S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity.

Proceedings of the National Academy of Sciences of the United States of America
Anna PrudovaRuma Banerjee

Abstract

The transsulfuration pathway converts homocysteine to cysteine and represents the metabolic link between antioxidant and methylation metabolism. The first and committing step in this pathway is catalyzed by cystathionine beta-synthase (CBS), which is subject to complex regulation, including allosteric activation by the methyl donor, S-adenosylmethionine (AdoMet). In this study, we demonstrate that methionine restriction leads to a >10-fold decrease in CBS protein levels, and pulse proteolysis studies reveal that binding of AdoMet stabilizes the protein against degradation by approximately 12 kcal/mol. These observations predict that under pathological conditions where AdoMet levels are diminished, CBS, and therefore glutathione levels, will be reduced. Indeed, we demonstrate this to be the case in a mouse model for spontaneous steatohepatitis in which the gene for the MAT1A isoenzyme encoding AdoMet synthetase has been disrupted, and in human hepatocellular carcinoma, where MAT1A is silenced. Furthermore, diminished CBS levels are associated with reduced cell viability in hepatoma cells challenged with tert-butyl hydroperoxide. This study uncovers a mechanism by which CBS is allosterically activated by AdoMet under normal condi...Continue Reading

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Citations

Jul 9, 2009·Journal of Inherited Metabolic Disease·Ivo Barić
Feb 18, 2010·Journal of Inherited Metabolic Disease·Martha H Stipanuk, Iori Ueki
Dec 17, 2008·The British Journal of Nutrition·Rafael DeminiceAlceu Afonso Jordao
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Feb 15, 2011·Biochimica Et Biophysica Acta·Sangita Singh, Ruma Banerjee

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