The Folate Cycle
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The Folate Cycle is the first of the 5 subcycles that make up the Lifecode Gx Methylation report.
Folate (vitamin B9) is a generic term encompassing natural folates in food and synthetic folic acid in supplements and fortified foods. After ingestion folates are converted (reduced) to dihydrofolate (DHF) then further reduced to tetrahydrofolate (THF). Tetrahydrofolate is required to: 1. make DNA and RNA (left hand cycle on the diagram) and 2. as precursor to methylfolate (5-MTHF) to supply methyl (CH3) to the methionine cycle.
Folate cycle function can be impacted by genetic and environmental factors. Personal genetic results are presented as coloured dots - green (no/ low impact), amber (some risk) or red (higher risk). Whilst each individual gene/ SNP result can be meaningful, it is important to look at the whole cycle (and report) noting groups and patterns of amber and red results. The good news is that any/ all combinations of results can be be supported through diet and lifestyle.
Key Considerations -
Increased requirements for folate, such as fertility, pregnancy, stress, injury, infection.
Symptoms of low folate - anaemia, immune issues, high homocysteine (test).
Gut health - GI damage, coeliac disease, inflammation, Crohn's disease, impacting absorption.
Diet - food first (if possible). Folate rich foods often includes cofactor (helper) nutrients too.
Cofactor nutrients - particularly B3, B2, B6, B12 and zinc, and inhibitors/ depletors - alcohol, and UV light both damage (oxidise) folates. Folates do not work in isolation.
If supplementing, consider pros and cons of using different forms of folate, in light of genetics (see below) and other factors. Consider supplements that include cofactor nutrients.
Genetics:
If DHFR SNPs - Limit folic acid intake (200 mcg), including from fortified food (bread, cereals). Food folate or methylfolate supplements likely more effective.
If FOLH SNPs - Less proportion of food form folates will be absorbed. Methylfolate (preferable) or folinic acid supplements likely more effective. If no DHFR SNPs folic acid may be effective (upto 400mcg).
If MTHFR SNPs - The C677T is more impactful (by far). Consider upstream folate supply and vitamin B2 cofactor. If no MTHFR SNPs consider surrounding genes. A wild (green) MTHFR may give you a false sense of security.
Overall SNPs - more than 4 yellows/ reds in the whole cycle. Consider all of the above - increased need, symptoms, gut health, and diet.
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 which catalyses conversion of 5-10 methylene THF to 'active' methylfolate (5-MTHF). As MTHFR is the only route for methylfolate synthesis SNPs can have high impact. The C677T variant (which at about 30% frequency is common), has up to 70% lower activity (for homozygous (red) genotypes), resulting in significantly lower 5-MTHF. Encouragingly, vitamin B2 (riboflavin) can almost totally compensate for the C677T SNP. The A1298C variant has less impact on 5-MTHF levels but is associated with depletion of biopterin. MTHFR activity can be improved by upstream support - folate and cofactor supply, or bypassed by directly supplementing methyl folate.
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.