THF conversion can occur via 2 parallel routes and 2 different enzymes. SHMT (Serine hydroxymethyltransferase) is the main enzyme for direct conversion and catalyses the reversible conversion of serine to glycine, and THF to 5,10-Methylene THF. SNPs in SHMT1 are associated with lower activity and reduce the pool of 5,10-MTHF, impacting DNA synthesis and repair (via thymidine), as well as availability of methyl folate to support methylation. SHMT can be supported with the cofactor vitamin B6, or bypassed with a direct supply of methyl folate. 

MTHFD1

MTHFD1 is the second route for conversion of THF to 5,10-Methylene THF, but does so via 3 stages, which result in the purine and thymidine synthesis already mentioned. These are reversible reactions that can be directed towards 5-MTHF or away from it. MTHFD1 SNPs can impact DNA synthesis and repair, and increase demand for choline as a methyl-group donor in the methionine cycle. SNPs are linked to increased risk of neural tube defects, and endometriosis-related infertility. Support with vitamins B3 and B6, choline, or bypass with a direct supply of methyl folate.

MTHFR

The infamous MTHFR gene codes for methylenetetrahydrofolate reductase, a vital rate-limiting enzyme, which catalyses conversion of 5-10 methylene THF to 'active' folate - 5-MTHF. SNPs can be highly significant, with the C677T variant, which occurs in about 30% of people, resulting in very reduced 5-MTHF levels - as high as 70% for homozygotes. The A1298C variant has less impact on 5-MTHF levels but is associated with depletion of biopterin. MTHFR activity can be improved by supporting the preceding stages, or bypassed by directly supplementing methyl folate. Riboflavin (vitamin B2) and niacin (vitamin B3) are also key cofactors. 

Now we have our precious 5-MTHF, where does it go? There are two options, both important. On the one hand, it may feed into the biopterin cycle for neurotransmitter synthesis. On the other, it can be passed over to the methionine cycle, rather like handing over a torch or baton, to re-methylate homocysteine, ultimately providing a refreshed supply of SAMe for methylation.

Next, read about the Methionine Cycle.