The biochemical function of tetrahydrofolate is the binding and activation of single-carbon units, rendering them interconvertible by oxidation or reduction and transferable to appropriate acceptor molecules. The polyglutamic acid form of folic acid is required for nucleotide synthesis, while pteroylmonoglutamate is the transport form of folic acid (Wagner, 1984; Brody, 1991).
Numerous reactions involving single-carbon transfer require folic acid. These include:
- Purine and pyrimidine synthesis (adenine, guanine, thymine, cystosine and uracil);
- Interconversion of serine and glycine;
- Utilization of glycine as a carbon source for synthetic pathways (glycine cleavage system);
- Histidine degradation;
- Methionine synthetase, a vitamin B12 enzyme using 5-methyl-THF and homocysteine as substrates;
- Methionyl-tRNA transformylase, a required step in initiation of all protein synthesis.
Purine bases (adenine and guanine), as well as thymine, are constituents of nucleic acids, and with a folic acid deficiency, there is a reduction in the biosynthesis of nucleic acids essential for cell formation and function. Hence, deficiency of the vitamin leads to impaired cell division and alterations of protein synthesis; these effects are most noticeable in rapidly growing tissues such as red blood cells, leukocytes, intestinal mucosa, and embryonic and fetal tissues. Without adequate folate, the normal maturation of primordial red blood cells in bone marrow is arrested at the megaloblast stage. As a result, a characteristic macrocytic anemia develops. White blood cell formation is also affected, resulting in abnormalities such as thrombopenia, leukopenia and multilobed neutrophils.
Vitamin B12 is necessary for the synthesis of labile methyl groups and in this way interacts with folic acid, which is also essential for these reactions. The metabolism of labile methyl groups plays an important role in the biosynthesis of methionine from homocysteine and of choline from ethanolamine. Folic acid has a sparing effect on choline requirement. Vitamin B6is required for the serine and glycine metabolizing pathways and can therefore interact with folic acid status.