Document Detail


S-adenosyl-L-homocysteine hydrolase, key enzyme of methylation metabolism, regulates phosphatidylcholine synthesis and triacylglycerol homeostasis in yeast: implications for homocysteine as a risk factor of atherosclerosis.
MedLine Citation:
PMID:  18591246     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In eukaryotes, S-adenosyl-L-homocysteine hydrolase (Sah1) offers a single way for degradation of S-adenosyl-L-homocysteine, a product and potent competitive inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases. De novo phosphatidylcholine (PC) synthesis requires three AdoMet-dependent methylation steps. Here we show that down-regulation of SAH1 expression in yeast leads to accumulation of S-adenosyl-L-homocysteine and decreased de novo PC synthesis in vivo. This decrease is accompanied by an increase in triacylglycerol (TG) levels, demonstrating that Sah1-regulated methylation has a major impact on cellular lipid homeostasis. TG accumulation is also observed in cho2 and opi3 mutants defective in methylation of phosphatidylethanolamine to PC, confirming that PC de novo synthesis and TG synthesis are metabolically coupled through the efficiency of the phospholipid methylation reaction. Indeed, because both types of lipids share phosphatidic acid as a precursor, we find in cells with down-regulated Sah1 activity major alterations in the expression of the INO1 gene as well as in the localization of Opi1, a negative regulatory factor of phospholipid synthesis, which binds and is retained in the endoplasmic reticulum membrane by phosphatidic acid in conjunction with VAMP/synaptobrevin-associated protein, Scs2. The addition of homocysteine, by the reversal of the Sah1-catalyzed reaction, also leads to TG accumulation in yeast, providing an attractive model for the role of homocysteine as a risk factor of atherosclerosis in humans.
Authors:
Nermina Malanovic; Ingo Streith; Heimo Wolinski; Gerald Rechberger; Sepp D Kohlwein; Oksana Tehlivets
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Publication Detail:
Type:  Journal Article     Date:  2008-06-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-25     Completed Date:  2008-10-03     Revised Date:  2014-04-17    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23989-99     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosylhomocysteinase / biosynthesis*,  genetics
Atherosclerosis / enzymology*,  genetics
Down-Regulation / genetics
Endoplasmic Reticulum / enzymology,  genetics
Gene Expression Regulation, Enzymologic* / genetics
Gene Expression Regulation, Fungal* / genetics
Homeostasis / genetics
Homocysteine / genetics,  metabolism
Humans
Membrane Proteins / genetics,  metabolism
Methylation
Myo-Inositol-1-Phosphate Synthase / biosynthesis,  genetics
Phosphatidylcholines / biosynthesis*,  genetics
Phosphatidylethanolamine N-Methyltransferase / biosynthesis,  genetics
Repressor Proteins / biosynthesis,  genetics
Risk Factors
S-Adenosylhomocysteine / metabolism
Saccharomyces cerevisiae / enzymology*,  genetics
Saccharomyces cerevisiae Proteins / biosynthesis,  genetics,  metabolism
Triglycerides / biosynthesis*,  genetics
Grant Support
ID/Acronym/Agency:
F 3005-B19//Austrian Science Fund FWF
Chemical
Reg. No./Substance:
0/Membrane Proteins; 0/OPI1 protein, S cerevisiae; 0/Phosphatidylcholines; 0/Repressor Proteins; 0/Saccharomyces cerevisiae Proteins; 0/Scs2 protein, S cerevisiae; 0/Triglycerides; 0LVT1QZ0BA/Homocysteine; 979-92-0/S-Adenosylhomocysteine; EC 2.1.1.17/CHO2 protein, S cerevisiae; EC 2.1.1.17/Phosphatidylethanolamine N-Methyltransferase; EC 3.3.1.1/Adenosylhomocysteinase; EC 5.5.1.4/INO1 protein, S cerevisiae; EC 5.5.1.4/Myo-Inositol-1-Phosphate Synthase
Comments/Corrections

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