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

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 conditions but is destabilized under pathological conditions, for redirecting the metabolic flux toward methionine conservation. A mechanistic basis for the coordinate changes in redox and methylation metabolism that are a hallmark of several complex diseases is explained by these observations.

• Authors: Anna Prudova, Zachary Bauman, Aaron Braun, Victor Vitvitsky, Shelly C Lu, Ruma Banerjee
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 103 Issue 17 Pg. 6489-94 (Apr 25 2006) ISSN: 0027-8424 [Print] United States
• PMID: 16614071 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• S-Adenosylmethionine
• Methionine
• MAT1A protein, human
• Mat1a protein, mouse
• Methionine Adenosyltransferase
• Cystathionine beta-Synthase

Topics

• Allosteric Regulation
• Animals
• Carcinoma, Hepatocellular (enzymology, genetics)
• Cell Line
• Cystathionine beta-Synthase (deficiency, genetics, metabolism)
• Enzyme Stability
• Fatty Liver (enzymology, genetics)
• Gene Silencing
• Humans
• Liver Neoplasms (enzymology, genetics)
• Methionine (metabolism)
• Methionine Adenosyltransferase (deficiency, genetics, metabolism)
• Mice
• Mice, Knockout
• Oxidation-Reduction
• Recombinant Proteins (genetics, metabolism)
• S-Adenosylmethionine (metabolism)