One Carbon Pool By Folate

The 1-carbon transformations require folic acid (folate). Folic acid participates in both the activation of single carbons as well as in the oxidation and reduction of single carbons. Folate-dependent single-carbon reactions are important in amino acid metabolism and in biosynthetic pathways leading to DNA, RNA, membrane lipids, and neurotransmitters. To carry out the transfer of 1-carbon units, NADPH must reduce folic acid two times in the cell. The pyrazine ring of the 6-methylpterin is reduced at each of the two N-C double bonds. More precisely, the pathway leading to the formation of tetrahydrofolate (THF) begins when folate (F) is reduced to dihydrofolate (DHF) which is then reduced to THF. Dihydrofolate reductase catalyses the last step. Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. The resulting 5,6,7,8-tetrahydrofolate (THF) is the acceptor of 1-carbon groups. Tetrahydrofolate accepts methyl groups, usually from serine. The product, N5,N10-methylene-tetrahydrofolate, is the central compound in 1-carbon metabolism. Methylene-THF (CH2FH4) is formed from THF by the addition of methylene groups from one of three carbon donors: formaldehyde, serine, or glycine. Tetrahydrofolate can also accept a methyl group from the complete breakdown of glycine. 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. 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. Methyl tetrahydrofolate (CH3-THF) can be made from methylene-THF by reduction of the methylene group with NADPH. Another form of THF, formyl-THF or folinic acid) results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Finally, histidine can donate a single carbon to THF to form methenyl-THF.

References

1. Lehninger, A.L. (2005) Lehninger principles of biochemistry (4 ^th ed.). New York: W.H Freeman.
2. Salway, J.G. (2004) Metabolism at a glance (3 ^rd ed.). Alden, Mass. : Blackwell Pub.