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In-depth understanding of molecular mechanisms of aldehyde toxicity to engineer robust Saccharomyces cerevisiae

Abstract

Aldehydes are ubiquitous electrophilic compounds that ferment microorganisms including Saccharomyces cerevisiae encounter during the fermentation processes to produce food, fuels, chemicals, and pharmaceuticals. Aldehydes pose severe toxicity to the growth and metabolism of the S. cerevisiae through a variety of toxic molecular mechanisms, predominantly via damaging macromolecules and hampering the production of targeted compounds. Compounds with aldehyde functional groups are far more toxic to S. cerevisiae than all other functional classes, and toxic potency depends on physicochemical characteristics of aldehydes. The yeast synthetic biology community established a design–build–test–learn framework to develop S. cerevisiae cell factories to valorize the sustainable and renewable biomass, including the lignin-derived substrates. However, thermochemically pretreated biomass-derived substrate streams contain diverse aldehydes (e.g., glycolaldehyde and furfural), and biological conversions routes of lignocellulosic compounds consist of toxic aldehyde intermediates (e.g., formaldehyde and methylglyoxal), and some of the high-value targeted products have aldehyde functional group (e.g., vanillin and benzaldehyde). Numerous studies comprehensively characterized both single and additive effects of aldehyde toxicity via systems biology investigations, and novel molecular approaches have been discovered to overcome the aldehyde toxicity. Based on those novel approaches, researchers successfully developed synthetic yeast cell factories to convert lignocellulosic substrates to valuable products, including aldehyde compounds. In this mini-review, we highlight the salient relationship of physicochemical characteristics and molecular toxicity of aldehydes, the molecular detoxification and macromolecules protection mechanisms of aldehydes, and the advances of engineering robust S. cerevisiae against complex mixtures of aldehyde inhibitors.

Key points

• We reviewed structure–activity relationships of aldehyde toxicity on S. cerevisiae.

• Two-tier protection mechanisms to alleviate aldehyde toxicity are presented.

• We highlighted the strategies to overcome the synergistic toxicity of aldehydes.

Graphical abstract

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References

  • Achkor H, Díaz M, Fernández MR, Biosca JA, Parés X, Martínez MC (2003) Enhanced formaldehyde detoxification by overexpression of glutathione-dependent formaldehyde dehydrogenase from Arabidopsis. Plant Physiol 132(4):2248–2255

    CAS  PubMed  PubMed Central  Google Scholar 

  • Agadjanyan Z, Dmitriev L, Dugin S (2005) A new role of phosphoglucose isomerase. Involvement of the glycolytic enzyme in aldehyde metabolism. Biochemistry (moscow) 70(11):1251–1255

    CAS  Google Scholar 

  • Alriksson B, Horváth IS, Jönsson LJ (2010) Overexpression of Saccharomyces cerevisiae transcription factor and multidrug resistance genes conveys enhanced resistance to lignocellulose-derived fermentation inhibitors. Process Biochem 45(2):264–271

    CAS  Google Scholar 

  • Aranda A, del Olmo M (2003) Response to acetaldehyde stress in the yeast Saccharomyces cerevisiae involves a strain-dependent regulation of several ALD genes and is mediatedby the general stress response pathway. Yeast 20(8):747–759

    CAS  PubMed  Google Scholar 

  • Ask M, Mapelli V, Höck H, Olsson L, Bettiga M (2013) Engineering glutathione biosynthesis of Saccharomyces cerevisiae increases robustness to inhibitors in pretreated lignocellulosic materials. Microb Cell Fact 12(1):87

    PubMed  PubMed Central  Google Scholar 

  • Ayala A, Muñoz MF, Argüelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:1–31

    CAS  Google Scholar 

  • Baert JJ, De Clippeleer J, Hughes PS, De Cooman L, Aerts G (2012) On the origin of free and bound staling aldehydes in beer. J Agric Food Chem 60(46):11449–11472

    CAS  PubMed  Google Scholar 

  • Bakker BM, Overkamp KM, van Maris AJ, Kötter P, Luttik MA, van Dijken JP, Pronk JT (2001) Stoichiometry and compartmentation of NADH metabolism in Saccharomyces cerevisiae. FEMS Microbiol Rev 25(1):15–37

    CAS  PubMed  Google Scholar 

  • Bankapalli K, Saladi S, Awadia SS, Goswami AV, Samaddar M, D’Silva P (2015) Robust glyoxalase activity of Hsp31, a ThiJ/DJ-1/PfpI family member protein, is critical for oxidative stress resistance in Saccharomyces cerevisiae. J Biol Chem 290(44):26491–26507

    CAS  PubMed  PubMed Central  Google Scholar 

  • Binder JB, Raines RT (2010) Fermentable sugars by chemical hydrolysis of biomass. Proc Natl Acad Sci USA 107(10):4516–4521

    CAS  PubMed  Google Scholar 

  • Black BA, Michener WE, Ramirez KJ, Biddy MJ, Knott BC, Jarvis MW, Olstad J, Mante OD, Dayton DC, Beckham GT (2016) Aqueous stream characterization from biomass fast pyrolysis and catalytic fast pyrolysis. ACS Sustainable Chem Eng 4(12):6815–6827

    CAS  Google Scholar 

  • Blair JM, Bavro VN, Ricci V, Modi N, Cacciotto P, Kleinekathӧfer U, Ruggerone P, Vargiu AV, Baylay AJ, Smith HE (2015) AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity. Proc Natl Acad Sci USA 112(11):3511–3516

    CAS  PubMed  Google Scholar 

  • Blank LM, Narancic T, Mampel J, Tiso T, O’Connor K (2020) Biotechnological upcycling of plastic waste and other non-conventional feedstocks in a circular economy. Curr Opin Biotechnol 62:212–219

    CAS  PubMed  Google Scholar 

  • Blount BA, Weenink T, Ellis T (2012) Construction of synthetic regulatory networks in yeast. FEBS Lett 586(15):2112–2121

    CAS  PubMed  Google Scholar 

  • Brodeur G, Yau E, Badal K, Collier J, Ramachandran K, Ramakrishnan S (2011) Chemical and physicochemical pretreatment of lignocellulosic biomass: a review. Enzyme Res 2011:1–17

    Google Scholar 

  • Cao D, Tu M, Xie R, Li J, Wu Y, Adhikari S (2014) Inhibitory activity of carbonyl compounds on alcoholic fermentation by Saccharomyces cerevisiae. J Agric Food Chem 62(4):918–926

    CAS  PubMed  Google Scholar 

  • Carlquist M, Gibson B, Karagul Yuceer Y, Paraskevopoulou A, Sandell M, Angelov AI, Gotcheva V, Angelov AD, Etschmann M, de Billerbeck GM (2015) Process engineering for bioflavour production with metabolically active yeasts—a mini-review. Yeast 32(1):123–143

    CAS  PubMed  Google Scholar 

  • Castro FAV, Mariani D, Panek AD, Eleutherio ECA, Pereira MD (2008) Cytotoxicity mechanism of two naphthoquinones (menadione and plumbagin) in Saccharomyces cerevisiae. PloS one 3(12):e3999

    PubMed  PubMed Central  Google Scholar 

  • Chen B, Ling H, Chang MW (2013) Transporter engineering for improved tolerance against alkane biofuels in Saccharomyces cerevisiae. Biotechnol biofuels 6(1):21

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Li S, Liu L (2014) Engineering redox balance through cofactor systems. Trends Biotechnol 32(6):337–343

    CAS  PubMed  Google Scholar 

  • Conrado RJ, Wu GC, Boock JT, Xu H, Chen SY, Lebar T, Turnšek J, Tomšič N, Avbelj M, Gaber R (2012) DNA-guided assembly of biosynthetic pathways promotes improved catalytic efficiency. Nucleic Acids Res 40(4):1879–1889

    CAS  PubMed  Google Scholar 

  • Cunha JT, Romaní A, Costa CE, Sá-Correia I, Domingues L (2019) Molecular and physiological basis of Saccharomyces cerevisiae tolerance to adverse lignocellulose-based process conditions. Appl Microbiol Biotechnol 103(1):159–175

    CAS  PubMed  Google Scholar 

  • Cunningham RP (1996) DNA repair: how yeast repairs radical damage. Curr Biol 6(10):1230–1233

    CAS  PubMed  Google Scholar 

  • Deponte M (2013) Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta Gen Subj 1830(5):3217–3266

    CAS  Google Scholar 

  • Dingler FA, Patel KJ (2017) Of sizzling steaks and DNA repair. Science 357(6347):130–131

    CAS  PubMed  Google Scholar 

  • Doyle SM, Genest O, Wickner S (2013) Protein rescue from aggregates by powerful molecular chaperone machines. Nat Rev Mol Cell Biol 14(10):617–629

    CAS  PubMed  Google Scholar 

  • Duan M, Selvam K, Wyrick JJ, Mao P (2020) Genome-wide role of Rad26 in promoting transcription-coupled nucleotide excision repair in yeast chromatin. Proc Natl Acad Sci USA 117(31):18608–18616

    CAS  PubMed  Google Scholar 

  • Dunlop MJ, Dossani ZY, Szmidt HL, Chu HC, Lee TS, Keasling JD, Hadi MZ, Mukhopadhyay A (2011) Engineering microbial biofuel tolerance and export using efflux pumps. Mol Syst Biol 7(1):487

    PubMed  PubMed Central  Google Scholar 

  • Dunstan S, Henbest H (1957) 984. Amine oxidation. Part IV. Reactions of tertiary amines with N-bromosuccinimide: the formation of aldehydes and secondary amines. J Chem Soc (Resumed) 4905-4908

  • Ebeler SE, Spaulding RS (1998) Characterization and measurement of aldehydes in wine. In: Waterhouse AL, Ebeler SE (eds) Chemistry of wine flavor. ACS Publications, Washington, DC, pp 166–169

    Google Scholar 

  • Ekins S, Nikolsky Y, Nikolskaya T (2005) Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol Sci 26(4):202–209

    CAS  PubMed  Google Scholar 

  • Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radical Biol Med 11(1):81–128

    CAS  Google Scholar 

  • Estruch F (2000) Stress-controlled transcription factors, stress-induced genes and stress tolerance in budding yeast. FEMS Microbiol Rev 24(4):469–486

    CAS  PubMed  Google Scholar 

  • Fielden J, Ruggiano A, Popović M, Ramadan K (2018) DNA protein crosslink proteolysis repair: from yeast to premature ageing and cancer in humans. DNA Repair 71:198–204

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fisher MA, Boyarskiy S, Yamada MR, Kong N, Bauer S, Tullman-Ercek D (2014) Enhancing tolerance to short-chain alcohols by engineering the Escherichia coli AcrB efflux pump to secrete the non-native substrate n-butanol. ACS Synth Biol 3(1):30–40

    CAS  PubMed  Google Scholar 

  • Fletcher E, Gao K, Mercurio K, Ali M, Baetz K (2019) Yeast chemogenomic screen identifies distinct metabolic pathways required to tolerate exposure to phenolic fermentation inhibitors ferulic acid, 4-hydroxybenzoic acid and coniferyl aldehyde. Metab Eng 52:98–109

    CAS  PubMed  Google Scholar 

  • Ford G, Ellis EM (2002) Characterization of Ypr1p from Saccharomyces cerevisiae as a 2-methylbutyraldehyde reductase. Yeast 19(12):1087–1096

    CAS  PubMed  Google Scholar 

  • Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30(1-2):1–12

    CAS  PubMed  Google Scholar 

  • Franden MA, Jayakody LN, Li W-J, Wagner NJ, Cleveland NS, Michener WE, Hauer B, Blank LM, Wierckx N, Klebensberger J (2018) Engineering Pseudomonas putida KT2440 for efficient ethylene glycol utilization. Metab Eng 48:197–207

    CAS  PubMed  Google Scholar 

  • Franken B, Eggert T, Jaeger KE, Pohl M (2011) Mechanism of acetaldehyde-induced deactivation of microbial lipases. BMC Biochem 12(1):10

    CAS  PubMed  PubMed Central  Google Scholar 

  • Glomb MA, Monnier VM (1995) Mechanism of protein modification by glyoxal and glycolaldehyde, reactive intermediates of the Maillard reaction. J Biol Chem 270(17):10017–10026

    CAS  PubMed  Google Scholar 

  • Gomes RA, Miranda HV, Silva MS, Graça G, Coelho AV, Ferreira AE, Cordeiro C, Freire AP (2006) Yeast protein glycation in vivo by methylglyoxal: molecular modification of glycolytic enzymes and heat shock proteins. FEBS J 273(23):5273–5287

    CAS  PubMed  Google Scholar 

  • Gorsich S, Dien B, Nichols N, Slininger P, Liu Z, Skory C (2006) Tolerance to furfural-induced stress is associated with pentose phosphate pathway genes ZWF1, GND1, RPE1, and TKL1 in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 71(3):339–349

    CAS  PubMed  Google Scholar 

  • Gottardi M, Knudsen JD, Prado L, Oreb M, Branduardi P, Boles E (2017) De novo biosynthesis of trans-cinnamic acid derivatives in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 101(12):4883–4893

    CAS  PubMed  Google Scholar 

  • Gounaris Y (2010) Biotechnology for the production of essential oils, flavours and volatile isolates. A review. Flavour Fragrance J 25(5):367–386

    CAS  Google Scholar 

  • Guéraud F, Atalay M, Bresgen N, Cipak A, Eckl PM, Huc L, Jouanin I, Siems W, Uchida K (2010) Chemistry and biochemistry of lipid peroxidation products. Free Radic Res 44(10):1098–1124

    PubMed  Google Scholar 

  • Hayes JD, McLELLAN LI (1999) Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Radic Res 31(4):273–300

    CAS  PubMed  Google Scholar 

  • Heer D, Heine D, Sauer U (2009) Resistance of Saccharomyces cerevisiae to high concentrations of furfural is based on NADPH-dependent reduction by at least two oxireductases. Appl Environ Microbiol 75(24):7631–7638

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67(1):425–479

    CAS  PubMed  Google Scholar 

  • Hong K-K, Nielsen J (2012) Metabolic engineering of Saccharomyces cerevisiae: a key cell factory platform for future biorefineries. Cell Mol Life Sci 69(16):2671–2690

    CAS  PubMed  Google Scholar 

  • Hoon S, Gebbia M, Costanzo M, Davis RW, Giaever G, Nislow C (2011) A global perspective of the genetic basis for carbonyl stress resistance. G3: Genes Genom Genet 1(3):219–231

    CAS  Google Scholar 

  • Ishii J, Yoshimura K, Hasunuma T, Kondo A (2013) Reduction of furan derivatives by overexpressing NADH-dependent Adh1 improves ethanol fermentation using xylose as sole carbon source with Saccharomyces cerevisiae harboring XR–XDH pathway. Appl Microbiol Biotechnol 97(6):2597–2607

    CAS  PubMed  Google Scholar 

  • Iwaki A, Ohnuki S, Suga Y, Izawa S, Ohya Y (2013) Vanillin inhibits translation and induces messenger ribonucleoprotein (mRNP) granule formation in Saccharomyces cerevisiae: application and validation of high-content, image-based profiling. PLoS One 8(4):e61748

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jayakody LN, Ferdouse J, Hayashi N, Kitagaki H (2016a) Identification and detoxification of glycolaldehyde, an unattended bioethanol fermentation inhibitor. Crit Rev Biotechnol 1–13

  • Jayakody LN, Ferdouse J, Hayashi N, Kitagaki H (2017) Identification and detoxification of glycolaldehyde, an unattended bioethanol fermentation inhibitor. Crit Rev Biotechnol 37(2):177–189

    CAS  PubMed  Google Scholar 

  • Jayakody LN, Hayashi N, Kitagaki H (2013a) Molecular mechanisms for detoxification of major aldehyde inhibitors for production of bioethanol by Saccharomyces cerevisiae from hot-compressed water-treated lignocellulose. Materials and processes for energy: communicating current research and technological developments Badajoz, Spain, Formatex Research Center 302–311

  • Jayakody LN, Horie K, Hayashi N, Kitagaki H (2013b) Engineering redox cofactor utilization for detoxification of glycolaldehyde, a key inhibitor of bioethanol production, in yeast Saccharomyces cerevisiae. Appl Microbiol Biotechnol 97(14):6589–6600

    CAS  PubMed  Google Scholar 

  • Jayakody LN, Johnson CW, Whitham JM, Giannone RJ, Black BA, Cleveland NS, Klingeman DM, Michener WE, Olstad JL, Vardon DR (2018a) Thermochemical wastewater valorization via enhanced microbial toxicity tolerance. Energy Environ Sci 11(6):1625–1638

    CAS  Google Scholar 

  • Jayakody LN, Kadowaki M, Tsuge K, Horie K, Suzuki A, Hayashi N, Kitagaki H (2015) SUMO expression shortens the lag phase of Saccharomyces cerevisiae yeast growth caused by complex interactive effects of major mixed fermentation inhibitors found in hot-compressed water-treated lignocellulosic hydrolysate. Appl Microbiol Biotechnol 99(1):501–515

    CAS  PubMed  Google Scholar 

  • Jayakody LN, Lane S, Kim H, Jin Y-S (2016b) Mitigating health risks associated with alcoholic beverages through metabolic engineering. Curr Opin Biotechnol 37:173–181

    CAS  PubMed  Google Scholar 

  • Jayakody LN, Turner TL, Yun EJ, Kong II, Liu J-J, Jin Y-S (2018b) Expression of Gre2p improves tolerance of engineered xylose-fermenting Saccharomyces cerevisiae to glycolaldehyde under xylose metabolism. Appl Microbiol Biotechnol 102(18):8121–8133

    CAS  PubMed  Google Scholar 

  • Jönsson LJ, Martín C (2016) Pretreatment of lignocellulose: formation of inhibitory by-products and strategies for minimizing their effects. Bioresour Technol 199:103–112

    PubMed  Google Scholar 

  • Jungwirth H, Wendler F, Platzer B, Bergler H, Högenauer G (2000) Diazaborine resistance in yeast involves the efflux pumps Ycf1p and Flr1p and is enhanced by a gain-of-function allele of gene YAP1. Eur J Biochem 267(15):4809–4816

    CAS  PubMed  Google Scholar 

  • Kalinina E, Chernov N, Novichkova M (2014) Role of glutathione, glutathione transferase, and glutaredoxin in regulation of redox-dependent processes. Biochemistry (Moscow) 79(13):1562–1583

    CAS  Google Scholar 

  • Kim D, Hahn J-S (2013) Roles of the Yap1 transcription factor and antioxidants in Saccharomyces cerevisiae's tolerance to furfural and 5-hydroxymethylfurfural, which function as thiol-reactive electrophiles generating oxidative stress. Appl Environ Microbiol 79(16):5069–5077

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim I-K, Roldão A, Siewers V, Nielsen J (2012) A systems-level approach for metabolic engineering of yeast cell factories. FEMS Yeast Res 12(2):228–248

    CAS  PubMed  Google Scholar 

  • Kim S-K, Jin Y-S, Choi I-G, Park Y-C, Seo J-H (2015) Enhanced tolerance of Saccharomyces cerevisiae to multiple lignocellulose-derived inhibitors through modulation of spermidine contents. Metab Eng 29:46–55

    CAS  PubMed  Google Scholar 

  • Kim SR, Skerker JM, Kang W, Lesmana A, Wei N, Arkin AP, Jin Y-S (2013) Rational and evolutionary engineering approaches uncover a small set of genetic changes efficient for rapid xylose fermentation in Saccharomyces cerevisiae. PloS one 8(2):e57048

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kitson TM (1985) High concentrations of aldehydes slow the reaction of cytoplasmic aldehyde dehydrogenase with thiol-group modifiers. Biochem J 228(3):765–767

    CAS  PubMed  PubMed Central  Google Scholar 

  • Klass DL (1998) Biomass for renewable energy, fuels, and chemicals. Elsevier, Amsterdam

    Google Scholar 

  • Klinke HB, Thomsen A, Ahring BK (2004) Inhibition of ethanol-producing yeast and bacteria by degradation products produced during pre-treatment of biomass. Appl Microbiol Biotechnol 66(1):10–26

    CAS  PubMed  Google Scholar 

  • Knott HM, Brown BE, Davies MJ, Dean RT (2003) Glycation and glycoxidation of low-density lipoproteins by glucose and low-molecular mass aldehydes. Eur J Biochem 270(17):3572–3582

    CAS  PubMed  Google Scholar 

  • Kotopka BJ, Smolke CD (2020) Model-driven generation of artificial yeast promoters. Nature Commun 11(1):1–13

    Google Scholar 

  • Krivoruchko A, Nielsen J (2015) Production of natural products through metabolic engineering of Saccharomyces cerevisiae. Curr Opin Biotechnol 35:7–15

    CAS  PubMed  Google Scholar 

  • Kumar P, Barrett DM, Delwiche MJ, Stroeve P (2009) Methods for pretreatment of lignocellulosic biomass for efficient hydrolysis and biofuel production. Ind Eng Chem Res 48(8):3713–3729

    CAS  Google Scholar 

  • Kunjapur AM, Prather KL (2015) Microbial engineering for aldehyde synthesis. Appl Environ Microbiol 81(6):1892–1901

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuykendall JR, Bogdanffy MS (1994) Formation and stability of acetaldehyde-induced crosslinks between poly-lysine and poly-deoxyguanosine. Mutat Res 311(1):49–56

    CAS  PubMed  Google Scholar 

  • Kwak S, Jin Y-S (2017) Production of fuels and chemicals from xylose by engineered Saccharomyces cerevisiae: a review and perspective. Microbial Cell Fact 16(1):82

    Google Scholar 

  • Laadan B, Wallace-Salinas V, Carlsson ÅJ, Almeida JR, Rådström P, Gorwa-Grauslund MF (2014) Furaldehyde substrate specificity and kinetics of Saccharomyces cerevisiae alcohol dehydrogenase 1 variants. Microb Cell Fact 13(1):112

    PubMed  PubMed Central  Google Scholar 

  • Larroy C, Parés X, Biosca JA (2002) Characterization of a Saccharomyces cerevisiae NADP (H)-dependent alcohol dehydrogenase (ADHVII), a member of the cinnamyl alcohol dehydrogenase family. Eur J Biochem 269(22):5738–5745

    CAS  PubMed  Google Scholar 

  • Lee S-M, Jellison T, Alper HS (2014) Systematic and evolutionary engineering of a xylose isomerase-based pathway in Saccharomyces cerevisiae for efficient conversion yields. Biotechnol Biofuels 7(1):122

    PubMed  PubMed Central  Google Scholar 

  • Li Z-S, Szczypka M, Lu Y-P, Thiele DJ, Rea PA (1996) The yeast cadmium factor protein (YCF1) is a vacuolar glutathione S-conjugate pump. J Biol Chem 271(11):6509–6517

    CAS  PubMed  Google Scholar 

  • Liang Z, Wang X, Bao X, Wei T, Hou J, Liu W, Shen Y (2020) Newly identified genes contribute to vanillin tolerance in Saccharomyces cerevisiae. Microb Biotechnol. https://doi.org/10.1111/1751-7915.13643

  • Ling H, Chen B, Kang A, Lee J-M, Chang MW (2013) Transcriptome response to alkane biofuels in Saccharomyces cerevisiae: identification of efflux pumps involved in alkane tolerance. Biotechnol Biofuels 6(1):95

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ling H, Teo W, Chen B, Leong SSJ, Chang MW (2014) Microbial tolerance engineering toward biochemical production: from lignocellulose to products. Curr Opin Biotechnol 29:99–106

    CAS  PubMed  Google Scholar 

  • Liu C-G, Li K, Li K-Y, Sakdaronnarong C, Mehmood MA, Zhao X-Q, Bai F-W (2020) Intracellular redox perturbation in Saccharomyces cerevisiae improved furfural tolerance and enhanced cellulosic bioethanol production. Front Bioeng Biotechnol 8:615

    PubMed  PubMed Central  Google Scholar 

  • Liu ZL (2011) Molecular mechanisms of yeast tolerance and in situ detoxification of lignocellulose hydrolysates. Appl Microbiol Biotechnol 90(3):809–825

    CAS  PubMed  Google Scholar 

  • Liu ZL (2018) Understanding the tolerance of the industrial yeast Saccharomyces cerevisiae against a major class of toxic aldehyde compounds. Appl Microbiol Biotechnol 102(13):5369–5390

    CAS  PubMed  Google Scholar 

  • LoPachin RM, Gavin T (2014) Molecular mechanisms of aldehyde toxicity: a chemical perspective. Chem Res Toxicol 27(7):1081–1091

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lü X, Saka S (2012) New insights on monosaccharides’ isomerization, dehydration and fragmentation in hot-compressed water. J Supercrit Fluids 61:146–156

    Google Scholar 

  • Luo P, Zhang Y, Suo Y, Liao Z, Ma Y, Fu H, Wang J (2018) The global regulator IrrE from Deinococcus radiodurans enhances the furfural tolerance of Saccharomyces cerevisiae. Biochem Eng J 136:69–77

    CAS  Google Scholar 

  • Matsufuji Y, Yamamoto K, Yamauchi K, Mitsunaga T, Hayakawa T, Nakagawa T (2013) Novel physiological roles for glutathione in sequestering acetaldehyde to confer acetaldehyde tolerance in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 97(1):297–303

    CAS  PubMed  Google Scholar 

  • Moon J, Liu ZL (2012) Engineered NADH-dependent GRE2 from Saccharomyces cerevisiae by directed enzyme evolution enhances HMF reduction using additional cofactor NADPH. Enzyme Microb Technol 50(2):115–120

    CAS  PubMed  Google Scholar 

  • Moradas-Ferreira P, Costa V, Piper P, Mager W (1996) The molecular defences against reactive oxygen species in yeast. Mol Microbiol 19(4):651–658

    CAS  PubMed  Google Scholar 

  • Morgan PE, Dean RT, Davies MJ (2002) Inactivation of cellular enzymes by carbonyls and protein-bound glycation/glycoxidation products. Arch Biochem Biophys 403(2):259–269

    CAS  PubMed  Google Scholar 

  • Natkańska U, Skoneczna A, Sieńko M, Skoneczny M (2017) The budding yeast orthologue of Parkinson’s disease-associated DJ-1 is a multi-stress response protein protecting cells against toxic glycolytic products. Biochim Biophys Acta Mol Cell Res 1864(1):39–50

    PubMed  Google Scholar 

  • Netzeva TI, Schultz TW (2005) QSARs for the aquatic toxicity of aromatic aldehydes from Tetrahymena data. Chemosphere 61(11):1632–1643

    CAS  PubMed  Google Scholar 

  • Nevoigt E (2008) Progress in metabolic engineering of Saccharomyces cerevisiae. Microbiol Mol Biol Rev 72(3):379–412

    CAS  PubMed  PubMed Central  Google Scholar 

  • Noguchi C, Grothusen G, Anandarajan V, Martinez-Lage Garcia M, Terlecky D, Corzo K, Tanaka K, Nakagawa H, Noguchi E (2017) Genetic controls of DNA damage avoidance in response to acetaldehyde in fission yeast. Cell Cycle 16(1):45–58

    CAS  PubMed  Google Scholar 

  • Nomi Y, Aizawa H, Kurata T, Shindo K, Nguyen CV (2009) Glutathione reacts with glyoxal at the N-terminal. Biosci Biotechnol Biochem 73(11):2408–2411

    CAS  PubMed  Google Scholar 

  • Nykänen L (1986) Formation and occurrence of flavor compounds in wine and distilled alcoholic beverages. Am J Enol Vitic 37(1):84–96

    Google Scholar 

  • O’Brien PJ, Siraki AG, Shangari N (2005) Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health. Crit Rev Toxicol 35(7):609–662

    PubMed  Google Scholar 

  • Oh EJ, Skerker JM, Kim SR, Wei N, Turner TL, Maurer MJ, Arkin AP, Jin Y-S (2016) Gene amplification on demand accelerates cellobiose utilization in engineered Saccharomyces cerevisiae. Appl Environ Microbiol 82(12):3631–3639

    CAS  PubMed  PubMed Central  Google Scholar 

  • Palmqvist E, Hahn-Hägerdal B (2000) Fermentation of lignocellulosic hydrolysates. II: inhibitors and mechanisms of inhibition. Bioresour Technol 74(1):25–33

    CAS  Google Scholar 

  • Payet L-A, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F (2016) Mechanistic details of early steps in coenzyme Q biosynthesis pathway in yeast. Cell Chem Biol 23(10):1241–1250

    CAS  PubMed  Google Scholar 

  • Perrone GG, Tan S-X, Dawes IW (2008) Reactive oxygen species and yeast apoptosis. Biochim Biophys Acta Mol Cell Res 1783(7):1354–1368

    CAS  Google Scholar 

  • Pichler H, Emmerstorfer-Augustin A (2018) Modification of membrane lipid compositions in single-celled organisms—From basics to applications. Methods 147:50–65

    CAS  PubMed  Google Scholar 

  • Pizzimenti S, Ciamporcero ES, Daga M, Pettazzoni P, Arcaro A, Cetrangolo G, Minelli R, Dianzani C, Lepore A, Gentile F (2013) Interaction of aldehydes derived from lipid peroxidation and membrane proteins. Front Physiol 4:242

    PubMed  PubMed Central  Google Scholar 

  • Portnoy VA, Bezdan D, Zengler K (2011) Adaptive laboratory evolution—harnessing the power of biology for metabolic engineering. Curr Opin Biotechnol 22(4):590–594

    CAS  PubMed  Google Scholar 

  • Praefcke GJ, Hofmann K, Dohmen RJ (2012) SUMO playing tag with ubiquitin. Trends Biochem Sci 37(1):23–31

    CAS  PubMed  Google Scholar 

  • Pyne ME, Narcross L, Melgar M, Kevvai K, Mookerjee S, Leite GB, Martin VJ (2018) An engineered Aro1 protein degradation approach for increased cis, cis-muconic acid biosynthesis in Saccharomyces cerevisiae. Appl Environ Microbiol 84(17)

  • Querol A, Fleet GH (2006) Yeasts in food and beverages. Springer, Berlin

    Google Scholar 

  • Ramana KV, Bhatnagar A, Srivastava S, Yadav UC, Awasthi S, Awasthi YC, Srivastava SK (2006) Mitogenic responses of vascular smooth muscle cells to lipid peroxidation-derived aldehyde 4-hydroxy-trans-2-nonenal (HNE) role of aldose reductase-catalyzed reduction of the HNE-glutathione conjugates in regulating cell growth. J Biol Chem 281(26):17652–17660

    CAS  PubMed  Google Scholar 

  • Raner GM, Chiang EW, Vaz AD, Coon MJ (1997) Mechanism-based inactivation of cytochrome P450 2B4 by aldehydes: relationship to aldehyde deformylation via a peroxyhemiacetal intermediate. Biochemistry 36(16):4895–4902

    CAS  PubMed  Google Scholar 

  • Richarme G, Liu C, Mihoub M, Abdallah J, Leger T, Joly N, Liebart J-C, Jurkunas UV, Nadal M, Bouloc P (2017) Guanine glycation repair by DJ-1/Park7 and its bacterial homologs. Science 357(6347):208–211

    CAS  PubMed  Google Scholar 

  • Rigoulet M, Aguilaniu H, Avéret N, Bunoust O, Camougrand N, Grandier-Vazeille X, Larsson C, Pahlman I-L, Manon S, Gustafsson L (2004) Organization and regulation of the cytosolic NADH metabolism in the yeast Saccharomyces cerevisiae. Mol Cell Biochem 256(1-2):73–81

    PubMed  Google Scholar 

  • Roca A, Rodríguez-Herva JJ, Duque E, Ramos JL (2008) Physiological responses of Pseudomonas putida to formaldehyde during detoxification. Microb Biotechnol 1(2):158–169

    CAS  PubMed  Google Scholar 

  • Runguphan W, Keasling JD (2014) Metabolic engineering of Saccharomyces cerevisiae for production of fatty acid-derived biofuels and chemicals. Metab Eng 21:103–113

    CAS  PubMed  Google Scholar 

  • Said MR, Begley TJ, Oppenheim AV, Lauffenburger DA, Samson LD (2004) Global network analysis of phenotypic effects: protein networks and toxicity modulation in Saccharomyces cerevisiae. Proc Natl Acad Sci USA 101(52):18006–18011

    CAS  PubMed  Google Scholar 

  • Salvachúa D, Johnson CW, Singer CA, Rohrer H, Peterson DJ, Black BA, Knapp A, Beckham GT (2018) Bioprocess development for muconic acid production from aromatic compounds and lignin. Green Chem 20(21):5007–5019

    Google Scholar 

  • Sawada K, Sato T, Hamajima H, Jayakody LN, Hirata M, Yamashiro M, Tajima M, Mitsutake S, Nagao K, Tsuge K (2015) Glucosylceramide contained in koji mold-cultured cereal confers membrane and flavor modification and stress tolerance to Saccharomyces cerevisiae during coculture fermentation. Appl Environ Microbiol 81(11):3688–3698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Serbyn N, Bagdiul I, Michel AH, Suhandynata RT, Zhou H, Kornmann B, Stutz F (2020) SUMO orchestrates multiple alternative DNA-protein crosslink repair pathways. bioRxiv. https://doi.org/10.1101/2020.06.08.140079

  • Skerker JM, Leon D, Price MN, Mar JS, Tarjan DR, Wetmore KM, Deutschbauer AM, Baumohl JK, Bauer S, Ibánez AB (2013) Dissecting a complex chemical stress: chemogenomic profiling of plant hydrolysates. Mol Syst Biol 9(1):674

    PubMed  PubMed Central  Google Scholar 

  • Smit BA, Engels WJ, Smit G (2009) Branched chain aldehydes: production and breakdown pathways and relevance for flavour in foods. Appl Microbiol Biotechnol 81(6):987–999

    CAS  PubMed  PubMed Central  Google Scholar 

  • Soares EV, Soares HM (2012) Bioremediation of industrial effluents containing heavy metals using brewing cells of Saccharomyces cerevisiae as a green technology: a review. Environ Sci Pollut Res 19(4):1066–1083

    Google Scholar 

  • Sorek N, Yeats TH, Szemenyei H, Youngs H, Somerville CR (2014) The implications of lignocellulosic biomass chemical composition for the production of advanced biofuels. Bioscience 64(3):192–201

    Google Scholar 

  • Sousa BC, Ashman J, Spickett CM, Pitt AR (2018) Effect of short-chain aldehydes on the enzymatic activity of pyruvate kinase. Free Radical Biol Med 120:S32

    Google Scholar 

  • Starace AK, Black BA, Lee DD, Palmiotti EC, Orton KA, Michener WE, ten Dam J, Watson MJ, Beckham GT, Magrini KA (2017) Characterization and catalytic upgrading of aqueous stream carbon from catalytic fast pyrolysis of biomass. ACS Sustain Chem Eng 5(12):11761–11769

    CAS  Google Scholar 

  • Stone MP, Cho Y-J, Huang H, Kim H-Y, Kozekov ID, Kozekova A, Wang H, Minko IG, Lloyd RS, Harris TM (2008) Interstrand DNA cross-links induced by α, β-unsaturated aldehydes derived from lipid peroxidation and environmental sources. Acc Chem Res 41(7):793–804

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tan Z, Yoon JM, Nielsen DR, Shanks JV, Jarboe LR (2016) Membrane engineering via trans unsaturated fatty acids production improves Escherichia coli robustness and production of biorenewables. Metab Eng 35:105–113

    CAS  PubMed  Google Scholar 

  • Toropov A, Benfenati E (2004) QSAR modelling of aldehyde toxicity by means of optimisation of correlation weights of nearest neighbouring codes. J Mol Struct 676(1-3):165–169

    CAS  Google Scholar 

  • Trotter EW, Collinson EJ, Dawes IW, Grant CM (2006) Old yellow enzymes protect against acrolein toxicity in the yeast Saccharomyces cerevisiae. App Environ Microbiol 72(7):4885–4892

    CAS  Google Scholar 

  • Uemura H (2012) Synthesis and production of unsaturated and polyunsaturated fatty acids in yeast: current state and perspectives. Appl Microbiol Biotechnol 95(1):1–12

    CAS  PubMed  Google Scholar 

  • Unrean P, Gätgens J, Klein B, Noack S, Champreda V (2018) Elucidating cellular mechanisms of Saccharomyces cerevisiae tolerant to combined lignocellulosic-derived inhibitors using high-throughput phenotyping and multiomics analyses. FEMS Yeast Res 18(8):foy106

    CAS  Google Scholar 

  • van der Pol EC, Bakker RR, Baets P, Eggink G (2014) By-products resulting from lignocellulose pretreatment and their inhibitory effect on fermentations for (bio) chemicals and fuels. Appl Microbiol Biotechnol 98(23):9579–9593

    PubMed  Google Scholar 

  • van Iersel ML, Ploemen J-PH, Bello ML, Federici G, van Bladeren PJ (1997) Interactions of α, β-unsaturated aldehydes and ketones with human glutathione S-transferase P1-1. Chem Biol Interact 108(1):67–78

    PubMed  Google Scholar 

  • Van Uden N (1985) Ethanol toxicity and ethanol tolerance in yeasts. Annual reports on fermentation processes. vol 8. Elsevier, pp 11–58

  • Vander Jagt DL, Hunsaker LA, Vander Jagt TJ, Gomez MS, Gonzales DM, Deck LM, Royer RE (1997) Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes. Biochem Pharmacol 53(8):1133–1140

    CAS  PubMed  Google Scholar 

  • Voulgaridou G-P, Anestopoulos I, Franco R, Panayiotidis MI, Pappa A (2011) DNA damage induced by endogenous aldehydes: current state of knowledge. Mutat Res 711(1-2):13–27

    CAS  PubMed  Google Scholar 

  • Wang G, Huang M, Nielsen J (2017) Exploring the potential of Saccharomyces cerevisiae for biopharmaceutical protein production. Curr Opin Biotechnol 48:77–84

    PubMed  Google Scholar 

  • Wang H, Li Q, Kuang X, Xiao D, Han X, Hu X, Li X, Ma M (2018) Functions of aldehyde reductases from Saccharomyces cerevisiae in detoxification of aldehyde inhibitors and their biotechnological applications. Appl Microbiol Biotechnol 102(24):10439–10456

    CAS  PubMed  Google Scholar 

  • Wang H, Li Q, Zhang Z, Zhou C, Ayepa E, Abrha GT, Han X, Hu X, Yu X, Xiang Q (2019) YKL107W from Saccharomyces cerevisiae encodes a novel aldehyde reductase for detoxification of acetaldehyde, glycolaldehyde, and furfural. Appl Microbiol Biotechnol 103(14):5699–5713

    CAS  PubMed  Google Scholar 

  • Wang Z, Gao C, Wang Q, Liang Q, Qi Q (2012) Production of pyruvate in Saccharomyces cerevisiae through adaptive evolution and rational cofactor metabolic engineering. Biochem Eng J 67:126–131

    CAS  Google Scholar 

  • Wanner P, Tressl R (1998) Purification and characterization of two enone reductases from Saccharomyces cerevisiae. Eur J Biochem 255(1):271–278

    CAS  PubMed  Google Scholar 

  • Wei N, Quarterman J, Kim SR, Cate JH, Jin Y-S (2013) Enhanced biofuel production through coupled acetic acid and xylose consumption by engineered yeast. Nature Commun 4(1):1–8

    Google Scholar 

  • White WH, Skatrud PL, Xue Z, Toyn JH (2003) Specialization of function among aldehyde dehydrogenases: the ALD2 and ALD3 genes are required for β-alanine biosynthesis in Saccharomyces cerevisiae. Genetics 163(1):69–77

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wonisch W, Kohlwein SD, Schaur J, Tatzber F, Guttenberger H, Zarkovic N, Winkler R, Esterbauer H (1998) Treatment of the budding yeast Saccharomyces cerevisiae with the lipid peroxidation product 4-HNE provokes a temporary cell cycle arrest in G1 phase. Free Radical Biol Med 25(6):682–687

    CAS  Google Scholar 

  • Wonisch W, Schaur RJ, Bilinski T, Esterbauer H (1995) Assessment of growth inhibition by aldehydic lipid peroxidation products and related aldehydes by Saccharomyces cerevisiae. Cell Bioche Funct 13(2):91–98

    CAS  Google Scholar 

  • Xia P, Turner T, Jayakody L (2016) The role of GroE chaperonins in developing biocatalysts for biofuel and chemical production. Enz Eng 5(153):2

    Google Scholar 

  • Xie M-Z, Shoulkamy MI, Salem AM, Oba S, Goda M, Nakano T, Ide H (2016) Aldehydes with high and low toxicities inactivate cells by damaging distinct cellular targets. Mutat Res 786:41–51

    CAS  PubMed  Google Scholar 

  • Yaguchi A, Spagnuolo M, Blenner M (2018) Engineering yeast for utilization of alternative feedstocks. Curr Opin Biotechnol 53:122–129

    CAS  PubMed  Google Scholar 

  • Yasokawa D, Murata S, Iwahashi Y, Kitagawa E, Nakagawa R, Hashido T, Iwahashi H (2010) Toxicity of methanol and formaldehyde towards Saccharomyces cerevisiae as assessed by DNA microarray analysis. Appl Biochem Biotechnol 160(6):1685–1698

    CAS  PubMed  Google Scholar 

  • Zhang N, Cao L (2017) Starvation signals in yeast are integrated to coordinate metabolic reprogramming and stress response to ensure longevity. Curr Genet 63(5):839–843

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

LNJ acknowledges new faculty startup funding from the Office of the Vice-Chancellor for Research and the Fermentation Science Institute, Southern Illinois University Carbondale. YSJ acknowledges the funding from the DOE Center for Advanced Bioenergy and Bioproducts Innovation (US Department of Energy, Office of Science, Office of Biological and Environmental Research under Award Number DE-SC0018420). Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the US Department of Energy. The authors thank Christine Atkinson for proofreading this manuscript.

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LNJ and YSJ outlined the manuscript, surveyed the literature, and drafted the article. Both authors read and approved the final version of the manuscript prior to its submission.

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Correspondence to Lahiru N. Jayakody.

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Jayakody, L.N., Jin, YS. In-depth understanding of molecular mechanisms of aldehyde toxicity to engineer robust Saccharomyces cerevisiae. Appl Microbiol Biotechnol 105, 2675–2692 (2021). https://doi.org/10.1007/s00253-021-11213-1

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Keywords

  • S. cerevisiae
  • Aldehydes
  • Toxicity
  • Detoxification
  • Lignocellulose