The Folate Cycle

The Folate Cycle is the first subcycle of Methylation. It is involved in the digestion, transport, activation and recycling of folates for:

1. DNA synthesis and repair – important for oxygen, nutrient delivery and energy (red blood cells), immunity (white blood cells), and fertility & pregnancy; wound healing, and cancer prevention
2. Methylation – supply of methyl to recycle homocysteine to methionine, and synthesise SAMe – the 'master methyl donor' for hormones, neurotransmitters, histamine etc.
3. Biopterin regeneration – synthesis of neurotransmitters (dopamine and serotonin)

Symptoms of Folate Cycle dysfunction include low energy, anaemia, poor immunity, autoimmunity, cancer, fertility issues, poor wound healing, hair loss, gut & digestive issues, cancer, neurological issues and anything impacted by methylation in general.

The Folate Cycle genetic results can help to understand your personal requirements for folic acid or methylfolate, (other) B vitamins – B2, B3, B6 and B12, and Zinc. Genetic results should be considered in the context of diet, and lifestyle, lifestage, symptoms and health objectives (which can require more or less nutrient support). Deficiency or excess of nutrients – as food or supplements – may be harmful.

Folate Cycle Summary

Folates enter the cycle in different forms. Natural folates from food (or food form supplements) need to be broken down by FOLH1 in order to be absorbed (digested). Folate in the form of synthetic folic acid doesn't require this step, and may be more easily absorbed. However, folic acid requires an additional action by DHFR in order to enter the folate cycle. SNPs on the DHFR gene can limit its capacity and cause build up of 'unmetabolised' folic acid. This can also saturate, or 'jam' up the DHFR so it is less effective at reducing (activating) all forms of folate from DHF (dihydrofolate) to THF (tetrahydrofolate). All forms of folate require transportation into cells by RFC (the reduced folate carrier).

It is helpful to think of the Folate Cycle as two linked cycles – 1. DNA synthesis and repair, and 2. Methylfolate synthesis and handover. Tetrahydrofolate (THF) is 'reduced', by either of two genes – SHMT1 or MTHFD1 (in the middle of the diagram below) and the resulting 5,10-methylene THF is the substrate for both cycles. The left hand cycle requires TYMS activity for DNA synthesis and the resulting DHF can re-enter the main folate cycle. Alternatively the 5,10-methylene THF is converted to methylfolate (5-MTHF) by the infamous MTHFR gene.

Methylfolate is the most prevalent form of folate in circulation. The main function of methylfolate is to supply a methyl group (1 carbon and 3 hydrogen compound) to the Methionine cycle. The MTR gene helps to split methylfolate into methyl – which is transferred over to vitamin B12 (to make methylcobalamin), and folate (THF) – which is recycled (into the folate cycle). If there is insufficient B12 or zinc (a cofactor) methylfolate can be 'trapped', limiting availability of folate for DNA synthesis and repair and limiting methyl supply to the Methionine cycle.

Accompanying Video

Folate Cycle Genes

FOLH1 folate hydrolase

FOLH1 enables digestion of dietary poly-glutamate folates by breaking them down to mono-glutamate form. SNPs are associated with impaired absorption of dietary folates, low blood folate levels, anaemia and hyperhomocysteinemia. Folic acid, as a monoglutamate folate, may be helpful for Individuals with FOLH1 SNPs.

RFC1 reduced folate carrier 1

Also known as SLC19A1 (solute carrier family 19 member 1), RFC is a folate transporter and is involved in the uptake of folate to tissues. RFC1 SNPs can impact DNA synthesis required for red blood cell production and result in megaloblastic anaemia (large red blood cells and impaired oxygen delivery). As RFC1 is significantly more effective at transporting reduced folates, methylfolate (or another THF form) may be more beneficial than folic acid.

DHFR dihydrofolate reductase

Dihydrofolate reductase (DHFR) converts dihydrofolate (DHF), produced by the TYMS subcycle, to tetrahydrofolate (THF), thereby supporting DNA synthesis and repair. The 19bp del SNP confers higher risk of folate deficiency, and is more vulnerable to saturation (blockage) by the folic acid form of folate. It may also support the recycling of tetrahydrobiopterin (BH4) for nitric oxide synthase (NOS) activity (see Urea Cycle) and for synthesis of neurotransmitters dopamine and serotonin (see BH4 Cycle).

SHMT1 serine hydroxymethyltransferase 1

Serine hydroxymethyltransferase is a pyridoxal phosphate-containing enzyme, hence requires vitamin B6 as a cofactor, that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate. This reaction provides one-carbon units for synthesis of methionine (via MTHFR) and thymidylate, and purines required for DNA synthesis (via TYMS). 

MTHFD1 methylenetetrahydrofolate dehydrogenase

MTHFD1 catalyzes three sequential reactions in the interconversion of one-carbon derivatives of tetrahydrofolate, which are substrates for synthesis of methionine (via MTHFR) and thymidylate, and purines required for DNA synthesis (via TYMS).  SNPs have been linked to increased risk of folate sensitive neural tube defects, and endometriosis related fertility issues due to choline depletion.

TYMS thymidylate synthase

Thymidylate synthase plays a crucial role in DNA replication and damage repair. Using 5,10-methylene-THF as the substrate, TYMS transfers a methyl unit to dUMP to make dTMP for nucleotide and DNA synthesis. This is necessary for cell proliferation – in pregnancy, hematopoiesis (blood cell production), as well as cancer. Hence underactive TYMS – due to SNPs or insufficient folate – can result in birth defects, anaemia, bleeding (lack of clotting) and immune deficiency. Conversely (and along with DHFR), TYMS is upregulated in cancer and autoimmune conditions – such as psoriasis and rheumatoid arthritis, hence is a target of antifolate drugs, such as methotrexate.

MTHFR methylenetetrahydrofolate reductase

The infamous MTHFR gene codes for the methylenetetrahydrofolate reductase protein which supports conversion of 5,10-Methylene THF (folate) to methylfolate (5-MTHF).

We report two common MTHFR variants (SNPs) associated with reduced function. The C677T (rs1801133) SNP has most impact – upto 40% lower for heterozygotes (reported as amber on our report) and 70% for homozygotes (reported as red). The second SNP A1298C (rs1801131) can confer upto 40% lower capacity. Variance at both locations increases the likelihood of reduced function (rather than increasing the effect).

Individuals with MTHFR SNPs ....

Although MTHFR SNPs have been associated with a multitude of health issues, they can be compensated by folate and the cofactor riboflavin (vitamin B2). Alternatively increasing methylfolate (the product of MTHFR) from food or supplements may be effective.

MTR 5-methyltetrahydrofolate-homocysteine methyltransferase

MTR, also known as cobalamin-dependent methionine synthase (MS), facilitates the transfer of methyl from methylfolate to synthesis methyl B12 (methylcobalamin) and THF (tetrahydrofolate). THF is replayed into the folate cycle (for maximum benefit), whilst MTR facilitates a second methyl transfer from methyl B12 to homocysteine to make methionine. Leading us nicely to the Methionine Cycle.

Note: Lifecode Gx always report the forward DNA strand. For the MTHFR SNP rs1801133 (C677T) our reported alleles are G (wild) (equivalent to C677) and A (variant) (equivalent to 677T), and for rs1801131 (A1298C) the reported alleles are T (wild) (equivalent to A1298) and G (variant) (equivalent to 1298C).