S-Adenosyl-L-homocysteine hydrolase, key enzyme of methylation metabolism, regulates phosphatidylcholine synthesis and triacylglycerol homeostasis in yeast

Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/II, Graz, Austria.
Journal of Biological Chemistry (Impact Factor: 4.57). 07/2008; 283(35):23989-99. DOI: 10.1074/jbc.M800830200
Source: PubMed


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 novophosphatidylcholine(PC)synthesisrequiresthreeAdoMet-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.

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    • "Methionine, as a constituent of proteins, is also critical to biochemical pathways, including the “methyl cycle” which generates the key metabolite S-adnosylmethioinine (AdoMet) [32]. As the main donor of methyl groups in methylation reactions, AdoMet plays a vital role in de novo phosphatidylcholine (PC) synthesis that requires three AdoMet-dependent methylation steps [33]. "
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    • "Several epidemiological surveys, as well as observations from in vitro and in vivo studies, provided evidence that AdoHcy elevation parallels HHcy [8], [9], [12], [29], [30]. Since AdoHcy is a strong methyltransferase inhibitor, a reduced cellular methylation capacity due to accumulation of AdoHcy may account for the detrimental effects associated with HHcy. "
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