Folate is a B-vitamin (B9) required for numerous bodily processes. The term “folate” refers to the naturally occurring forms found in foods like leafy greens and legumes. In contrast, “folic acid” is the synthetic version used in fortified foods and most standard supplements. Folic acid is biologically inert and must undergo a transformation, often called “methylating,” to become the active, usable compound known as methylfolate.
Folate’s Core Functions in Health
The active form of folate, 5-methyltetrahydrofolate, plays a role in the body’s one-carbon metabolism cycle. This cycle moves single carbon units around, which is necessary for synthesizing key biological molecules. Folate’s functions include the creation and repair of DNA and RNA. This action is important during periods of rapid cell division and growth, such as fetal development and the regeneration of blood cells.
Folate is also necessary for regulating the amino acid homocysteine. Active folate works with vitamin B12 to convert homocysteine into methionine, which produces S-adenosylmethionine (SAMe). SAMe is the body’s universal methyl donor, supplying methyl groups for hundreds of reactions, including those regulating gene expression. Insufficient folate stalls this process, leading to homocysteine accumulation in the bloodstream. Elevated homocysteine is associated with various health concerns.
The Activation Step Converting Folic Acid to Usable Folate
Synthetic folic acid must be metabolized into the active form, methylfolate. This conversion is a multi-stage biochemical cascade occurring primarily in the liver and gut lining. The initial step involves the enzyme dihydrofolate reductase (DHFR), which converts folic acid into an intermediate form of folate.
The intermediate product moves through several more enzymatic transformations to reach its final, biologically active state. The final step is carried out by the enzyme Methylenetetrahydrofolate Reductase (MTHFR). MTHFR adds a methyl group to the precursor molecule, creating 5-methyltetrahydrofolate (5-MTHF). Without functional MTHFR, the body cannot efficiently complete this final methylation step. Because folic acid is stable and used extensively in fortified foods, large amounts can enter the body, and a bottleneck in this pathway can cause the synthetic form to accumulate.
Genetic Differences Affecting Folate Use
The efficiency of the MTHFR enzyme can be impacted by common genetic variations known as single nucleotide polymorphisms (SNPs). These are common differences in the DNA sequence that change how the enzyme functions. The two most studied variants are MTHFR C677T and MTHFR A1298C, both of which affect the enzyme’s ability to catalyze the final conversion step.
The C677T variant is significant; inheriting two copies (homozygous) can reduce the enzyme’s functional activity by 60% to 70%. The A1298C variant also reduces enzyme activity, usually to a lesser degree. Effects are compounded when individuals inherit both a C677T and an A1298C variant. For the estimated 40% of the population carrying one of these variants, the conversion of synthetic folic acid to active methylfolate is slowed.
This reduced efficiency means that consuming large amounts of synthetic folic acid can cause the precursor to build up in the bloodstream as unmetabolized folic acid (UMFA). While folic acid supplementation is safe, high UMFA levels have raised concerns, especially in individuals with the C677T variant. The issue is that the body may not produce enough active 5-MTHF, potentially impairing the methylation cycle and homocysteine metabolism.
Choosing the Right Supplement Form
When selecting a supplement, it is helpful to understand the difference between the various forms of B9: Folic Acid, Folate (from food), and Methylfolate. Folic acid is the synthetic form requiring the full, multi-step enzymatic conversion. Natural folate, found in foods, is metabolized more easily than synthetic folic acid.
Methylfolate, often labeled as 5-MTHF or L-methylfolate, is the active form the body uses immediately. This form bypasses the entire conversion process, including the MTHFR enzyme step. For individuals with known MTHFR variants, or those wishing to avoid the accumulation of unmetabolized folic acid, methylfolate is often the preferred supplemental choice.
Standard folic acid is effective for most people and has been widely used in fortification programs to prevent issues like neural tube defects. However, methylfolate can serve as an alternative. When choosing a supplement, look for the specific name “methylfolate” or “5-MTHF” on the ingredient list rather than the generic term “folate” or “folic acid.” Consulting a healthcare provider can help determine the appropriate form and dosage based on individual genetic status and health needs.