folate metabolism

Metabolism of folate centers about tetrahydrofolate which is involved two different metabolic pathways: 1) methionine metabolism 2) DNA synthesis Tetrahydrofolate (THF) is an activated carrier of one carbon units. Other carriers included S-adenosylmethionine (SAM, a carrier of -CH₃) & biotin (a carrier of -CO₂). The carbon carried by THF is bound to N5 or N10 of THF or both. The most reduced form carries a -CH₃ group; the intermediate form carries a methylene group; the most oxidized forms carry a methenyl, formyl or formino group. The one carbon units carried by THF are interconvertible. The THF derivatives serve as methyl donors in a variety of biosyntheses: 1) N5-methyl-THF -> homocysteine to methionine 2) N5,N10-methylene-THF -> dUMP to dTMP & in glycine biosynthesis 3) N10-formyl-THF -> biosynthesis of purines * see figure Biochemistry: - methionine metabolism 5 - enzyme methionine synthase - substrate homocysteine + 5-methyltetrahydrofolate - product methionine + tetrahydrofolate - methionine metabolism 6 - enzyme serine hydroxymethyltransferase - substrate tetrahydrofolate + serine - product N5,N10-methylene tetrahydrofolate + glycine - methionine metabolism 7 - enzyme methylenetetrahydrofolate reductase - substrate N5,N10-methylene tetrahydrofolate + NADPH - product N5-methyl tetrahydrofolate + NAD⁺ - folate metabolism 1 - enzyme: thymidylate synthase - substrate: deoxyuridine monophosphate + N5,N10-methylene tetrahydrofolate - product: thymidine monophosphate + dihydrofolate - generation of thymidylate for DNA synthesis - folate metabolism 2 - enzyme: dihydrofolate reductase - substrate: dihydrofolate + NADPH + H⁺ - product: tetrahydrofolate + NADP+ - regeneration of tetrahydrofolate using reducing equivalents from NADPH - folate metabolism 3 - enzyme: amine oxidoreductase - substrate: folate + NADPH + H⁺ - product: dihydrofolate + NADP+) - folate metabolism 4 - enzyme: transferase - substrate: tetrahydrofolate + formate + ATP - product: N10-formyl tetrahydrofolate + ADP - folate metabolism 5 - enzyme: isomerase - substrate: N10-formyl tetrahydrofolate - product: N5-formyl tetrahydrofolate - folate metabolism 6 - enzyme: dehydrogenase - substrate: N5,N10-methylene tetrahydrofolate + NADP+ - product: N5,N10-methenyl tetrahydrofolate + NADPH + H⁺ - folate metabolism 7 - enzyme: hydrolase - substrate: N5,N10-methenyl tetrahydrofolate + ADP + H₂O - product: N10-formyl tetrahydrofolate + ATP - folate metabolism 8 - enzyme:bstrate aminotransferase - substrate: N5,N10-methenyl tetrahydrofolate + NH₃ - product: N5-formimino tetrahydrofolate

References

Stryer Biochemistry WH Freeman & Co, New York, 1988 pg 580, 614