S-adenosyl-L-homocysteine hydrolase and methylation disorders: yeast as a model system

Abstract

S-adenosyl-L-methionine (AdoMet)-dependent methylation is central to the regulation of many biological processes: more than 50 AdoMet-dependent methyltransferases methylate a broad spectrum of cellular compounds including nucleic acids, proteins and lipids. Common to all AdoMet-dependent methyltransferase reactions is the release of the strong product inhibitor S-adenosyl-L-homocysteine (AdoHcy), as a by-product of the reaction. S-adenosyl-L-homocysteine hydrolase is the only eukaryotic enzyme capable of reversible AdoHcy hydrolysis to adenosine and homocysteine and, thus, relief from AdoHcy inhibition. Impaired S-adenosyl-L-homocysteine hydrolase activity in humans results in AdoHcy accumulation and severe pathological consequences. Hyperhomocysteinemia, which is characterized by elevated levels of homocysteine in blood, also exhibits a similar phenotype of AdoHcy accumulation due to the reversal of the direction of the S-adenosyl-L-homocysteine hydrolase reaction. Inhibition of S-adenosyl-L-homocysteine hydrolase is also linked to antiviral effects. In this review the advantages of yeast as an experimental system to understand pathologies associated with AdoHcy accumulation will be discussed.

Fig. 1

AdoMet-dependent methylation: the role of AdoHcy and S-adenosyl-L-homocysteine hydrolase a) in yeast and b) in mammals. Reverse transsulfuration pathway in yeast converts cysteine into homocysteine via cystathionine γ-synthase, Str2, and cystathionine β-lyase, Str3. AdoMet, S-adenosyl-L-methionine; AdoHcy, S-adenosyl-L-homocysteine; Hcy, homocysteine; Met, methionine; Sah1, S-adenosyl-L-homocysteine hydrolase in yeast; AHCY, S-adenosyl-L-homocysteine hydrolase in mammals; CTT, cystathionine; Sam1, AdoMet synthetase 1; Sam2, AdoMet synthetase 2; Sam4, AdoMet-homocysteine methyltransferase; Mht1, S-methylmethionine–homocysteine methyltransferase; Met6, methionine synthase; Met25, O-acetylhomoserine sulfhydrylase; Str1, cystathionine γ-lyase; Str2, cystathionine γ-synthase; Str3, cystathionine β-lyase; Str4, cystathionine β-synthase; Gsh1, γ-glutamylcysteine synthetase; MAT, methionine adenosyltransferase; MS, methionine synthase; BHMT, betaine-homocysteine methyltransferase; CBS, cystathionine β-synthase; CTH, cystathionine γ-lyase; GCS, γ-glutamylcysteine synthetase.

Fig. 2

S-adenosyl-L-homocysteine hydrolase: sequence and structural conservation. The sequence conservation based on ConSurf calculations using 166 unique S-adenosyl-L-homocysteine hydrolase sequences is color coded (from blue – identity to red – least conservation) and mapped onto the structure of the Pf-SAHH (PDB 1v8b [77]). Shown is one monomer of the functional tetrameric S-adenosyl-L-homocysteine hydrolase protein in cartoon drawing, the NAD⁺ cofactor (yellow) is shown in a stick representation and the substrate (Ado) was omitted for clarity. Note that the 40 amino acid insertion consisting of 3 helices and a loop (black circle), which is not present in mammalian and yeast S-adenosyl-L-homocysteine hydrolases, shows the least degree of conservation.

Fig. 3

Catalytic activity of S-adenosyl-L-homocysteine hydrolase.

Fig. 4

Role of AdoHcy and S-adenosyl-L-homocysteine hydrolase in lipid metabolism in yeast. AdoMet, S-adenosyl-L-methionine; AdoHcy, S-adenosyl-L-homocysteine; Hcy, homocysteine; Met, methionine; Sah1, S-adenosyl-L-homocysteine hydrolase; CTT, cystathionine; Sam1, AdoMet synthetase 1; Sam2, AdoMet synthetase 2; Sam4, AdoMet-homocysteine methyltransferase; Mht1, S-methylmethionine–homocysteine methyltransferase; Met6, methionine synthase; Met25, O-acetylhomoserine sulfhydrylase; Str1, cystathionine γ-lyase; Str2, cystathionine γ-synthase; Str3, cystathionine β-lyase; Str4, cystathionine β-synthase; Gsh1, γ-glutamylcysteine synthetase; Gro, glycerol; DHAP, dihydroacetone phosphate; LPA, lysophosphatidic acid; PA, phosphatidic acid; DAG, diacylglycerol; TAG, triacylglycerol; CDP-DAG, CDP-diacylglycerol; Cho, choline; Etn, ethanolamine; CL, cardiolipin; PG, phosphatidylglycerol; PGP, phosphatidylglycerol phosphate; Glc, glucose; Ins, inositol; PI, phosphatidylinositol; PS, phosphatidylserine; PE, phosphatidylethanolamine; PC, phosphatidylcholine; Cho2, phosphatidylethanolamine methyltransferase catalyzing first methylation from PE to PC; Opi3, phospholipid methyltransferase catalyzing two last methylation steps from PE to PC.