title: Cytoplasmic serine hydroxymethyltransferase regulates the metabolic partitioning of methylenetetrahydrofolate but is not essential in mice.
abstract: The hydroxymethyl group of serine is a primary source of tetrahydrofolate (THF)-activated one-carbon units that are required for the synthesis of purines and thymidylate and for S-adenosylmethionine (AdoMet)-dependent methylation reactions. Serine hydroxymethyltransferase (SHMT) catalyzes the reversible and THF-dependent conversion of serine to glycine and 5,10-methylene-THF. SHMT is present in eukaryotic cells as mitochondrial SHMT and cytoplasmic (cSHMT) isozymes that are encoded by distinct genes. In this study, the essentiality of cSHMT-derived THF-activated one-carbons was investigated by gene disruption in the mouse germ line. Mice lacking cSHMT are viable and fertile, demonstrating that cSHMT is not an essential source of THF-activated one-carbon units. cSHMT-deficient mice exhibit altered hepatic AdoMet levels and uracil content in DNA, validating previous in vitro studies that indicated this enzyme regulates the partitioning of methylenetetrahydrofolate between the thymidylate and homocysteine remethylation pathways. This study suggests that mitochondrial SHMT-derived one-carbon units are essential for folate-mediated one-carbon metabolism in the cytoplasm.
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: MacFarlane
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Liu
authors.forename: Cheryll A
authors.initials: CA
authors.lastname: Perry
authors.forename: Per
authors.initials: P
authors.lastname: Flodby
authors.forename: Robert H
authors.initials: RH
authors.lastname: Allen
authors.forename: Sally P
authors.initials: SP
authors.lastname: Stabler
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Stover
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D012696:Glycine Hydroxymethyltransferase / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D013763:Tetrahydrofolates / Q000737:chemistry* / Q000378:metabolism
chemical_list: D013763:Tetrahydrofolates; C013123:5,10-methylenetetrahydrofolic acid; D012696:Glycine Hydroxymethyltransferase; C005984:5-methyltetrahydrofolate