Folate
Folate is a group of essential watersoluble vitamins 8 that includes folic acid , folinic acid 9 and the active form methylfolate ( calcium‐l‐methylfolate 10 and ( 6S ) ‐5‐methyltetrahydrofolic acid glucosamine 10 ). Chemical structures of the folate family include a pteridine ring , p-aminobenzoic acid , and one or more gamma-linked glutamate residues . 7
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Humans cannot synthesise folate , and it must be consumed in the diet or via fortified foods , or obtained from supplements ( such as folic acid , folinic acid or 5-MTHF ) to maintain normal folate levels . 15 , 23 The dietary reference intake for folate for adults is 400 micrograms of dietary folate equivalents . 6
Folic acid is a synthetic form of folate . 9 , 24 It lacks coenzyme activity and must be reduced to the metabolically active tetrahydrofolate ( THF ) form within the cell . 24 Supplemental folic acid must be reduced to dihydrofolate ( DHF ) and then to THF to be able to enter the folate cycle . 6 , 9 Folinic acid is also a synthetic molecule . 9 It is a 5-formyl derivative of THF that is readily converted to 5-methyltetrahydrofolate ( 5-MTHF ) without requiring the action of DHFR . The primary form of folate is 5-MTFH . 22 , 25 which is the folate form normally found in the circulation , 26 blood
6,9 and umbilical cord blood . 6 , 9 It has significant advantages over folic acid as it is well absorbed , and its bioavailability is not affected by metabolic defects . 23 Studies have found 5-MTHF to be highly effective at increasing folate levels . 6 , 13 Additionally , it has been found to increase plasma folate more effectively than folic acid . 26 This is irrespective of the 677C-- > T mutation of MTHFR polymorphism . 26 Supplementing with 5-MTHF instead of folic acid reduces the potential for masking haematological and other symptoms of vitamin B12 deficiency . 23 Furthermore , 5-MTHF reduces interactions with drugs that inhibit dihydrofolate reductase ( DHFR ), overcomes metabolic defects caused by MTHFR polymorphism , and prevents the potential adverse effects of unmetabolised or unconverted folic acid in the peripheral circulation . 23 High doses of folic acid can induce a pseudo-MTHFR syndrome via a Michaelis-Menten effect ( substrate concentration kinetics and rate of an enzymatic reaction ) on enzymes that have weak or slow activity . 9 High doses of folic acid lead to a rapid saturation or inhibition of the DHFR enzyme , causing an accumulation of unmetabolised folic acid . 9 Unmetabolised folic acid is detected in the systemic circulation , even after low oral doses of folic acid ( e . g ., 200 micrograms ). 6 , 9 , 26 The concentration of unmetabolised folic acid increases parallel to that of total folic acid after supplementation . 9 Unmetabolised folic acid in blood is thought to interfere with the metabolism , transport , and functions of the natural folates in the human body . 9 , 26 Unmetabolised folic acid may compete with natural folate ( MTHF ) for the folate transporter ( SLC19A1 ) and the folate receptor ( FolR1 ), consequently depleting MTHF for participation in the two metabolic cycles . 9 Unmetabolised folic acid has been detected in mothers ’ milk , cord blood , and infant blood , and is a concern due to potential adverse effects on health . 9 Research has found sex-related differences in blood folate markers . 6 This may suggest that men and women could differ in absorption , metabolism , or elimination of folate derivatives , 6 with further research being suggested to determine the differences .
Functions of folate
The functions of folate 5-MTHF are far and wide and are briefly covered here .
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5-MTHF is the primary form of folate and is essential for normal healthy growth and development , 11 plays a critical role in cell growth and division , 6 the synthesis of DNA , 8 , 11-13 RNA , and proteins , 11 and is required for critical enzymatic reactions . 14 It is involved in one-carbon metabolism , 6-8 , 11 , 12 , 22 , 27 methylation , 6 , 22 amino acid metabolism , 14 purine and pyrimidine synthesis , 6 , 14 DNA repair , 12 DNA methylation , 8 , 14 and re-methylation of homocysteine to methionine . 5 , 6 , 22 It is also involved in the methylation cycle , providing one-carbon transference to choline phospholipids , adrenaline , creatine , and DNA . 27 Methylation is a common regulation process of gene expression that influences cellular development and function . 22 Genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine levels . 22 5-MTHF is involved in immune function 13 and supports a Th1 cytokine-mediated immune response . 28
Deficiency of folate
Low folate status , or folate insufficiency , may be caused by low dietary intake , 23 poor absorption and assimilation of ingested folate , 23 malabsorption conditions , 11 inflammatory bowel disease ( Crohn ’ s disease and ulcerative colitis ), 11 coeliac disease , 11 altered folate metabolism due to genetic polymorphisms ( e . g ., MTHFR ), 23 or drug interactions ( e . g ., altered absorption or excretion of folate ). 11 , 23 Alcoholism is a common cause of low folate status , due to reduced folate intake , reduced intestinal absorption , reduced storage of folates , and increased urinary excretion . 11 Alcohol consumption depletes 5-MTHF . 29 Body stores of folate generally represent a 2-3 month supply . 11 Erythrocytes accumulate folate only during erythropoiesis . 27 The lifespan of a red blood cell is 120 days ; accordingly , the folate content of red blood cells reflects folate status for the previous 3 months and is not influenced by recent dietary intake . 27
The classical symptom of folate deficiency is megaloblastic anaemia . 7 A deficiency of folate disrupts DNA synthesis and methylation 6 and results in reduced DNA synthesis and altered cell division , 14 altered synthesis of purines and pyrimidines , 14 peripheral neuropathy , 14 megaloblastic 11 , 30 and macrocytic anaemia , 14 , 31 anaemia , 6 cardiovascular diseases , 11 6 , 11 , 12
hyperhomocysteinaemia , depression , 6 and cognitive dysfunction and decline . 11 A deficiency of folate leads to the reduced capacity of erythroblast replication , resulting in reduced and abnormal erythrocyte production and so leading to anaemia and reduced oxygencarrying capacity of the blood . 11 This may lead to symptoms of weakness , fatigue , irritability , and shortness of breath . 11
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