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

Figure 6

Proposed mechanism for GSH-dependent reactivation of MS activity. During primary turnover, MS carries out methylation of HCY using methylfolate-derived methyl groups which are transiently bound to cobalamin as MeCbl (a). Depending upon redox conditions, the Cbl(I) state can oxidize to Cbl(II), inactivating the enzyme. Reactivation requires either reduction of Cbl(II) to Cbl(I) by methionine synthase reductase (MTRR), followed by SAM-dependent methylation of Cbl(I) to form MeCbl (a), or GSH-dependent formation of MeCbl via conversion of Cbl(II) to OHCbl (b). The latter GSH-dependent mechanism may be associated with alternatively spliced forms of MS for whom the probability of oxidation is enhanced.

(a)

(b)