Folate

Folate Folic acid is the term used to refer to the oxidized form of the vitamin found in fortified foods and in supplements. Folate refers to the reduced form of the vitamin found naturally in foods and in biological tissues. The Latin word folium means “leaf,” and the word folate from Italian means “foliage.” Folate’s and vitamin B12’s discovery resulted from the search to cure the disorder megablastic anemia, a problem in the late 1870s and early 1880s. As with many of the other vitamins, eating liver was shown to cure the condition.

Folate structure Folate is made up of three distinct parts, all must be present for vitamin activity. Called pteridine or pterin P-aminobenzoic acid (PABA). L-glutamic acid to form folate Although humans can synthesize all the component parts of the vitamin, they do not have the enzyme necessary for the coupling of the pterin molecule to PABA to form pteroic acid.

Folic Acid - Folate (Petroyl-monoglutamic acid)

Sources Good food sources of folate include mushrooms and green vegetables such as spinach, brussels sprouts, broccoli, asparagus, and turnip greens, okra, among others, as well as peanuts, legumes (especially lima, pinto, and kidney beans), lentils, fruits (especially strawberries and oranges) and their juices, and liver. Raw foods typically are higher in folate than cooked foods because of folate losses incurred with cooking. Fortification of flours, grains, and cereals with folic acid (140 μg folic acid per 100 g of product) wasinitiated in 1998. Thus, fortified cereals, breads, and grain products now represent major sources of the vitamin. Some juices also are now fortified with folic acid.

Sources

Sources Folate bioavailability from foods varies, from about 10% to 98%, because of a variety of factors. Variations in intestinal conditions such as pH, genetic variations in enzymatic activity needed for folate digestion, dietary constituents such as inhibitors, and the food matrix, for example, influence bioavailability. Reduced forms of folate pteroylpolyglutamates in foods are labile and easily oxidized. The folate in milk is bound to a high-affinity folate-binding-protein, which appears to enhance its bioavailability.

DIGESTION, ABSORPTION, TRANSPORT, AND STORAGE Before the polyglutamate forms of folate in foods can be absorbed, they must be hydrolyzed to the monoglutamate form. This hydrolysis or deconjugation is performed by at least two hydrolases or conjugases. The conjugases found in human jejunal mucosa, pancreatic juice and bile. The conjugases are: Brush border conjugase is zinc-dependent. Zinc deficiency can diminish folate absorption. Chronic alcohol ingestion can diminish absorbtion. Conjugase inhibitors in foods such as legumes, lentils, cabbage, and oranges also diminish conjugase activity to impair digestion. pH sensitive.

Absorption Transport system by several carriers: carriers mediated in the proximal small intestine low concentration. Saturable, energy, and sodium. Affected by pH (5.5-6) and glucose. folate protein carrier Carrier mediated for reduced folate white blood cells and other tissues transports 5-methyl THF Simple diffusion pharmacological doses of the vitamin are consumed. Absorption is most efficient in the jejunum. Inside the intestinal cell: Folate reduced to THF Occurs via NADPH-dependent dihydrofolate reductase. Four additional hydrogens added at positions 5, 6, 7, and 8. THF methylated to 5-methyl THF or formylated.

Transport and Storage Free in plasma: monoglyutamate derivatives, mainly THF. Uptake by the liver using carrier and converted to 5-methyl THF and 10- formyl-THF (tightly formulated). 33% as THF, 37% as 5-methyl THF, 23% as 10-formyl THF and 7% as 5-formyl THF. Most of 5-methyl THF and 10-formyl THF is excreted into the bile. glutamates typically varying in length from 3 to 9. Folylpolyglutamate The liver stores about one-half of the body’s folate. And polyglutamate form. Liver / tissue Demethylation Elongation of glutamate tail, this addition Pteroyloplyglutamate syntheses (PPS) Traps folate inside cell Allows production of other forms

Transport and storage Blood: Folate is found as monoglutamate Primarily N5-mythyle-NHF 2/3 bound to protein albumin, 1/3 free RBC- folate level is index of longer-term (2-3mo) folate status than dose plasma.

Tissue distribution Total body content: 5-10mg (50% in liver) In tissues with: Rapid cell division: low 5-methyl-THF and high 10 formyl-THF Low cell division: 5-methyl-THF dominates Folate mainly in mitochondriah (10-formyl-THF) and cytosol (5-methyl-THF) Stored as polyglutamates

FUNCTIONS AND MECHANISMS OF ACTION THF functions in the body as a coenzyme in both the mitochondria and cytoplasm to accept one-carbon groups typically generated from amino acid metabolism. These THF derivatives then serve as donors of one-carbon units in a variety of synthetic reactions, such as dispensable amino acid synthesis. Methyl group accepted by THF is bonded to its nitrogen in position 5 or 10 or to both.

FUNCTIONS AND MECHANISMS OF ACTION Genetic polymorphisms in some of the folate-dependent enzymes have been identified. Several mutations in methylene THF reductase (MTHFR) have been demonstrated converts 5,10-methylene THF to 5-methyl THF. Its requires riboflavin as FAD as a prosthetic group. Mutations in MTHFR impair 5-methyl THF formation and thus reduce remethylation of homocysteine, resulting in hyperhomocysteinemia, a risk factor for heart disease.

FUNCTIONS AND MECHANISMS OF ACTION The THF derivatives, which participate in a variety of reactions, are illustrated as follows:

Function and mechanism of action Amino acid metabolism Histidine Histidine metabolism requires THF. Histidine undergo to determination and further metabolism to yield formiminoglutamate (FIGLU). This reaction can be used as a basis for determining folate deficiency. With folate deficiency, FIGLU accumulates in the blood and excreted in higher concentration in the urine.

METABOLISM AND EXCRETION Folate is excreted from the body in both the urine and the feces. Within the kidney, folate-binding proteins present in the renal brush border and coupled with tubular reabsorption of folate help the body retain needed folate. Excess folate is excreted in the urine with some folate excreted intact and some catabolized in the liver prior to excretion. In addition to urinary losses, folate (up to about 100 μg) is secreted by the liver into the bile. Most of this folate, however, is reabsorbed following enterohepatic recirculation, so losses in the stool are minimal.

Folate in pregnancy During the 1980s a considerable body of evidence accumulated that spina bifida and other neural tube defects (which occur in about 0.75–1% of pregnancies) were associated with low intakes of folate, and that increased intake during pregnancy might be protective. It is now established that supplements of folate significantly reduce the incidence of neural tube defects, and it is recommended that intakes be increased by 400 μg/day before conception.

Folate and cancer There is evidence that some cancers (and especially colorectal cancer) are associated with low folate status. A number of small studies have suggested that folate supplements may be protective against colorectal cancer, but no results from large-scale randomized controlled trials have yet been reported, and to date there is no evidence of a decrease in colorectal cancer in countries where folate enrichment of flour is mandatory.

INTERACTIONS WITH OTHER NUTRIENTS A relationship exists between folate and vitamin B12 (cobalamin). Without vitamin B12 the methyl group from 5-methyl THF can’t be removed and thus is trapped, is sometimes called the (methyl-folate trap). With adequate vitaminB12 status, the convention of Hcy to Meth is going well, which is resulting THF, that converted into other coenzyme forms. 5-methyl THF is required for

Folate deficiency: megaloblastic anemia Dietary deficiency of folic acid is common and, leads to functional folic acid deficiency. The cells of the bone marrow that form red blood cells, the cells of the intestinal mucosa and the hair follicles. Clinically, folate deficiency leads to megaloblastic anemia, the release into the circulation of immature precursors of red blood cells.

Folate deficiency: megaloblastic anemia Megaloblastic anemia is also seen in vitamin B12 deficiency, where it is due to functional folate deficiency as a result of trapping folate as methyl-tetrahydrofolate. However, the neurological degeneration of pernicious anemia is rarely seen in folate deficiency, and indeed a high intake of folate can mask the development of megaloblastic anemia in vitamin B12 deficiency, so that the presenting sign is irreversible nerve damage.

Folate requirements Folate equivalents are used in RDA for dietary folate intakes, because of differences in efficiency of folate absorbtion from foods versus folic acid (supplements and fortified products). According to the 1998 RDAs For adults 400 µg dietary folate requirements (DFE)/d Pregnancy 600 µg DFE/d Lactation 500 µg DFE/d The center for Disease Control and Prevention (CDC) for women 400 µg synthetic folic acid /day for NTD prevention.

TOXICITY Toxicity of oral folic acid in moderate doses reportedly is virtually nonexistent. Folate intakes of up to 15 mg daily are problematic, include insomnia, malaise, irritability, and gastrointestinal distress. A tolerable upper intake level for adults of 1,000 μg (1 mg) for synthetic folic acid in supplements or from fortified foods (not natural foods) has been suggested based on the ability of folate to mask the neurological manifestations of vitamin B12 deficiency. Use of folic acid supplements is usually discouraged for some people, such as those with cancer receiving chemotherapy with methotrexate.