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Methionine Synthase as a Sensor of Cellular Redox Status: Implications for Neurological Disorders
Author(s) -
Deth Richard Carlton,
Muratore Christina,
Waly Mostafa,
Bojkovic Jade
Publication year - 2007
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.21.5.a345
Subject(s) - methylation , methionine , glutathione , chemistry , biochemistry , homocysteine , methionine synthase , cortex (anatomy) , methyltransferase , microbiology and biotechnology , enzyme , biology , dna , amino acid , neuroscience
Cobalamin (Cbl)‐dependent methionine synthase (MS) utilizes folate‐derived methyl groups to convert homocysteine (HCY) to methionine, and also supports dopamine‐stimulated phospholipid methylation and its role in neuronal synchronization. MS also exerts powerful control over cellular methylation, including DNA methylation. Depending upon the level of oxidative stress, the Cbl(I) state of MS is readily oxidized, halting activity and diverting HCY toward transsulfuration and glutathione (GSH) synthesis. In SH‐SY5Y human neuronal cells and rat cortex, reactivation of MS depends upon methylCbl, whose synthesis requires GSH, thereby assuring that MS activity is keyed to redox status. Several neurodevelopmental toxins, as well as inhibitors of PI3‐kinase and MEK, reduce GSH levels and MS activity. PCR studies using mRNA primers for each of the five domains of MS, show that the Cap domain, which limits Cbl(I) oxidation, is almost completely absent in SH‐SY5Y cells, but not in human lymphoblasts. Similar PCR studies showed that the Cap domain is absent from MS mRNA in human cortex, but is present in mRNA of rat cortex. These results indicate that MS in human cortex is configured to be more readily inactivated by oxidation, implying a unique redox and methylation status.