Increase in Plasma Homocysteine Associated with Parallel Increases in Plasma S-Adenosylhomocysteine and Lymphocyte DNA Hypomethylation*
By P. Yi, S. Melnyk, M. Pogribna, I. Pogribny, R. Hine, S. James. Journal of Biological Chemistry, 2000
683 citations recorded by the source corpus.
S-Adenosylmethionine andS-adenosylhomocysteine (SAH), as the substrate and product of essential cellular methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation of SAH, secondary to the homocysteine-mediated reversal of the SAH hydrolase reaction, reduces methylation of DNA, RNA, proteins, and phospholipids. High affinity binding of SAH to the active site of cellular methyltransferases results in product inhibition of the enzyme. Using a sensitive new high pressure liquid chromatography method with coulometric electrochemical detection, plasma SAH levels in healthy young women were found to increase linearly with mild elevation in homocysteine levels (r = 0.73; p < 0.001); however,S-adenosylmethionine levels were not affected. Plasma SAH levels were positively correlated with intracellular lymphocyte SAH levels (r = 0.81; p < 0.001) and also with lymphocyte DNA hypomethylation (r = 0.74,p < 0.001). These results suggest that chronic elevation in plasma homocysteine levels, such as those associated with nutritional deficiencies or genetic polymorphisms in the folate pathway, may have an indirect and negative effect on cellular methylation reactions through a concomitant increase in intracellular SAH levels.
Subfields: Molecular Biology, Rheumatology, Surgery
View Paper: https://www.semanticscholar.org/paper/4ad126230e7a9e019a0ea48b79cf3da395cfd9ee
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- S. James
- S. Melnyk
- S. Jernigan
- M. Cleves
- C. Halsted
- J. James
- Donna H. Wong
- P. Cutler
Citations in the corpus
- Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. (2001, background): “However, since mild MTHFR deficiency in the heterozygous knockout mice is associated with a disruption of the methionine cycle, it is possible that mild hyperhomocysteinemia is an indirect biomarker for disturbances in cellular methylation reactions (52).”
- Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. (2004, background): “Low methionine and SAM concentrations in combination with increased SAH and adenosine concentrations were shown previously to be associated with reduced cellular methylation capacity (39).”
- Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism (2006, background): “A low SAM/SAH ratio has been associated with impaired methylation capacity for membrane phosphatidylcholine synthesis and DNA methylation in humans [Yi et al., 2000; Innis et al., 2003].”