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Regulation of folate‐mediated one‐carbon metabolic kinetics by glycine supply
Author(s) -
Chiang EnPei Isabel,
Huang YuHsuan
Publication year - 2017
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.31.1_supplement.lb393
Subject(s) - glycine , sarcosine , biochemistry , serine , methionine , chemistry , glycine cleavage system , amino acid , formate , serine hydroxymethyltransferase , metabolism , biosynthesis , endogeny , in vivo , methionine synthase , biology , enzyme , microbiology and biotechnology , catalysis
Glycine‐N methyltransferase (GNMT) is a major hepatic enzyme that converts S ‐adenosylmethionine to S ‐adenosylhomocysteine while generating sarcosine from glycine. The metabolic role of GNMT in folate‐mediated one‐carbon metabolism and how glycine supply may affect one carbon metabolic kinetics are under investigated in the present study. Hepatocyte‐derived cell‐lines with and without GNMT expression were cultured in minimum essential medium (MEM) with and without high glycine supply. Methylene‐tetrahydrofolate (mTHF) utilization and endogenous formate biosynthesis were carefully investigated using stable isotopic tracers and GC‐MS. We discovered that high glycine inhibits the M+1 specie enrichments in deoxythymidine (dT+1) from 2,3,3 D3‐serine, suggesting that high glycine may inhibit endogenous formate production in these in vitro models. In a parallel experiment that exogenous formate was used as the 1C source, enrichments in dT+1 significantly increased from exogenous formate, supporting our hypothesis that high glycine inhibits endogenous formate production for thymidine synthesis. Mice fed in amino acid based diet supplemented with high glycine had significantly lower plasma formate concentrations that provide in vivo evidence on our hypothesis. On the other hand, high glycine promotes M+1 specie enrichments in methionine from 2,3,3 D3‐serine, indicating that high glycine supply may favor the utilization of methyleneTHF derived one carbon for homocysteine remethylation. High glycine supply can promote folate dependent methionine synthesis in our cell models. Preliminary in vivo experiments demonstrated that high dietary glycine alters folate dependent methionine synthesis, consistent with our in vitro findings. We demonstrated how glycine supply regulates folate‐mediated one‐carbon metabolic kinetics in vitro and in vivo . Support or Funding Information MOST 105‐2320‐B005‐010‐MY3; MOST104‐2911‐I005‐301; and Ministry of Education, Taiwan, R.O.C. under the ATU plan)