Abstract
S-Adenosyl-l-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades AdoHcy, a by-product and strong product inhibitor of S-adenosyl-l-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy). This reaction is reversible, so any elevation of Hcy levels, such as in hyperhomocysteinemia (HHcy), drives the formation of AdoHcy, with detrimental consequences for cellular methylation reactions. HHcy, a pathological condition linked to cardiovascular and neurological disorders, as well as fatty liver among others, is associated with a deregulation of lipid metabolism. Here, we developed a yeast model of HHcy to identify mechanisms that dysregulate lipid metabolism. Hcy supplementation to wildtype cells up-regulated cellular fatty acid and triacylglycerol content and induced a shift in fatty acid composition, similar to changes observed in mutants lacking Sah1. Expression of the irreversible bacterial pathway for AdoHcy degradation in yeast allowed us to dissect the impact of AdoHcy accumulation on lipid metabolism from the impact of elevated Hcy. Expression of this pathway fully suppressed the growth deficit of sah1 mutants as well as the deregulation of lipid metabolism in both the sah1 mutant and Hcy-exposed wildtype, showing that AdoHcy accumulation mediates the deregulation of lipid metabolism in response to elevated Hcy in yeast. Furthermore, Hcy supplementation in yeast led to increased resistance to cerulenin, an inhibitor of fatty acid synthase, as well as to a concomitant decline of condensing enzymes involved in very long-chain fatty acid synthesis, in line with the observed shift in fatty acid content and composition.
Highlights
S-Adenosyl-L-homocysteine hydrolase (AdoHcy hydrolase; Sah1 in yeast/AHCY in mammals) degrades adenosylhomocysteine nucleosidase; homocysteine (AdoHcy), a by-product and strong product inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methylation reactions, to adenosine and homocysteine (Hcy)
Hcy synthesized in the course of methylation metabolism or by the sulfur assimilation pathway can be remethylated to methionine, which can be further activated to AdoMet, or converted to cysteine, a precursor of glutathione (Fig. 1A) [5]
Sah1/AHCY plays an important role in regulating methylation metabolism by degrading AdoHcy, but in mammals it constitutes the sole pathway for the synthesis of Hcy, which is typically absent from the diet [5]
Summary
Elevated Hcy and/or AdoHcy are associated with triacylglycerol (TG) accumulation in liver, endothelial, and smooth muscle cells [7, 17,18,19], adipocyte dysfunction [20, 21], and overall loss of fat mass [22], indicating a major impact on cellular lipid homeostasis in mammals. LuxS, S-ribosylhomocysteine lyase; AltPW, alternative pathway for AdoHcy catabolism; PC, phosphatidylcholine; PE, phosphatidylethanolamine; FAS, FA synthase; GST, glutathione S-transferase; GFP, green fluorescent protein; DG, diacylglycerol; ISTD, internal standard; CM, chloroform/methanol; SD, synthetic defined; ER, endoplasmic reticulum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase
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