Cytoplasmic serine hydroxymethyltransferase mediates competition between folate-dependent deoxyribonucleotide and S-adenosylmethionine biosyntheses.
Folate-dependent one-carbon metabolism is required for the synthesis of purines and thymidylate and for the remethylation of homocysteine to methionine. Methionine is subsequently adenylated to S-adenosylmethionine (SAM), a cofactor that methylates DNA, RNA, proteins, and many metabolites. Previous experimental and theoretical modeling studies have indicated that folate cofactors are limiting for cytoplasmic folate-dependent reactions and that the synthesis of DNA precursors competes with SAM synthesis. Each of these studies concluded that SAM synthesis has a higher metabolic priority than dTMP synthesis. The influence of cytoplasmic serine hydroxymethyltransferase (cSHMT) on this competition was examined in MCF-7 cells. Increases in cSHMT expression inhibit SAM concentrations by two proposed mechanisms: (1) cSHMT-catalyzed serine synthesis competes with the enzyme methylenetetrahydrofolate reductase for methylenetetrahydrofolate in a glycine-dependent manner, and (2) cSHMT, a high affinity 5-methyltetrahydrofolate-binding protein, sequesters this cofactor and inhibits methionine synthesis in a glycine-independent manner. Stable isotope tracer studies indicate that cSHMT plays an important role in mediating the flux of one-carbon units between dTMP and SAM syntheses. We conclude that cSHMT has three important functions in the cytoplasm: (1) it preferentially supplies one-carbon units for thymidylate biosynthesis, (2) it depletes methylenetetrahydrofolate pools for SAM synthesis by synthesizing serine, and (3) it sequesters 5-methyltetrahydrofolate and inhibits SAM synthesis. These results indicate that cSHMT is a metabolic switch that, when activated, gives dTMP synthesis higher metabolic priority than SAM synthesis.
Herbig
Katherine
K
Cornell University, Division of Nutritional Sciences, Ithaca, New York 14853, USA.
Chiang
En-Pei
EP
Lee
Ling-Ru
LR
Hills
Jessica
J
Shane
Barry
B
Stover
Patrick J
PJ
D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000096:biosynthesis*; D005492:Folic Acid / Q000737:chemistry / Q000378:metabolism*; D005998:Glycine / Q000378:metabolism*; D012696:Glycine Hydroxymethyltransferase / Q000235:genetics / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D008745:Methylation; D012436:S-Adenosylmethionine / Q000096:biosynthesis*; D013763:Tetrahydrofolates / Q000378:metabolism; D013938:Thymidine Monophosphate / Q000737:chemistry / Q000378:metabolism
D003854:Deoxyribonucleotides; D013763:Tetrahydrofolates; D006710:Homocysteine; D013938:Thymidine Monophosphate; D012436:S-Adenosylmethionine; D004247:DNA; D005492:Folic Acid; D012696:Glycine Hydroxymethyltransferase; D005998:Glycine