The methylation and transsulfuration pathways are under tonic modulation by various signaling molecules as well as homeostatic feedback modulation by various intermediates within the pathways themselves, most notably SAMe. Many of the effects of SAMe (Adomet) on the activity of enzymes within these pathways can be seen as to ultimately act to homeostatically regulate its own production. For instance SAMe has been shown to induce CBS 1 and inhibit BHMT 2 and MTHFR 3,4. SAMe has been shown in many studies to augment glutathione metabolism through induction of glutathione synthesis 5,6, protection of GCL activity 7,8, and dose-dependent induction of GST 9–12. There is also the possibility that SAMe modulates GPx, GR and SODase activity 5,10,11. Below are some of the other modulators of various key enzymes within the methylation and transsulfuration pathways.
SAMe acts as allosteric activator of CBS by preventing enzyme degradation 13. CBS also contains a heme domain which confers redox sensitivity. Oxidants can increase CBS activity; however CBS can be inhibited by peroxynitrite 14. CBS activity has further been shown to be regulated by various other molecules in different tissues. CBS activity is increased by vitamin D 15 and glucocorticoids 16. In the brain neuronal Ca2+/calmodulin stimulates CBS activity and H2S generation 17,18. CBS activity is lowered by insulin 16 and testosterone (in humans) 19.
LPS-TLR4 signaling induces CSE expression and H2S synthesis in macrophages 20.
Inhibited by peroxynitrite 21.
GSH/GSSG redox balance 22
I don’t think cellular cobalamin (B12) metabolism is completely pinned down yet, but below is a nice diagram for how cobalamin metabolism likely works once the transcobalamin carrier protein has delivered it from blood to cell.
OH-cobalamin (hydroxy or aquacobalamin) forms an irreversible 1:1 complex with glutathione called glutathionylcobalamin, which is thought to serve as a precursor to the active coenzyme forms: methylcobalamin and adenosylcobalamin 23,24. In this way glutathione can protect cobalamin from oxidation 25. Recent research supports the importance of glutathione in cobalamin metabolism; in rats chronic ethanol consumption depletes MS (methionine synthase) activity in a glutathione-dependant manner 26.
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15. Kriebitzsch, C. et al. 1,25-dihydroxyvitamin D(3) influences cellular homocysteine levels in murine pre-osteoblastic MC3T3-E1 cells by direct regulation of cystathionine β-synthase. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research (2011). doi:10.1002/jbmr.493
16. Ratnam, S. et al. Hormonal regulation of cystathionine beta-synthase expression in liver. The Journal of biological chemistry 277, 42912–8 (2002).
17. Eto, K., Ogasawara, M., Umemura, K., Nagai, Y. & Kimura, H. Hydrogen sulfide is produced in response to neuronal excitation. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 3386–91 (2002).
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19. Vitvitsky, V. et al. Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels. American journal of physiology. Renal physiology 293, F594–600 (2007).
20. Zheng, Y. et al. Lipopolysaccharide regulates biosynthesis of cystathionine γ-lyase and hydrogen sulfide through toll-like receptor-4/p38 and toll-like receptor-4/NF-κB pathways in macrophages. In vitro cellular & developmental biology. Animal (2013). doi:10.1007/s11626-013-9659-4
21. Pucciarelli, S. et al. Peroxynitrite-mediated oxidation of the C85S/C152E mutant of dihydrofolate reductase from Escherichia coli: functional and structural effects. Archives of biochemistry and biophysics 434, 221–31 (2005).
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25. Watson, W. P., Munter, T. & Golding, B. T. A new role for glutathione: protection of vitamin B12 from depletion by xenobiotics. Chemical research in toxicology 17, 1562–7 (2004).
26. Waly, M. I., Kharbanda, K. K. & Deth, R. C. Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner. Alcoholism, clinical and experimental research 35, 277–83 (2011).