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Article Publish Status: FREE
Abstract Title:

Alternatively Spliced Methionine Synthase in SH-SY5Y Neuroblastoma Cells: Cobalamin and GSH Dependence and Inhibitory Effects of Neurotoxic Metals and Thimerosal.

Abstract Source:

Oxid Med Cell Longev. 2016 ;2016:6143753. Epub 2016 Feb 18. PMID: 26989453

Abstract Author(s):

Mostafa Waly, Verna-Ann Power-Charnitsky, Nathaniel Hodgson, Alok Sharma, Tapan Audhya, Yiting Zhang, Richard Deth

Article Affiliation:

Mostafa Waly

Abstract:

The folate and cobalamin (Cbl-) dependent enzyme methionine synthase (MS) is highly sensitive to oxidation and its activity affects all methylation reactions. Recent studies have revealed alternative splicing of MS mRNA in human brain and patient-derived fibroblasts. Here we show that MS mRNA in SH-SY5Y human neuroblastoma cells is alternatively spliced, resulting in three primary protein species, thus providing a useful model to examine cofactor dependence of these variant enzymes. MS activity was dependent upon methylcobalamin (MeCbl) or the combination of hydroxocobalamin (OHCbl) and S-adenosylmethionine (SAM). OHCbl-based activity was eliminated by depletion of the antioxidant glutathione (GSH) but could be rescued by provision of either glutathionylcobalamin (GSCbl) or MeCbl. Pretreatment of cells with lead, arsenic, aluminum, mercury, or the ethylmercury-containing preservative thimerosal lowered GSH levels and inhibited MS activity in association with decreased uptake of cysteine, which is rate-limiting for GSH synthesis. Thimerosal treatment decreased cellular levels of GSCbl and MeCbl. These findings indicate that the alternatively spliced form of MS expressed in SH-SY5Y human neuronal cells is sensitive to inhibition by thimerosal and neurotoxic metals, and lower GSH levels contribute to their inhibitory action.

Study Type : Human In Vitro
Additional Links
Problem Substances : Thimerosal : CK(618) : AC(151)
Adverse Pharmacological Actions : Glutathione Down-Regulation : CK(5) : AC(3)

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Sayer Ji
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