Vitamin B12 and folic deficiencies always coexist. Deficiency of one vitamin can precipitate the deficiency of the other vitamin also.
Folic acid participates in the transfer of single carbon units. Folate-dependent single-carbon transfer reactions are important in amino acid metabolism and in pathways leading to biosynthesis of DNA, RNA, membrane lipids, and neurotransmitters.
Structure of folic acid
Folic acid is a composite molecule, being made up of three parts: a pteridine ring system (6-methylpterin), para-aminobenzoic acid,and Glutamic acid.
The Glutamic acid doesn’t participate in the coenzyme functions of folic acid. Instead, folic acid in the interior of the cell may contain a “chain” of three to eight (3–8) Glutamic acid residues,which serves as a negatively charged “handle” to keep the coenzyme inside cells and/or bound to the appropriate enzymes. The pteridine portion of the coenzyme and the p-aminobenzoic acid portion participate directly in the metabolic reactions of folate.
To carry out the transfer of 1-carbon units, NADPH must reduce folic acid twice in the cell. The 6-methyl pterin ring is reduced at each of the two N-C double bonds by folate reductase enzyme.
The resulting 5, 6, 7, 8-tetrahydrofolate is the acceptor of 1-carbon groups.(See figure-1)
Forms of folic acid as one carbon carrier
Tetrahydrofolate can carry one-carbon fragments attached to N-5 (Formyl, formimino, or methyl groups), N-10 (formyl) or bridging N-5–N-10(methylene or methenyl groups).
Sources of one carbon fragments
The major point of entry for one-carbon fragments into substituted folates is methylene-Tetrahydrofolate, which is formed by the reaction of glycine, serine,and choline with tetrahydrofolate. Serine is the most important source of substituted folates for biosynthetic reactions. One carbon fragments are also produced from the metabolism of Tryptophan and Histidine.
Utilization of one carbon fragments
Methylene-, methenyl-, and 10-formyl-tetrahydrofolates are interconvertible.
The N5,N10-methylene-tetrahydrofolate can either donate its single-carbon group directly, be oxidized by NADP to the methenyl form, or be reduced by NADH to the methyl form (See figure-2). Depending on the biosynthetic pathway involved, any of these species can donate the 1-carbon group to an acceptor. The methylene form donates its methyl group during the biosynthesis of thymidine nucleotides for DNA synthesis, the methenyl form donates its group as a Formyl group during purine biosynthesis, and the methyl form is the donor of the methyl group to sulfur during methionine formation. When one-carbon folates are not required, the oxidation of formyl-tetrahydrofolate to yield carbon dioxide provides a means of maintaining a pool of free folate.
Figure-2- Showing the interconversion of various one carbon compounds
The conversion of 5,10-methylene-THF into 5-methyl-THF, which is catalyzed by MTHFR (5,10-methylene tetrahydrofolate reductase), is irreversible. The only way to make further use of 5-methyl-THF and to maintain the folate cycle consists in the vitamin-B12-dependent remethylation of homocysteine to methionine (regenerating THF). The reaction is catalyzed by Methionine synthase. The methyl group transfer is therefore greatly dependent on 5-methyl-THF and the availability of vitamin-B12. In humans, this is the only known direct link of the metabolism of two vitamins; folic acid and vitamin-B12 both need each other ( See figure-3 below).
Figure- 3- showing the interdependence of folic acid and vitamin B12 and the methylation cycle.
Methionine is activated to S-Adenosyl Methionine which acts as a methyl group donor, for a variety of reactions under the activity of Methyl Transferase enzyme. The methylated products serve important functions in the body.
In cases of vitamin-B12 deficiency,it is possible that, in spite of sufficient availability of folates (and5-methyl-THF), an intracellular deficiency of biologically active THF arises. This situation is called a ‘folate trap’ (or methyl group trap) because,on one hand, the concentration of 5-methyl-THF continues to rise and on the other hand, due to it being prevented from releasing methyl groups, a ‘metabolic dead-end situation’ develops, which leads to the inevitable blockage of the methylation cycle. The co-factors for the C1-transfers decrease and replication as well as the cell division rate are reduced.
Hence, the principal problem is the decreasing activity of methionine synthase under vitamin-B12 deficiency with secondary disorders affecting the folate metabolism and insufficient de-novo synthesis of purines and pyrimidines. There is therefore functional deficiency of folate, secondary to the deficiency of vitamin B12.
The deficiency in active folic acids first affects the quickly dividing and highly proliferating hematopoiesis cells in the bone marrow and can even lead to pancytopenia.
Clinically, there is no difference between vitamin-B12 deficiency anemia and folic acid deficiency anemia. If such anemia is treated with vitamin-B12, the blockage is immediately stopped and the blood count quickly normalizes. However, if the anemia is exclusively treated with folic acid, it is simply converted to dihydrofolate and THF.
Long-term therapy using high doses of folic acid could therefore conceal the real cause i.e. pernicious (vitaminB12-deficiency) anaemia for a long time. The serum folate continues to rise(congestion of non-regenerated 5-methyl-THF) while the intracellular folate concentration (erythrocytes) drops. This situation interrupts the methylation cycle with numerous cell processes, among them the synthesis of myelin, the nerve fiber lining, being blocked due to a deficiency of methyl groups.
A long undetected (causal) vitamin-B12-deficiency can therefore result in serious neurological damage.
Exclusive folic acid therapy can thus lead to neurological damage or even cause serious damage progression.