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REGULATION OF HOMOCYSTEINE REMETHYLATION BY CYTOPLASMIC SERINE HYDROXYMETHYLTRANSFERASE
Author(s) -
MacFarlane Amanda Jane,
Liu Xiaowen,
Perry Cheryll A.,
Allen Sylvia,
Stover Patrick J.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a958-a
Subject(s) - serine hydroxymethyltransferase , serine , methionine , biochemistry , metabolism , cytoplasm , biology , homocysteine , glycine , cystathionine beta synthase , methylation , methionine synthase , methyltransferase , cysteine , amino acid , microbiology and biotechnology , chemistry , gene , enzyme
Serine hydroxymethyltransferase (SHMT) catalyzes the reversible interconversion of serine and tetrahydrofolate (THF) to glycine and methyleneTHF. Mammals express cytoplasmic and mitochondrial isozymes that are encoded by separate genes. Mitochondrial SHMT (mSHMT) is expressed ubiquitously and functions to generate one‐carbons from serine for cytoplasmic folate‐mediated one‐carbon metabolism. Conversely, the expression of cytoplasmic SHMT (cSHMT) is tissue‐specific, found primarily in liver, kidney, skeletal muscle and small intestinal and colonic crypts. cSHMT regulates the flow of one carbon units in the folate metabolic pathway by preferentially shuttling methylene THF into dTMP synthesis over methionine synthesis. We have generated cSHMT loss‐of‐function mice by deleting the cSHMT gene in the germ line. The cSHMT null mice are fertile and viable but demonstrate 3 to 5‐fold elevations in the hepatic SAM/SAH ratio, indicating altered homocysteine metabolism. The data confirm results from cell culture models that indicate cSHMT represses the homocysteine remethylation cycle. Thus, alterations in cSHMT expression could impact cellular methylation reactions. This mouse model confirms the role of mitochondrial one‐carbon metabolism as a primary source of one‐carbons for cytoplasmic folate‐mediated one‐carbon metabolism. (Supported by NCI CA105440)