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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #170451
Title: METHYLENETETRAHYDROFOLATE REDUCTASE 677C->T POLYMORPHISM AND FOLATE STATUS AFFECT ONE-CARBON INCORPORATION INTO HUMAN DNA DEOXYNUCLEOSIDES

Author
item QUINLIVAN, EOIN - UNIV OF FLORIDA-GAINES.
item DAVIS, STEVEN - UNIV OF FLORIDA-GAINES.
item SHELNUTT, KARLA - UNIV OF FLORIDA-GAINES.
item HENDERSON, GEORGE - UNIV OF FLORIDA-GAINES.
item GHANDOUR, HAIFA - TUFTS/HNRCA
item SHANE, BARRY - UNIV CALIFORNIA BERKELEY
item SELHUB, JACOB - TUFTS/HNRCA
item BAILY, LYNN - UNIV OF FLORIDA-GAINES.
item STACPOOLE, PETER - UNIV OF FLORIDA-GAINES.
item GREGORY, JESSE - UNIV OF FLORIDA-GAINES.

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2004
Publication Date: 3/1/2005
Citation: Quinlivan, E.P., Davis, S.R., Shelnutt, K.P., Henderson, G.N., Ghandour, H., Shane, B., Selhub, J., Baily, L.B., Stacpoole, P.W., Gregory, J.F. 2005. Methylenetetrahydrofolate reductase 677C->T polymorphism and folate status affect one-carbon incorporation into human DNA deoxynucleosides. Journal of Nutrition. 135(3):389-96.

Interpretive Summary: Methylene tetrahydrofolate reductase is an enzyme which is responsible to synthesize a form of folate called 5-methyltetrahydrofolate. This study is intended to determine what are the consequences when this enzyme is only partially active as it occurs in about 12% of the people. To do so we used specific labeling of serine and methionine, two amino acids which are involved in the metabolism of the vitamin folic acid. This labeling allows the tracking of what happens with people that have this deficiency. Our finding show that people of this deficiency tend to make DNA more efficiently than people without this deficiency. Moreover a diet which was low in folic acid tend to result in less availability of 5-methyltetrahydrofolate.

Technical Abstract: The methylenetetrahydrofolate reductase (MTHFR) 677C T polymorphism is thought to influence the partitioning of one-carbon units between methylation and other components of one-carbon metabolism and influences the risk and etiology of several major cancers and cardiovascular disease. Our objective was to determine the effect of the MTHFR 677C T polymorphism and folate status on the relative rate and extent of in vivo synthesis of DNA precursors. Adequately nourished, healthy females (9CC, 9TT) were infused with [3-13C]serine and [13C5]methionine over 9 h before and after a 7-wk low-folate diet. Blood was drawn over 5 days for monocyte DNA isolation. Isotopic enrichment of the nucleosides in DNA digests was determined by LC-MS/MS. Maximum thymidine enrichment tended to be higher (p=0.07) in TT than in CC-subjects, consistent with marginally higher mean thymidylate synthesis. However, the subset of TT-subjects that exhibited formyltetrahydrofolate in erythrocytes (an indicator of one-carbon partitioning) had significantly higher thymidine enrichment than CC-subjects who had no erythrocyte formyltetrahydrofolate. Purine enrichment was not effected by genotype or folate depletion. However, the deoxyadenosine to deoxyguanosine enrichment ratio was significantly higher in TT-subjects, suggesting a greater relative rate of adenine synthesis. The significantly greater labeling of the methyl-group of methyldeoxycytidine during folate depletion suggests a change in the origin of this one-carbon unit. This is the first time one-carbon incorporation into human DNA has been measured in vivo following infusion of 13C-labeled one-carbon precursors. These findings support the feasibility of further assessment of factors affecting deoxynucleotide synthesis and DNA methylation in human one-carbon metabolism.