Folic acid, folate, 5-mthf, folinic acid, AHHHHH!

We frequently hear “don’t forget to eat your greens, especially your folate containing foods like spinach” or “make sure you are taking a pre-natal vitamin with enough folic acid,” but most people are confused about the various forms of folate or if there is a difference in what these different forms do in the body. 

Why is folate so important to the body? 

Folate, also called B9, is a vital nutrient needed for overall human health.  The body uses folate to make many things including:

1. Purines and pyrimidines which make nucleotides: building blocks of DNA
2. Neurotransmitters (chemicals that carry messages to nerves): serine and glycine
3. Methylate DNA: adding methyl (CH3) groups to DNA. Methylated DNA plays a role in embryonic development and stops certain genes from being copied. Not having enough methylated DNA or having too much methylated DNA has been associated with cancer and aging.
4. Methionine (a type of amino acid that has to come from your diet). Methionine comes from protein sources and is used to make S-adenosylmethionine (SAM) which is another key methyl donor for the body.

Because the body does not store as much folate as the body utilizes, it is very easy for a person to become folate deficient.Research has associated low levels of folate with:

1. Certain types of Anemia
2. Neural tube defects
3. Disease associated with cognitive conditions
4. Certain cancers
5. Elevated homocysteine which some research has associated with cardiovascular disease

The body has 3 ways to obtain folate: food, supplements or from bacteria [1]in your GI tract.  When folate is consumed either through food or supplements, it undergoes many chemical reactions which include adding and subtracting methyl groups.  SNPs (single nucleotide polymorphisms) control many of the enzymes that are responsible for these chemical reactions.  These folate-dependent SNPs include:

MTHFD1: is a gene that forms a special kind of folic acid called tetrahydrofolate (THF) in the mitochondria. THF is responsible for making purines and thymidylate (used in DNA) and also plays a role in converting the amino acid homocysteine into methionine.

SHMT1: is a gene that converts serine and THF (tetrahydrofolate) to glycine and 5, 10-methylene tetrahydrofolate.  This conversion creates the products needed to make methionine and purines.

DHFR: is a gene that converts folic acid into THF.  The ability of this gene to convert folic acid into THF varies greatly among different people which can limit the amount of THF that can go into other cell cycles.  

MTHFR: a gene that influences how the body produces a specific form of folate. Variations in this gene can in turn leads to a buildup of an amino acid called homocysteine.

MTR: is a gene that converts homocysteine to methionine, both amino acids.  This enzyme depends on  methylcobalamin (a type of vitamin B12 v) and folate to carry out the reaction.

Research has found that intestines appear to be the location where the body attaches  most of its methyl groups and converts the folate into a usable form.  If you have food allergies, leaky gut, gut inflammation or take proton pump inhibitors and anti-acids, your body may struggle to convert folate into the necessary form compared to other people.

Types of folate and how they work in the body

Food

Folate is naturally occurring and comes from food such as spinach, chard, watercress and other foods.  The amount of folate the body can absorb from food is less than 100%. This is because more than 60% of the folate is bound to another molecule.   The body depends on an enzyme (FCGP) located in the intestines to breakdown the bound folate into a form that is usable by the cells. One of the reasons people struggle to raise their folate levels through food alone is the ability of FGCP to function.  Ideally, FGCP needs a pH level of 6.5-7 to be effective and foods such as alcohol, tomatoes and orange juice may prevent FGCP from working. FGCP is also dependent on the vitamin zinc to work properly. Therefore individuals that do not have enough zinc in their body may have less effective FGCP resulting in lower levels of folate.

Supplements

Before starting any folic acid supplements, it is important to talk to your healthcare provider to see if you are deficient in B12 because research has found taking folic acid supplements without checking for B12 deficiency before  may worsen your symptoms. 

Folic Acid is a synthetic, oxidized form of folate and added to various foods such as grains and cereals.  Although the body can absorb almost 100% of the folic acid because it is not bound to another molecule like folate, the enzyme DHFR has to break folic acid into a usable form in the body called THF (tetra-hydro-folate). Since DHFR is governed by a SNP, some people may have the gene which codes for a slower enzyme conversion into THF. When you have a slower enzyme conversion, the body often does not make as much of a particular product: in this case the very important THF.  People who have the MTHFR and DHFR gene may have a harder time utilizing folic acid form in their folate cycles.

5-MTHF (5-methyl-tetra-hydro-folate) is a reduced form of folate supplement that the body can absorb immediately and does not need to be broken down further as it moves through the various folate cell cycles.  5-MTHF has a methyl group on its structure that allows the body to easily transport it into the blood stream which may help explain why some people achieve higher folate levels by supplementing with 5-MTHF. The gene MTHFR is responsible for the final conversion of a type of folate (5, 10 methylene-THF) into L-5-MTHF.

Folinic Acid (5-formyltetrahydrofolate) is also considered a reduced form of folate, but it has very low bioavailability ~4%.  (Bioavailability is a measurement of how much product is available for the body to use). Research does not seem to support the use of folinic acid as a way to replenish folate stores in the body.

Even after you begin supplementing with folate through supplements, it can take a long time for folate levels to become sufficient in the body (~ average 4-6 weeks) and depends on many factors such as bacteria, intestinal health, folate transporters and the presence of other nutrients like riboflavin (another B-vitamin) and B12.

In conclusion, folate is a critical nutrient that is very important to many of the key products the cells make.  Understanding the differences between the different types of folate can help you and your healthcare provider make the best choices for you and your health.

References

Folate, folic acid and 5-methyltetrahydrofolate are not the same thing

Absorption and blood/cellular transport of folate and cobalamin: Pharmacokinetic and physiological considerations

Quantifying folate bioavailability: a critical appraisal of methods

Polymorphisms in 1-carbon metabolism, epigenetics and folate-related pathologies

Biomarkers of Nutrition for Development—Folate Review