Coordination of cellular methylation and lipid biosynthesis

Lipid metabolism is the major energy converting pathway in the cell. Both synthesis of lipids and their utilisation are, thus, subject to strict and complex control which, however, should also allow dynamic response to the metabolic status of the cell by conserving energy excess and compensating for energy shortage. Dysfunction of lipid metabolism is implicated in a number of increasing urban diseases: obesity, cardiovascular diseases, diabetes type II. However, molecular mechanisms of the lipid metabolism pathologies are not fully understood. In our previous work we have identified a coordinated regulation between methylation and phospholipid metabolism at the level of S-adenosyl-L-homocysteine hydrolase, the key enzyme of methylation metabolism, in the yeast S.cerevisiae. The enzyme is involved in the synthesis of the major yeast phospholipid, phosphatydylcholine, and a sterol intermediate, zymosterol. Our studies indicate that the modulation of Sah1p levels in the cell also affect the metabolism of triacylglycerols. Moreover, from mammalian system it is known that both DNA hypomethylation and high homocysteine levels, determined at least in part by the function of Sah1p, are implicated in cardiovascular disease. Thus, Sah1p appears to play a central role controlling methylation and homocysteine status, which are determining parameters important for cellular methylation as well as for balanced biosynthesis of lipids. The aim of this work is to understand at the cellular level the role of Sah1p, homocysteine and methylation potential for phospholipid and neutral lipid metabolism, and its regulation. These studies will be performed in the yeast Saccharomyces cerevisiae, which is a particularly attractive model system for biomedical research due to its significant structural and functional homologies to higher eukaryotic cells (highlighted by the fact of the Nobel Prize for Medicine awarded to two yeast researchers in 2001). Understanding of coordination between a major regulatory pathway in the cell and phospholipid/lipid metabolism will provide new insights into interpathway regulatory networks and conditions of lipid metabolism dysfunction.

Biological processes and their regulation are dependent on many central metabolites. One such metabolite S- adenosyl-L-methionine (AdoMet), so-called "activated methionine", is used by more than 50 enzymes to modify numerous cellular components, including proteins, lipids and nucleic acids - "methylation". Therefore, AdoMet- dependent methylation controls many cellular processes and is itself under several levels of stringent control. One major physiological regulator of AdoMet-dependent methylation is the enzyme S-adenosyl-L-homocysteine hydrolase (AHCY in humans; SAH1 in yeast). A recently discovered severe genetic disorder that leads to AdoMet depletion, termed S-adenosyl-L-homocysteine hydrolase deficiency (AHCY deficiency), is characterized by muscle weakness, developmental delay, mental insufficiency, liver disorders and, sometimes, death during childhood. A more common disorder, termed hyperhomocysteinemia (due to elevated levels of homocysteine in the blood), may lead to a similar phenotype of AdoMet insufficiency, and is connected to cardiovascular diseases, such as atherosclerosis, and neurodegenerative diseases. Although homocysteine is recognized as a risk factor of atherosclerosis for the past five decades, the mechanisms responsible for the dysfunction under conditions of decreased AdoMet availability are unknown. We have used baker`s yeast to understand the role of AdoMet-dependent methylation in fat metabolism. This simple unicellular organism can be efficiently used as a model system to analyze biological processes that are highly conserved between yeast and multicellular organisms. We could show that fat metabolism is very sensitive to AdoMet insufficiency, caused both by SAH1 malfunction as well as by elevated homocysteine levels. One of the consequences of AdoMet insufficiency in yeast is the massive accumulation of fat. This novel link uncovered in our studies suggests a potential mechanism that leads to deregulated fat metabolism, as a consequence of AHCY deficiency and hyperhomocysteinemia in humans.