Folate

Folate, also called vitamin B9 or folacin, is a member of the B-vitamin family. The body needs it to build DNA and RNA, and to process amino acids—tasks essential for cell division and the proper development of blood cells. Since humans cannot produce folate on their own, it must come from food, which makes it an essential nutrient. It is found naturally in many foods. In the United States, the recommended daily intake for adults is 400 micrograms, whether from food or supplements. The synthetic form, folic acid, is used in supplements and to fortify foods because it holds up better during processing and storage; the body converts it into active folate.

Folic acid is prescribed to treat anemia caused by a folate shortage. Pregnant women also take it to lower the risk of neural tube defects (NTDs) in their babies, such as anencephaly and spina bifida. Low folate levels early in pregnancy are thought to account for more than half of NTD cases. Over 80 countries have mandatory or voluntary folic acid fortification programs to reduce NTD rates. Long-term use of high-dose folic acid (at least 400 micrograms per day) is linked to a small decrease in stroke risk, but also to a higher risk of prostate cancer.

Not getting enough folate leads to deficiency, which can cause a type of anemia where red blood cells become abnormally large. Symptoms include fatigue, heart palpitations, shortness of breath, sores on the tongue, and changes in skin or hair color. In children, deficiency can develop within a month of poor diet. In adults, the body normally holds 10 to 30 mg of folate, with about half stored in the liver and the rest in blood and tissues. In plasma, natural folate levels range from 150 to 450 nM.

Folate was discovered between 1931 and 1943. It is on the World Health Organization’s List of Essential Medicines. In 2023, it was the 94th most prescribed medication in the United States, with over 7 million prescriptions. The word “folic” comes from the Latin *folium* (leaf), because it was first found in dark-green leafy vegetables.

The term “folates” (vitamin B9) covers many forms of folic acid and related compounds, including tetrahydrofolic acid (the active form), methyltetrahydrofolate (the main form in blood), methenyltetrahydrofolate, folinic acid, and other pteroylglutamates. Older names include *L. casei* factor, folacin, vitamin Bc, and vitamin M. In chemistry and biochemistry, “folate” (singular) refers to the conjugate base of folic acid, while “folates” (plural) refers to the whole family of pteroylglutamates, which may differ in how reduced the pterin ring is and how many glutamyl units they have. Some definitions also require biological activity. In nutrition, the terms are often used interchangeably, but when a distinction is made, “folate” means natural forms and “folic acid” means the synthetic supplement form.

Chemically, folates have three linked parts: a pterin ring (2-amino-4-hydroxy-pteridine) connected by a methylene bridge to a p-aminobenzoyl group (together forming a “pteroate”), which is bonded through an amide linkage to glutamic acid or poly-glutamate. The pterin ring can exist in three reduction states: no hydrogens (folic acid), two hydrogens (dihydrofolate), or four hydrogens (tetrahydrofolate and other active forms). In living organisms, one-carbon units at various oxidation states can attach to the N5 or N10 nitrogen atoms of tetrahydrofolate. Most folates are unstable to oxidation, except for folic acid and folinic acid.

Tetrahydrofolate’s main job in metabolism is to carry single-carbon groups (methyl, methylene, or formyl). These groups can be transferred to other molecules during the modification or creation of many biological compounds. Folates are essential for making DNA, modifying DNA and RNA, synthesizing methionine from homocysteine, and other cellular reactions—collectively called folate-mediated one-carbon metabolism.

Folate derivatives help build both purines and pyrimidines, the building blocks of DNA and RNA. Formyl folate is needed for two steps in making inosine monophosphate, the precursor to GMP and AMP. Methylenetetrahydrofolate supplies the carbon center for turning dUMP into dTMP, a reaction driven by thymidylate synthase.

Methyl-THF converts vitamin B12 into methyl-B12 (methylcobalamin). Methyl-B12 then converts homocysteine into methionine, with help from homocysteine methyltransferase. A defect in this enzyme or a lack of B12 can cause a “methyl-trap,” where THF turns into methyl-THF, leading to a folate deficiency. So, a B12 deficiency can mimic folate deficiency by causing methyl-THF to build up.

Folate is especially important during periods of rapid cell division and growth, such as infancy and pregnancy.