Folate metabolism - Which form of folate to take?

Folate (vitamin B9) performs its functions in the body only as various THF (tetrahydrofolate) forms, which are ultimately required for two things:

1. The biosynthesis of nucleotides, which in turn are required for RNA & DNA synthesis (ie. growth);
2. The conversion (remethylation) of homocysteine to methionine, which is required for SAMe synthesis and thus methylation.

One-carbon metabolism
In the body THF essentially acts as a transporter of one-carbon atom groups, such as methenyl (CH), methylene (CH2), methyl (CH3), formyl (CHO), and forminino (CHNH). THF bonds with these one-carbon groups which are released from the metabolism of various amino acids, and then it donates them to reactions which are required for the synthesis of various molecules, such as those involved in RNA and DNA synthesis (pyrimidines and purines), and methlyation (methionine). Folate itself is not used up in these reactions; once THF has donated its ligand (one-carbon group) it is returned to the pool of DHF and THF, where new THF derivatives are formed and the process continues.

B12 and the 'folate trap'
Folate is converted between its various different THF derivatives with the help of many cofactors, such as NAD(P)H, P5P, FAD and B12. Most THF forms are basically interchangeable, that is except for methyl-THF. The conversion of methylene-THF to methyl-THF is not reversible, and the enzyme MS (methionine synthase) is the only acceptor of methyl-THF. MS normally catalyses the reaction between methyl-THF and homocysteine to recycle both back to THF and methionine; this reaction requires methyl-B12 as a cofactor. So a B12 deficiency can cause a 'trapping' of folate as methyl-THF, and thus a deficiency of the other THF derivatives required for DNA synthesis. This is how a B12 deficiency can lead to anemia; i wrote more about the hematological changes that occur in a B12/folate deficiency here.

Folate transport
Most dietary folate is in polyglutamate form which must first be coverted into monoglutamate form (by GGH) before it can be absorbed. Transport of folate into cells is handled by the reduced folate carrier (RFC), and to a lesser extent the folate receptor (FOLR1). Once inside cells the mgATP-dependant enzyme folylpolyglutamate synthetase[19,20] adds glutamate residues to folate (making it a polyglutamate again) which increases its molecular size and prevents cellular loss via folate export pumps.

Which form of folate to take?
Folic acid is still the main form of folate found in supplements and fortified foods. Folic acid (pteroylglutamic acid) is the most basic form of folate, which all other folates are based upon. It does not significantly occour in dietary folate intake, and it must be converted to active THF forms before it can be of any use in the body. DHFR is the enzyme that is responsible for converting inactive folate into active THF forms, and it does this in two reduction reactions which transfer hydrogen atoms from NAD(P)H to folate. Some people might be really bad at running this reaction, for a few reasons:

- DHFR has been demonstrated to have very slow enzyme activity in humans and there is also 5-fold variability[1].
- DHFR can be deactivated by peroxynitrite[2], which might be produced in states of oxidative stress.
- DHFR might also function slowly if there is low availability of NAD(P)H[10].

Furthermore, unmetabolised folic acid in plasma has been associated with lowered NK cell activity[17], and folic acid can compete with active folate uptake at the BBB (blood-brain barrier)[21]. For all these reasons folic acid supplements may not be a reliable way to replete folate metabolism.

Folinic acid (5-formyl-THF) and methyl-THF supplements supply active folate forms directly into folate metabolism. These are natural folate forms that comprise some of our normal dietary folate intake. Methyl-THF also skips the MTHFR reaction, which may be of use to those who have the common C677T snp that slows enzyme activity[4].

Folate and immunity
to come...

Research

1. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Steven W. Bailey and June E. Ayling.
2. Peroxynitrite-mediated oxidation of the C85S/C152E mutant of dihydrofolate reductase from Escherichia coli: functional and structural effects.
3. http://bb-cfs.blogspot.com/2010/05/bh4-salvage-pathway.html

4. http://en.wikipedia.org/wiki/MTHFR
5. Laboratory evalulations - Richard S Lord.
6. http://www.genome.jp/kegg/pathway/map/map00670.html
7. Clinical activity of folinic acid in patients with chronic fatigue syndrome.
8. http://www.wikipathways.org/index.php/Pathway:WP241
9. Serum folate and chronic fatigue syndrome.
10. http://bb-cfs.blogspot.com/2010/05/cadmium-toxicity-summary-of-related.html
11. Folate absorption.
12. Intestinal absorption of different types of folate in healthy subjects with an ileostomy.
13. http://en.wikipedia.org/wiki/SLC19A1
14. Folate Deficiency Inhibits the Proliferation of Primary Human CD8+ T Lymphocytes In Vitro.
15. Immunoglobulin deficiency responding to vitamin B12 in two elderly patients with megaloblastic anaemia.
16. Blood Folate Status and Expression of Proteins Involved in Immune Function, Inflammation, and Coagulation: Biochemical and Proteomic Changes in the Plasma of Humans in Response to Long-Term Synthetic Folic Acid Supplementation.
17. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.
18. Reduced folate carrier: biochemistry and molecular biology of the normal and methotrexate-resistant cell.
19. http://www.ebi.ac.uk/interpro/IEntry?ac=IPR001645
20. http://www.genome.jp/dbget-bin/www_bget?ec+6.3.2.17
21. Blood-brain barrier transport of reduced folic acid.
22. The blood-brain barrier and folate deficiency.
23. Brain function in the elderly: role of vitamin b12 and folate.