SUMMARY PARAGRAPH for SFA1
Sfa1p is a member of the class III alcohol dehydrogenases (EC:188.8.131.524), which are bifunctional enzymes containing both alcohol dehydrogenase and glutathione-dependent formaldehyde dehydrogenase activities (3, 6, 7, 8). The glutathione-dependent formaldehyde dehydrogenase activity of Sfa1p is required for the detoxification of formaldehyde (3), and the alcohol dehydrogenase activity of Sfa1p can catalyze the final reactions in phenylalanine and tryptophan degradation (8). Sfa1p is also able to act as a hydroxymethylfurfural (HMF) reductase and catabolize HMF, a compound formed in the production of certain biofuels (9). Sfa1p has been localized to the cytoplasm (10) and the mitochondria (11), and can act on a variety of substrates, including S-hydroxymethylglutathione, phenylacetaldehyde, indole acetaldehyde, octanol, 10-hydroxydecanoic acid, 12-hydroxydodecanoic acid, and S-nitrosoglutathione (6, 7, 8).
The five ethanol dehydrogenases (Adh1p, Adh2p, Adh3p, Adh4p, and Adh5p) as well as the bifunctional enzyme Sfa1p are also involved in the production of fusel alcohols during fermentation (8). Fusel alcohols are end products of amino acid catabolism (of valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, and tyrosine) via the Ehrlich pathway and contribute to the flavor and aroma of yeast-fermented foods and beverages (12). They may also have physiological roles. For example, exposing cells to isoamyl alcohol, derived from catabolism of leucine, stimulates filamentous growth (13, 14). Similarly, other fusel alcohols also stimulate filamentous growth in S. cerevisiae and biofilm formation in the pathogens Candida albicans and Candida dubliniensis (15, 16, reviewed in 12).
Transcription of SFA1 is controlled by Sko1p, a negative regulator of the Hog1p transcription regulation pathway. SFA1 is induced in sko1 null mutants and in cells overproducing the transcription factor Yap1p (17, 4). Sfa1p expression is also induced by chemicals such as formaldehyde, ethanol and methyl methanesulfonate (3). sfa1 null mutants are viable and display hypersensitivity to formaldehyde (18), whereas overproduction of Sfa1p results in increased resistance to formaldehyde (18, 3).
Sfa1p displays similarity to Adh1p, Adh2p, Adh3p and Adh5p, and to the alcohol dehydrogenases of Escherichia coli, Schizosaccharomyces pombe, Kluyveromyces marxianus, Kluyveromyces lactis, Candida albicans, Candida maltosa, horse, rat, and mouse, as well as human ADH2 and ADH3, which are associated with the development of Parkinson disease (19, 6, 3). Sfa1p also exhibits similarity to the glutathione-dependent formaldehyde dehydrogenase of Arabidopsis (FALDH), which is able to complement the formaldehyde-hypersensitivity defects of sfa1 null mutants (20). Sfa1p is also similar to the glutathione-dependent formaldehyde dehydrogenases of mouse and human (ADH5), which are involved in the catabolism of S-nitrosoglutathione, a type of S-nitrosothiol central to signal transduction and host defense (7).
About glutathione-dependent formaldehyde oxidation
Formaldehyde is formed by oxidative demethylation reactions in many plants and methylotrophic organisms, but Saccharomyces cerevisiae is a nonmethylotrophic yeast and cannot metabolize methanol to formaldehyde. However, S. cerevisiae is exposed to exogenous formaldehyde from plant material or in polluted air and water.
Concentrations of formaldehyde of 1mM or higher are cytostatic or cytotoxic to haploid wild-type cells. Any free formaldehyde in vivo spontaneously reacts with glutathione to form S-hydroxymethylglutathione (20, 2, 21). The level of enzymes involved in the degradation of formaldehyde, such as Sfa1p and Yjl068p, determine the level of formaldehyde toxicity, and cells overproducing Sfa1p are resistant to formaldehyde and null mutants in either sfa1 or yjl068c are hypersensitive to formaldehyde. Sfa1p is induced in response to chemicals such as formaldehyde (FA), ethanol and methyl methanesulphonate, and Yjl068p is also induced in response to chemical stresses (22, 2, 21, 3, 18, 23, 24).
Formate dehydrogenase is encoded by FDH1/YOR388C and FDH2. In some strain backgrounds of S. cerevisiae, FDH2 is encoded by a continuous open reading frame comprised of YPL275W and YPL276W. However, in the systematic sequence of S288C, FDH2 is represented by these two separate open reading frames due to an in frame stop codon (25).
About the medium-chain dehydrogenase/reductase (MDR) family
Medium-chain dehydrogenase/reductases (MDRs), sometimes referred to as long-chain dehydrogenases (26), constitute an ancient and widespread enzyme superfamily with members found in Bacteria, Archaea, and Eukaryota (27, 28). Many MDR members are basic metabolic enzymes acting on alcohols or aldehydes, and thus these enzymes may have roles in detoxifying alcohols and related compounds, protecting against environmental stresses such as osmotic shock, reduced or elevated temperatures, or oxidative stress (27). The family also includes the mammalian zeta-crystallin lens protein, which may protect the lens against oxidative damage and enzymes which produce lignocellulose in plants (27).
MDR enzymes typically have subunits of about 350 aa residues and are two-domain proteins, with a catalytic domain and a second domain for binding to the nicotinamide cofactor, either NAD(H) or NADP(H) (27, 28). They contain 0, 1, or 2 zinc atoms (29). When zinc is present, it is involved in catalysis at the active site.
Based on phylogenetic and sequence analysis, the members of the MDR superfamily can be further divided into more closely related subgroups (27, 28). In families which are widespread from prokaryotes to eukaryotes, some members appear conserved across all species, while others appear to be due to lineage specific duplications. Some subgroups are only found in certain taxa. S. cerevisiae contains fifteen (27) or twenty-one (28) members of the MDR superfamily, listed below. The difference in number is due to six sequences that were included as members of the quinone oxidoreductase family by Riveros-Rosas et al. (28) but not by Nordling et al. (27).
Zinc-containing enzyme groups:
- PDH; "polyol" dehydrogenase family - BDH1, BDH2, SOR1, SOR2, XYL2
- ADH; class III alcohol dehydrogenase family - SFA1
- Y-ADH; "yeast" alcohol dehydrogenase family - ADH1, ADH2, ADH3, ADH5
- CADH; cinnamyl alcohol dehydrogenase family - ADH6, ADH7
Non-zinc-containing enzyme groups:
- NRBP; nuclear receptor binding protein (28) or MRF; mitochondrial respiratory function (27) family - ETR1
- QOR; quinone oxidoreductase family - ZTA1 (27, 28), AST1, AST2, YCR102C, YLR460C, YMR152W, YNL134C (28)
- LTD; leukotriene B4 dehydrogenases - YML131W
- ER; enoyl reductases (28) or ACR; acyl-CoA reductase (27) family - no members in S. cerevisiae
Last updated: 2006-01-24