11.1 Folate and Folic Acid

Folate & Folic Acid

Folate is a B vitamin that exists in either its reduced form (folate) or oxidized form (folic acid). When folate is used in this section, we are referring to the reduced form, not the vitamin itself. Another key distinction between the 2 terms is that folic acid refers to the synthetic form, while folate refers to the natural form. Folic acid is only found in certain foods because they have been fortified with it, not because they produce it. The structure of folic acid is shown below.

Figure 11.11 Structure of Folic Acid1

Another key difference between folate and folic acid is the number of glutamates in their tails. Notice that glutamate is boxed in the structure of folic acid above. Folic acid always exists as a monoglutamate, meaning it only contains one glutamate. On the other hand, about 90% of the folate found in foods are polyglutamates, meaning there is more than one glutamate in their tail. Folic acid is more stable than folate, which can be destroyed by heat, oxidation, and light2. Table 11.11 summarizes the key differences between folate and folic acid.

Table 11.11 Comparison of folate to folic acid

The bioavailability of folate was believed to be much lower than folic acid.3 To account for these differences, the DRI committee created dietary folate equivalents (DFEs) to set the RDAs4. DFEs are defined as follows:

1 DFE = 1 ug food folate = 0.6 ug food folic acid = 0.5 ug folic acid on an empty stomach OR

1 DFE = ug food folate + (ug folic acid X 1.7)

The 1.7 comes from research suggesting that folic acid from food was 85% bioavailable, compared to 50% for folate (85%/50% = 1.7)4.

Before folate (polyglutamates) can be taken up into the enterocyte, the extra glutamates must be cleaved prior to uptake into the enterocyte by the reduced folate transporter (RFT, aka reduced folate carrier)5-7. Folic acid, because it is a monoglutamate, requires no cleavage for uptake before it is taken up through the RFT. Once inside the enterocyte, the monoglutamate form is methylated (notice the addition of CH₃ to the lower monoglutamate) and transported into circulation through a yet unknown carrier5. This series of events is depicted in the figure below.

Figure 11.12 The uptake and absorption of folate and folic acid (orange boxes represent glutamate)

Thus, the methylated monoglutamate form is the circulating form. This is transported to the liver where it is converted back to the polyglutamate form for storage. Folate is excreted in both the urine and feces5.

For more information on folate, see the Required Web Link below.

Required Web LinkFolate Fact Sheet

Subsections:

• 11.11 Folate Functions
• 11.12 Folate Deficiency & Toxicity

References & Links

• http://en.wikipedia.org/wiki/File:Folat.svg
• Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw’s Perspectives in Nutrition. New York, NY: McGraw-Hill.
• Winkels R, Brouwer I, Siebelink E, Katan M, Verhoef P. (2007) Bioavailability of food folates is 80% of that of folic acid. Am J Clin Nutr 85(2): 465-473.
• Anonymous. (1998) Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington D.C.: National Academies Press.
• Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, editors. (2006) Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins.
• Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.
• Stipanuk MH. (2006) Biochemical, Physiological, & Molecular Aspects of Human Nutrition. St. Louis, MO: Saunders Elsevier.

Links

Folate Fact Sheet – https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

Folate Functions

The major function of folate is that it participates in 1-carbon metabolism. As described earlier, this is the transfer of 1-carbon units from one compound to another. The cofactor form of folate is tetrahydrofolate (THF). As is shown in Figure 11.111, in order for THF to be formed, a methyl group is transferred to cobalamin (vitamin B₁₂) forming methyl-cobalamin. You can see this on the left side of the figure below.

Figure 11.111 1-carbon metabolism

There are 2 major functions of THF1:

• DNA Synthesis – THF is required for the synthesis of DNA bases (purines and pyrimidines)1.
• Amino Acid Metabolism – THF is a cofactor for enzymes that metabolize histidine, serine, glycine, and methionine1.

References & Links

1. Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.

Folate Deficiency & Toxicity

Folate deficiency is a vitamin deficiency that affects some Americans. The hallmark symptom of folate deficiency is megaloblastic (a.k.a. macrocytic) anemia. Megaloblastic anemia, as the name suggests, is characterized by large, nucleated, immature red blood cells. This occurs because folate is needed for DNA synthesis. Without it, red blood cells are not able to divide properly1. As a result, fewer and poorer functioning red blood cells are produced that cannot carry oxygen as efficiently as normal red blood cells2.

A maternal folate deficiency can lead to neural tube defects in infants. The neural tube is the embryonic structure that gives rise to the brain and spinal cord. The exact cause of neural tube defects is unknown, but folate supplementation has been shown to decrease the incidence of neural tube defects3. The most common of these neural tube defects is spina bifida (1 out of 2500 babies born in the United States), which is a failure of the neural tube to close and the spinal cord and its fluid protrude out the infant’s back, as shown in Figure 11.1214,5.

Figure 11.121 Spina bifida6

The neural tube closes 21-28 days after conception1, and with 50% of pregnancies estimated to be unplanned, many women aren’t aware they are pregnant during this period1,2. Thus, it is recommended that women of childbearing age consume 400 ug of folic acid daily1. In addition, in 1998 the FDA mandated that all refined cereals and grains be fortified with 140 ug folic acid

/100 grams of product7. As you can see in Figure 11.122, spina bifida prevalence rates declined during the optional fortification years and declined further once fortification became mandatory in the United States.

Figure 11.122 Neural tube defect prevalence 1995-20118

However, more recent research has found that folic acid supplementation begun before conception reduced the occurrence and severity of neural tube defects9.

The following link is an interesting account of the history that led up to the folic acid fortification. It is debatable whether folic acid fortification was fully responsible for the decrease in spina bifida rates shown above, but the rates are lower than they were pre- fortification.

Web LinkFolic Acid Fortification: Fact and Folly

Folate/Folic acid is not toxic, but it can mask a vitamin B₁₂ deficiency and prevent its diagnosis. This effect will be discussed further in the vitamin B₁₂ deficiency section.

References & Links

• Byrd-Bredbenner C, Moe G, Beshgetoor D, Berning J. (2009) Wardlaw’s Perspectives in Nutrition. New York, NY: McGraw-Hill.
• Whitney E, Rolfes SR. (2008) Understanding Nutrition. Belmont, CA: Thomson Wadsworth.
• Stipanuk MH. (2006) Biochemical, Physiological, & Molecular Aspects of Human Nutrition. St. Louis, MO: Saunders Elsevier.
• http://www.cdc.gov/ncbddd/birthdefects/SpinaBifida.htm
• http://www.nlm.nih.gov/medlineplus/ency/imagepages/19087.htm
• https://www.cdc.gov/ncbddd/spinabifida/facts.html

• Gropper SS, Smith JL, Groff JL. (2008) Advanced Nutrition and Human Metabolism. Belmont, CA: Wadsworth Publishing.
• http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6401a2.htm
• Bergman JEH, Otten E, Verheij JBGM, de Walle HEK. (2016) Folic acid supplementation influences the distribution of neural tube defect subtypes: A registry-based study. Reprod Toxicol. 59:96-100.

Link

Folic Acid Fortification: Fact and Folly – http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUp dateseriesonFDAHistory/ucm091883.htm