Folic Acid

Structure
Functions
Sources
Metabolism
Requirements
Deficiency
Toxicity

1946 Angler reported synthesis of folic acid

I.  Structure

II.  Functions

1. Different THF derivatives (Figure 1) participate as coenzymes in one-carbon donating/receiving reactions
2. Folate as Ns, NTM methylene THF is required for synthesis of serine from glycine
3. Regeneration of methionine from homocysteine involves folate as Ns methyl THF
4. Metabolism of histidine through urocanic acid and formiminoglutamate (FIGLU) to yield glutamic acid requires THF
5. THF derivatives are involved in purine and pyrimidine synthesis so folate is essential for cell division
   1. Conversion of deoxy UMP to deoxy TMP which is required for DNA synthesis
   2. N¹⁰ formyl THF is needed for purine ring formation
6. N⁵, N¹⁰ methylene THF is involved in production of glycine for synthesis of heme
7. Interaction of folate and vitamin B₁₂ in anemia (Folate trap hypothesis)
   1. Methyl folate, the dominant form in the body's folate pool, is metabolically inactive (except as a methyl donor to convert homocysteine to methionine)
   2. Methyl folate can be returned to the active folate Pool only via a B₁₂ dependent step
   3. In absence of sufficient vitamin B12 methyl folate accumulates
   4. A vitamin B₁₂ containing enzyme transfers a methyl group from methyl folate to homocysteine converting it to methionine
   5. This regenerates THF from which 5, 10-methylene THF is made
   6. 5, 10-methylene THF delivers its methyl group to deoxyuridylate converting it to thymidylate which is necessary for synthesis of DNA
   7. Deficiency of either B~2 or 5, 10-methylene THF inhibits adequate DNA synthesis causing many hematopoietic cells to die in the bone marrow; anemia results

III.  Sources

1. Folates are most abundant in plant food sources, especially when raw
   1. Green leafy materials
   2. Whole grains and cereal byproducts
   3. Beans
2. Organ meats and animal byproducts

IV.  Metabolism

1. Digestion, absorption, transport
   1. Folate in foods is hydrolyzed to the monoglutanate form
   2. g-glutamylcarboxypeptidases (also called conjugases)
   3. Folate is transported across cell membranes by a carrier system believed to be saturable and pH, energy, and Na dependent
   4. Absorption is most efficient in the jejunum
   5. In the intestinal cell, folate is reduced to THF and methylated to N⁵ methyl THF
   6. Most of the folate in portal circulation is N⁵ methyl THF
   7. Within the liver, folate is present as about 33% THF, 37% N⁵ methyl THF, 23% N¹⁰ formyl THF and 7% as N⁵ formyl THF
   8. In blood, folate is found as monoglutomate, 2/3 bound to protein and 1/3 free
   9. Folate is transported into tissue cells by a carrier mediated process that may or may not require ATP
   10. Within cells THF is converted into a polyglutamate form to become a functional coenzyme
2. Excretion
   1. Normally, the body tenaciously retains absorbed folate
   2. Very little is excreted in urine
      1. Folate binding proteins
      2. Tubular resorption in kidney
   3. Although much of absorbed folate is secreted by liver into bile, it is reabsorbed

V.  Requirements

1. Recommended allowances
   1. Pig           0.5-2 mg/Kg
   2. Chick       1 mg/Kg
   3. Human    0.4-0.8 mg/day
2. Factors affecting requirement
   1. Conjugase required for cleaving polyglutamate into monoglutanate form of folate is inhibited by several factors
      1. Zinc deficiency
      2. Chronic alcoholism
      3. Inhibitors in legumes, lentils, cabbage and oranges
   2. Inflammatory bowel disease
   3. Achlorhydria (insufficient HCL in gastric juice)
   4. Malignancies
   5. Oral contraceptives
   6. Anticonvulsants used in treatment of epilepsy

VI.  Deficiency

1. Megaloblastic, macrocytic anemia in most species
   1. Release into the circulation of large, immature ethrocytes, often containing excess hemoglobin
   2. Also occurs due to a deficiency of vitamin B₁₂
2. Folate deficiency is suspected in the initiation of cancer
3. May be a risk factor for cardiac disease
4. Plasma homocyst(e)ine levels may be increased in the presence of decreased plasma folate
5. Increased neural tube defects in pregnant woman (see J. Am. Coll. Nutr. 15:121. 1996)

VII.  Toxicity

1. Folate supplements exceeding .4 mg/day are considered pharmacologic
2. Some reports suggest no adverse effects of 10 mg/day for 5 years
3. Other studies indicate 15 mg/day is toxic in same individuals
   1. Insomnia
   2. Malaise
   3. Irritability
   4. Diminished Zn status
   5. Gastrointestinal problems
4. Folate supplementation can mask vitamin B₁₂ deficiency
   1. Alleviates megaloblastic anemia due to vitamin B₁₂ deficiency
   2. Fails to prevent neurologic damage due to vitamin B₁₂ deficiency

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