Saturday, 10 July 2010

Methylation & glutathione pathway regulation

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.



CBS
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.

CSE
LPS-TLR4 signaling induces CSE expression and H2S synthesis in macrophages 20.

DHFR
Inhibited by peroxynitrite 21.

MAT
GSH/GSSG redox balance 22

Glutathionylcobalamin
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.

References
1.         Janosík, M., Kery, V., Gaustadnes, M., Maclean, K. N. & Kraus, J. P. Regulation of human cystathionine beta-synthase by S-adenosyl-L-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region. Biochemistry 40, 10625–33 (2001).
2.         Ou, X. et al. Inhibition of human betaine-homocysteine methyltransferase expression by S-adenosylmethionine and methylthioadenosine. The Biochemical journal 401, 87–96 (2007).
3.         Jencks, D. A. & Mathews, R. G. Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. Effects of adenosylmethionine and NADPH on the equilibrium between active and inactive forms of the enzyme and on the kinetics of approach to equilibrium. The Journal of biological chemistry 262, 2485–93 (1987).
4.         Matthews, R. G. & Daubner, S. C. Modulation of methylenetetrahydrofolate reductase activity by S-adenosylmethionine and by dihydrofolate and its polyglutamate analogues. Advances in enzyme regulation 20, 123–31 (1982).
5.         De La Cruz, J. P., Pavía, J., González-Correa, J. A., Ortiz, P. & Sánchez de la Cuesta, F. Effects of chronic administration of S-adenosyl-L-methionine on brain oxidative stress in rats. Naunyn-Schmiedeberg’s archives of pharmacology 361, 47–52 (2000).
6.         Mesa, M. L., Carrizosa, R., Martínez-Honduvilla, C., Benito, M. & Fabregat, I. Changes in rat liver gene expression induced by thioacetamide: protective role of S-adenosyl-L-methionine by a glutathione-dependent mechanism. Hepatology (Baltimore, Md.) 23, 600–6 (1996).
7.         Yang, H. et al. Dysregulation of glutathione synthesis during cholestasis in mice: molecular mechanisms and therapeutic implications. Hepatology (Baltimore, Md.) 49, 1982–91 (2009).
8.         Ko, K. et al. Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia in mice. Laboratory investigation; a journal of technical methods and pathology 88, 1121–9 (2008).
9.         Tchantchou, F., Graves, M., Falcone, D. & Shea, T. B. S-adenosylmethionine mediates glutathione efficacy by increasing glutathione S-transferase activity: implications for S-adenosyl methionine as a neuroprotective dietary supplement. Journal of Alzheimer’s disease : JAD 14, 323–8 (2008).
10.       Cavallaro, R. A., Fuso, A., Nicolia, V. & Scarpa, S. S-adenosylmethionine prevents oxidative stress and modulates glutathione metabolism in TgCRND8 mice fed a B-vitamin deficient diet. Journal of Alzheimer’s disease : JAD 20, 997–1002 (2010).
11.       Gonzalez-Correa, J. A. et al. Effects of S-adenosyl-L-methionine on hepatic and renal oxidative stress in an experimental model of acute biliary obstruction in rats. Hepatology (Baltimore, Md.) 26, 121–7 (1997).
12.       Tchantchou, F. et al. S-adenosyl methionine: A connection between nutritional and genetic risk factors for neurodegeneration in Alzheimer’s disease. The journal of nutrition, health & aging 10, 541–4 (2006).
13.       Prudova, A. et al. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proceedings of the National Academy of Sciences of the United States of America 103, 6489–94 (2006).
14.       Celano, L. et al. Inactivation of cystathionine beta-synthase with peroxynitrite. Archives of biochemistry and biophysics 491, 96–105 (2009).
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).
18.       Eto, K. & Kimura, H. A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase. The Journal of biological chemistry 277, 42680–5 (2002).
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).
22.       Martínez-Chantar, M. L. & Pajares, M. A. Role of thioltransferases on the modulation of rat liver S-adenosylmethionine synthetase activity by glutathione. FEBS letters 397, 293–7 (1996).
23.       Xia, L., Cregan, A. G., Berben, L. A. & Brasch, N. E. Studies on the formation of glutathionylcobalamin: any free intracellular aquacobalamin is likely to be rapidly and irreversibly converted to glutathionylcobalamin. Inorganic chemistry 43, 6848–57 (2004).
24.       Pezacka, E., Green, R. & Jacobsen, D. W. Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes. Biochemical and biophysical research communications 169, 443–50 (1990).
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).

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