SFA1/YDL168W Summary Help

Standard Name SFA1 1
Systematic Name YDL168W
Alias ADH5 2
Feature Type ORF, Verified
Description Bifunctional alcohol dehydrogenase and formaldehyde dehydrogenase; formaldehyde dehydrogenase activity is glutathione-dependent; functions in formaldehyde detoxification and formation of long chain and complex alcohols, regulated by Hog1p-Sko1p; protein abundance increases in response to DNA replication stress (2, 3, 4, 5 and see Summary Paragraph)
Name Description Sensitive to FormAldehyde 3
Chromosomal Location
ChrIV:159604 to 160764 | ORF Map | GBrowse
Gbrowse
Gene Ontology Annotations All SFA1 GO evidence and references
  View Computational GO annotations for SFA1
Molecular Function
Manually curated
Biological Process
Manually curated
Cellular Component
High-throughput
Regulators 1 genes
Resources
Pathways
Classical genetics
null
overexpression
Large-scale survey
null
Resources
87 total interaction(s) for 77 unique genes/features.
Physical Interactions
  • Affinity Capture-MS: 10
  • Affinity Capture-RNA: 1
  • PCA: 1
  • Two-hybrid: 1

Genetic Interactions
  • Negative Genetic: 61
  • Phenotypic Enhancement: 6
  • Positive Genetic: 7

Resources
Expression Summary
histogram
Resources
Length (a.a.) 386
Molecular Weight (Da) 41,042
Isoelectric Point (pI) 6.74
Localization
Phosphorylation PhosphoGRID | PhosphoPep Database
Structure
Homologs
sequence information
ChrIV:159604 to 160764 | ORF Map | GBrowse
SGD ORF map
Last Update Coordinates: 2011-02-03 | Sequence: 1996-07-31
Subfeature details
Relative
Coordinates
Chromosomal
Coordinates
Most Recent Updates
Coordinates Sequence
CDS 1..1161 159604..160764 2011-02-03 1996-07-31
Retrieve sequences
Analyze Sequence
S288C only
S288C vs. other species
S288C vs. other strains
Resources
External Links All Associated Seq | E.C. | Entrez Gene | Entrez RefSeq Protein | MIPS | Search all NCBI (Entrez) | UniProtKB
Primary SGDIDS000002327
SUMMARY PARAGRAPH for SFA1

Sfa1p is a member of the class III alcohol dehydrogenases (EC:1.1.1.284), 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 Contact SGD

References cited on this page View Complete Literature Guide for SFA1
1) Mack, M. and Brendel, M.  (1989) Personal Communication, Mortimer Map Edition 10
2) Grey M, et al.  (1996) Overexpression of ADH1 confers hyper-resistance to formaldehyde in Saccharomyces cerevisiae. Curr Genet 29(5):437-40
3) Wehner EP, et al.  (1993) Molecular structure and genetic regulation of SFA, a gene responsible for resistance to formaldehyde in Saccharomyces cerevisiae, and characterization of its protein product. Mol Gen Genet 237(3):351-8
4) Rep M, et al.  (2001) The Saccharomyces cerevisiae Sko1p transcription factor mediates HOG pathway-dependent osmotic regulation of a set of genes encoding enzymes implicated in protection from oxidative damage. Mol Microbiol 40(5):1067-83
5) Tkach JM, et al.  (2012) Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress. Nat Cell Biol 14(9):966-76
6) Fernandez MR, et al.  (1995) Class III alcohol dehydrogenase from Saccharomyces cerevisiae: structural and enzymatic features differ toward the human/mammalian forms in a manner consistent with functional needs in formaldehyde detoxication. FEBS Lett 370(1-2):23-6
7) Liu L, et al.  (2001) A metabolic enzyme for S-nitrosothiol conserved from bacteria to humans. Nature 410(6827):490-4
8) Dickinson JR, et al.  (2003) The catabolism of amino acids to long chain and complex alcohols in Saccharomyces cerevisiae. J Biol Chem 278(10):8028-34
9) Petersson A, et al.  (2006) A 5-hydroxymethyl furfural reducing enzyme encoded by the Saccharomyces cerevisiae ADH6 gene conveys HMF tolerance. Yeast 23(6):455-64
10) Huh WK, et al.  (2003) Global analysis of protein localization in budding yeast. Nature 425(6959):686-91
11) Sickmann A, et al.  (2003) The proteome of Saccharomyces cerevisiae mitochondria. Proc Natl Acad Sci U S A 100(23):13207-12
12) Hazelwood LA, et al.  (2008) The Ehrlich pathway for fusel alcohol production: a century of research on Saccharomyces cerevisiae metabolism. Appl Environ Microbiol 74(8):2259-66
13) Kern K, et al.  (2004) Isoamyl alcohol-induced morphological change in Saccharomyces cerevisiae involves increases in mitochondria and cell wall chitin content. FEMS Yeast Res 5(1):43-9
14) Hauser M, et al.  (2007) A transcriptome analysis of isoamyl alcohol-induced filamentation in yeast reveals a novel role for Gre2p as isovaleraldehyde reductase. FEMS Yeast Res 7(1):84-92
15) Dickinson JR  (1996) 'Fusel' alcohols induce hyphal-like extensions and pseudohyphal formation in yeasts. Microbiology 142 ( Pt 6)():1391-7
16) Lorenz MC, et al.  (2000) Characterization of alcohol-induced filamentous growth in Saccharomyces cerevisiae. Mol Biol Cell 11(1):183-99
17) DeRisi JL, et al.  (1997) Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278(5338):680-6
18) Gompel-Klein P, et al.  (1989) Molecular characterization of the two genes SNQ and SFA that confer hyperresistance to 4-nitroquinoline-N-oxide and formaldehyde in Saccharomyces cerevisiae. Curr Genet 16(2):65-74
19) Ladriere J, et al.  (2000) Kluyveromyces marxianus exhibits an ancestral Saccharomyces cerevisiae genome organization downstream of ADH2. Gene 255(1):83-91
20) Achkor H, et al.  (2003) Enhanced formaldehyde detoxification by overexpression of glutathione-dependent formaldehyde dehydrogenase from Arabidopsis. Plant Physiol 132(4):2248-55
21) Degrassi G, et al.  (1999) Purification and properties of an esterase from the yeast Saccharomyces cerevisiae and identification of the encoding gene. Appl Environ Microbiol 65(8):3470-2
22) Wehner E and Brendel M  (1993) Formaldehyde lacks genotoxicity in formaldehyde-hyperresistant strains of the yeast Saccharomyces cerevisiae. Mutat Res 289(1):91-6
23) Jelinsky SA and Samson LD  (1999) Global response of Saccharomyces cerevisiae to an alkylating agent. Proc Natl Acad Sci U S A 96(4):1486-91
24) Schaus SE, et al.  (2001) Gene transcription analysis of Saccharomyces cerevisiae exposed to neocarzinostatin protein-chromophore complex reveals evidence of DNA damage, a potential mechanism of resistance, and consequences of prolonged exposure. Proc Natl Acad Sci U S A 98(20):11075-80
25) Overkamp KM, et al.  (2002) Functional analysis of structural genes for NAD(+)-dependent formate dehydrogenase in Saccharomyces cerevisiae. Yeast 19(6):509-20
26) Jornvall H, et al.  (1981) Alcohol and polyol dehydrogenases are both divided into two protein types, and structural properties cross-relate the different enzyme activities within each type. Proc Natl Acad Sci U S A 78(7):4226-30
27) Nordling E, et al.  (2002) Medium-chain dehydrogenases/reductases (MDR). Family characterizations including genome comparisons and active site modeling. Eur J Biochem 269(17):4267-76
28) Riveros-Rosas H, et al.  (2003) Diversity, taxonomy and evolution of medium-chain dehydrogenase/reductase superfamily. Eur J Biochem 270(16):3309-34
29) Persson B, et al.  (1999) Bioinformatics in studies of SDR and MDR enzymes. Adv Exp Med Biol 463():373-7