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J. Biol. Chem., Vol. 277, Issue 41, 38381-38389, October 11, 2002
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From the 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.
Cytoplasmic Serine Hydroxymethyltransferase Mediates Competition
between Folate-dependent Deoxyribonucleotide and
S-Adenosylmethionine Biosyntheses*
,,¶
Cornell University, Division of Nutritional
Sciences, Ithaca, New York 14853 and the § Department of
Nutritional Sciences and Toxicology, University of California,
Berkeley, California 94720
*
This work was supported by United States Public Health
Services Grants DK58144 (to P. J. S.) and DK42033 (to B. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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