) and the amino acid glutamate. The biologically active derivatives are 5,6,7,8-tetrahydrofolates (THF) with 1C units at the N5, N10 positions or both. The important folate mediated 1C transfer reactions and the pathways and processes they support are presented here. The various aspects of folate uptake, processing and interconversion constitute the metabolic pathway of folate cycle and are presented in a separate diagram. Together they are part of the folate metabolic pathway. The 1C transfer reactions take place in the cytoplasm, nucleus and mitochondria. Serine, a major 1C donor is reversibly converted to glycine and 5,10-methyleneTHF by the pyridoxal-5'-phosphate (PLP)/vitamin B6 dependent Shmt1 and Shmt2 enzymes in the cytoplasm and mitochondria, respectively. 5,10-methyleneTHF can be oxidized to 10-formylTHF (FTHF) and formate or reduced to 5-methyl THF. 5,10-methyleneTHF, FTFH and 5-methylTHF are the 1C donors for the three important 1C transfer reactions and are highlighted along with the THF-co-factor with a different color. 5,10-methyleneTHF is the 1C donor for the de novo thymidylate synthesis in the reaction catalyzed by thymidylate synthase enzyme Tyms. The reversible reaction generates thymidine monophosphates (dTMP) and DHF using deoxyuridine monophosphate (dUMP) and the folate cofactor. The dTMPs are then phosphorylated by thymidine triphosphate for use in DNA synthesis and repair. DHF is reduced to THF by Dhfr. FTFH is required for de novo biosynthesis of purines where it is used in two separate steps that contribute the carbon 2 and 8 of the purine ring in the reactions catalyzed by Atic and Gart. Interconversion reactions involving FTHF and 5,10-methyleneTHF are carried out by separate enzymes in the mitochondria and the cytoplasm. In the cytoplasm, mitochondrially derived formate is condensed with THF to yield FTFH in the ATP-dependent reaction catalyzed by the trifunctional enzyme Mthfd1. 5-methylTHF is the 1C donor for the cobalamin dependent remethylation of Hcy and is generated by the irreversible reduction of 5,10-methyleneTHF by (Mthfr), an FAD (flavin adenine dinucleotide)/vitamin B2, NADPH dependent enzyme. Mtr carries out the cobalamin dependent remethylation of Hcy in a reaction that also generates THF which then re-enters the cycle. Oxidation of cobalamin co-factor renders the enzyme inactive; reductive methylation carried out by Mtrr restores the functional enzyme. The Mtr dependent route, one of the two homocysteine remethylation pathways, links folate with homocysteine and methionine metabolism. The other route uses the methyl group of betaine as 1C donor and is not folate mediated; it is however, the major Hcy remethylation pathway in the liver. Once reformed, Met can go through another metabolic cycle whose first step produces S-adenosylmethionine (AdoMet or Sam), the primary methyl donor for nucleic acids, protein, lipids and small molecules. Folate, methionine and homocysteine metabolic pathways are intimately interconnected. Mutations in the genes involved in folate metabolism have been associated with several deficiencies and conditions. To see the ontology report for Gviewer, annotations and download, click here ...(less)