Fig. 1

Topology of the folate and methionine cycles illustrating selected long-range allosteric regulatory interactions. Enzymes are indicated by ellipses, substrates by rectangles, and the allosteric regulatory actions by red arrows. These allosteric interactions serve to stabilize the DNA methylation reaction as follows. When S-adenosylmethionine (SAM) rises, due to increased methionine input, for instance, it inhibits 5,10-methylenetetrahydrofolate reductase (MTHFR). This reduces the level of 5-methyltetrahydrofolate (5mTHF), the co-substrate for methionine synthase (MS). This effect, together with the inhibition of betaine-homocysteine methyltransferase (BHMT), leads to a reduction in methionine synthesis. SAM also increases the rate of the CBS reaction, which removes the excess mass from the system. The reduction in 5mTHF, in turn, relieves inhibition of GNMT, causing more flux through this enzyme, which stabilizes the flux through the DNMT reaction until the level of SAM falls back to normal. Enzymes: AICART aminoimidazolecarboxamide ribonucleotide transferase, BHMT betaine-homocysteine methyltransferase, CBS cystathionine β-synthase, DHFR dihydrofolate reductase, DNMT DNA-methyltransferase, FTD 10-formyltetrahydrofolate dehydrogenase, FTS 10-formyltetrahydrofolate synthase, GNMT glycine N-methyltransferase, MAT-I methionine adenosyl transferase I, MAT-III methionine adenosyl transferase III, MS methionine synthase, MTCH 5,10-methenyltetrahydrofolate cyclohydrolase, MTD 5,10-methylenetetrahydrofolate dehydrogenase, MTHFR 5,10-methylenetetrahydrofolate reductase, NE non-enzymatic conversion, PGT phosphoribosyl glycinamidetransformalase, SAAH S-adenosylhomocysteine hydrolase, SHMT serinehydroxymethyltransferase, TS thymidylate synthase. Metabolites: 10f-THF 10-formyltetrahydrofolate, 5mTHF 5-methyltetrahydrofolate, CH = THF 5-10-methenyltetrahydrofolate, CH2-THF 5-10-methylenetetrahydrofolate, DHF dihydrofolate, Hcy homocysteine, MET methionine, SAH S-adenosylhomocysteine, SAM S-adenosylmethionine, THF tetrahydrofolate