Oxidative stress cobalamins

Methionine synthase is composed of five structural domains that provide for binding of its substrate HCY, the methyl donor 5-methyItetrahydrofolate, cobal-amin, and SAM (Fig. 4). In most tissues SAM is utilized to methylate oxidized cobalamin, in conjunction with electron donation by methionine synthase reductase, thereby restoring methylcobalamin and allowing resumption of activity. This mode of reactivation is required approximately every 100-1,000 turnovers, even under strictly anaerobic laboratory conditions (Bandarian et al., 2003). Under physiological conditions, oxidation of cobalamin is undoubtedly much more common, illustrating how vitamin B12 serves as a sensor of redox status. During oxidative stress, cobalamin is more frequently oxidized and more HCY is diverted toward cysteine and GSH synthesis. 

As illustrated in Fig. 1, methionine synthase is positioned at the intersection between transsulfuration and methylation pathways. As a consequence, its level of activity exerts control over cellular redox status, since it determines the proportion of HCY that will be diverted toward cysteine and GSH synthesis. Methionine synthase activity is exceptionally sensitive to inhibition during oxidative stress, primarily because its cobalamin cofactor is easily oxidized (Liptak and Brunold, 2006). This allows methionine synthase to serve as a redox sensor, lowering its activity whenever the level of oxidation increases, until increased GSH synthesis brings the system back into balance. Electrophilic compounds, such as oxygen-containing xenobiotic metabolites, also react with cobalamin, inactivating the enzyme and increasing diversion of HCY toward GSH synthesis (Watson et al., 2004). Thus, methionine synthase is a sensor of both redox and xenobiotic status. 

Neurons operate under unique redox conditions, increasing their vulnerability to oxidative stress, and recent studies provide evidence of oxidative stress and neuroinflammation in autism. Impaired methylation is a consequence of oxidative stress, mediated in major part by inhibition of the folate- and cobalamin-dependent enzyme methionine synthase. Since methionine synthase activity is essential for dopamine-stimulated phospholipid methylation, some symptoms of autism may reflect impairment of this process. For example, dopamine D4 receptor activation... 

Figure 47.1 Intracellular metabolism of vitamin Bi2- Cyanocobalamin is first converted into cob(II)alamin, which has no cyanogen group on the ligand occupying the upper axial position of the cobalamin structure. Cob(II)alamin is further reduced to cob(I)alamin, which can function as a coenzyme in the body. Removal of a cyanide molecule from cyanocobalamin is directly reduced by NADPH and flavoprotein in the presence of a cyanocobalamin trafficking chaperone. Cobalamin is reportedly converted into its inactive form, cob(H)alamin, under oxidative stress (Lemer-Ellis et al. 2006). NADPH nicotinamide adenine dinucleotide phosphate.

Cyanocobalamin must be decyanated before conversion into the enzyme forms to exert its activity. In CKD patients with cyanide metabolism disorder, the safety of cyanocobalamin is unclear. This mechanism may be associated with the occurrence of adverse events in patients with CKD who have been treated with cyanocobalamin in recent large-scale studies (Armitage et al. 2010 House et al. 2010). It has also to be noted that cobalamin cannot become its coenzyme form unless it is reduced to cob(I)alamin (Gregory Kelly 1997). Cobalamin is reportedly converted into its inactive form, cob(II)alamin, under oxidative stress (Chen et al. 1995). CKD is well known to be associated with increased oxidative stress (Annuk et al. 2001) and it is highly likely that CKD interferes with the conversion of cobalamin to its reduced forms (Figure 47.1). 

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