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Physiological Roles of Mycothiol in Detoxification and Tolerance to Multiple Poisonous Chemicals in Corynebacterium Glutamicum

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Physiological Roles of Mycothiol in Detoxification and Tolerance to Multiple Poisonous Chemicals in Corynebacterium Glutamicum Arch Microbiol (2013) 195:419–429 DOI 10.1007/s00203-013-0889-3 ORIGINAL PAPER Physiological roles of mycothiol in detoxification and tolerance to multiple poisonous chemicals in Corynebacterium glutamicum Ying‑Bao Liu · Ming‑Xiu Long · Ya‑Jie Yin · Mei‑Ru Si · Lei Zhang · Zhi‑Qiang Lu · Yao Wang · Xi‑Hui Shen Received: 15 December 2012 / Revised: 31 March 2013 / Accepted: 5 April 2013 / Published online: 25 April 2013 © Springer-Verlag Berlin Heidelberg 2013 Abstract Mycothiol (MSH) plays important roles in withstanding oxidative stress induced by various oxidants maintaining cytosolic redox homeostasis and in adapting in C. glutamicum. This study greatly expanded our current to reactive oxygen species in the high-(G C)-content knowledge on the physiological functions of mycothiol in + Gram-positive Actinobacteria. However, its physiologi- C. glutamicum and could be applied to improve the robust- cal roles are ill defined compared to glutathione, the func- ness of this scientifically and commercially important spe- tional analog of MSH in Gram-negative bacteria and most cies in the future. eukaryotes. In this research, we explored the impact of intracellular MSH on cellular physiology by using MSH- Keywords Corynebacterium glutamicum · Mycothiol · deficient mutants in the model organismCorynebacterium Oxidative stress · Detoxification glutamicum. We found that intracellular MSH contributes significantly to resistance to alkylating agents, glyphosate, ethanol, antibiotics, heavy metals and aromatic com- Introduction pounds. In addition, intracellular MSH is beneficial for Mycothiol (MSH), chemically 1-D-myo-inosityl-2-(N- acetyl-L-cysteinyl)amido-2-deoxy-α-D-glucopyranoside, Communicated by Shuang-Jiang Liu. is the dominant low molecular weight thiol (LMWT) restricted to the high-(G C)-content Gram-positive Act- Ying-Bao Liu and Ming-Xiu Long contributed equally to this work. + inobacteria, a very large and geographically diverse phy- Y.-B. Liu · M.-R. Si · L. Zhang · Y. Wang · X.-H. Shen (*) logenetic clade in the eubacteria, and has been regarded State Key Laboratory of Crop Stress Biology for Arid Areas as a functional equivalent of glutathione found in many and College of Life Sciences, Northwest A&F University, Gram-negative bacteria and most eukaryotes (Jothivasan Yangling 712100, Shaanxi, People’s Republic of China e-mail: [email protected] and Hamilton 2008; Newton et al. 2008). Structurally, mycothiol is an N-acetyl-Cys derivative of the pseudodisac- M.-X. Long charide of myo-inositol and N-glucosamine (Misset et al. College of Animal Science and Technology, Northwest A&F 1997). Mycothiol biosynthetic pathway consists of five University, Yangling 712100, Shaanxi, People’s Republic of China enzymatic steps including a glycosyltransferase (MshA), a phosphatase (MshA2), a deacetylase (MshB), an ATP- Y.-J. Yin dependent ligase (MshC) and an acetyltransferase (MshD) Environmental Microbiology and Ecology Research Center, (Koledin et al. 2002; Newton et al. 2003, 2006; Sareen Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 401122, et al. 2002). Like glutathione, mycothiol plays major roles People’s Republic of China in protecting the cell against oxidative stress and detoxifi- cation of exogenous toxic agents. In mycobacteria where Z.-Q. Lu MSH has been most intensively studied, MSH-deficient College of Plant Protection, Northwest A&F University, Yangling 712100, Shaanxi, mutants exhibit increased sensitivity to oxidative stress, People’s Republic of China alkylating agents and a wide range of antibiotics such as 1 3 420 Arch Microbiol (2013) 195:419–429 erythromycin, vancomycin, azithromycin, penicillin G and industry and bioremediation area for engineering of robust rifampin (Buchmeier and Fahey 2006; Rawat et al. 2002, C. glutamicum strains in the future. 2007). In Streptomyces coelicolor, MSH appears to detox- ify a variety of endogenously generated antibiotics and reactive intermediates by converting them to S-conjugates Materials and methods of mycothiol as evidenced by the isolation of mercapturic acids from fermentation broths (Carney et al. 1997). In Bacterial strains and growth conditions Amycolatopsis methanolica and Rhodococcus erythropolis, mycothiol detoxifies formaldehyde by acting as a cofac- Bacterial strains and plasmids used in this study are listed tor for a formaldehyde dehydrogenase, later identified as in Table 1. C. glutamicum and Escherichia coli strains nitrosomycothiol reductase (Eggeling and Sahm 1985; van were cultured in Luria–Bertani (LB) broth aerobically on Ophem et al. 1992; Vogt et al. 2003). However, although a rotary shaker (180 rpm) or on LB plates at 30 and 37 °C, substantial progress has been made in MSH researches in respectively. For generation of mutants and maintenance the last decade, information about the physiological roles of C. glutamicum, brain–heart broth with 0.5 M sorbitol of MSH is still largely lacking when compared to GSH, medium was used. When needed, antibiotics were used at 1 which greatly hampered the understanding of the protec- the following concentrations: chloramphenicol, 20 μg ml− 1 tion mechanisms of MSH in depth. for E. coli and 10 μg ml− for C. glutamicum; kanamycin, 1 1 For this reason, we intensively investigated the physi- 50 μg ml− for E. coli and 25 μg ml− for C. glutamicum; 1 ological functions of MSH by using Corynebacterium nalidixic acid, 30 μg ml− for C. glutamicum. glutamicum as a model organism. C. glutamicum, a soil bacterium of the actinomycetes family widely used for DNA manipulation the industrial production of amino acids and nucleotides, is also one of the most arsenic-resistant microorganisms General DNA manipulations, transformations and aga- described to date (Ordóñez et al. 2005), and its robust abil- rose gel electrophoresis were carried out by using stand- ity to metabolize aromatic compounds has been reported ard molecular techniques. DNA restriction enzymes, ligase previously (Lee et al. 2010; Shen et al. 2005a, b). Feng and DNA polymerase were used as recommended by the et al. (2006) found that mycothiol-deficient mutants lost manufacturer’s instructions (TaKaRa, Dalian, China). The the ability to assimilate several aromatic compounds such total genomic DNA of C. glutamicum was isolated accord- as gentisate and 3-hydroxybenzoate. This interesting ing to the procedure of Tauch et al. (1995). Plasmid DNA discovery led to the identification of a novel mycothiol- was isolated with the plasmid DNA miniprep spin columns dependent maleylpyruvate isomerase which linked the bio- (TIANGEN, Beijing, China), and DNA fragments were synthesis of mycothiol to gentisate and 3-hydroxybenzoate purified from agarose gels by using the EasyPure Quick degradation. More recently, Ordóñez et al. (2009) identi- Gel Extraction Kit (TransGen Biotech, Beijing, China). fied two novel mycothiol-dependent arsenate reductases C. glutamicum were transformed by electroporation from C. glutamicum, which depend for their function on according to the method of Tauch et al. (2002). DNA mycothiol as well as on mycoredoxin. With MSH biosyn- sequencing and primer synthesis were carried out by Inv- thesis pathway mutants, these authors discovered a clear itrogen (Shanghai, China). Primers used in this study are link between the production of mycothiol and the level listed in Table 1. of arsenate resistance (Ordóñez et al. 2009). Reports on MSH-dependent bioremediation open an exciting new area Genetic disruption and complementation in C. glutamicum of MSH research, implicating that MSH may get involved in many unknown physiological processes which remain The plasmid pK18mobsacBΔcopRS used to construct to be uncovered. ΔcopRS deletion mutant of C. glutamicum RES167 was In this study, by using MSH-deficient mutants, we not generated using the gene SOEing method described by only find that intracellular MSH plays important roles in Horton et al. (1989). In the first round of PCR, the 1110- detoxification of alkylating agents, oxidants, antibiotics bp upstream PCR product and 956-bp downstream PCR and aromatic compounds in C. glutamicum, but also dis- product of copRS were amplified using primer pair cover that MSH has clear physiological roles in resistance DcopRF/DcopRR and DcopSF/DcopSR, respectively. The to glyphosate, ethanol and multiple heavy metals, which resulting PCR products were used as template in the second greatly broaden the scope of mycothiol action. In addition, round of PCR with DcopRF and DcopSR as primers. The our insights into the versatile protective roles of MSH in final PCR product was digested with BamHI/EcoRI and C. glutamicum could be applied to the fermentation ligated into similarly digested pK18mobsacB resulting in 1 3 Arch Microbiol (2013) 195:419–429 421 Table 1 Bacterial strains, plasmids and primers used in this study Strain or plasmid Relevant characteristic(s) Source or reference Strains E.coli JM109 recA1 supE44 endA1 hsdR17 gyrA96 relA1 thi Δ(lac-proAB) Stratagene F′(traD36 proABlacIq lacΔZM15) C. glutamicum RES167 Restriction-deficient mutant of ATCC13032, Δ(cglIM-cglIR-cglIIR) Tauch et al. (2002) RES167ΔmshB mshB deleted in RES167 Feng et al. (2006) RES167ΔmshC mshC deleted in RES167 Feng et al. (2006) RES167ΔmshD mshD deleted in RES167 Feng et al. (2006) RES167ΔcopRS copRS deleted in RES167 This study RES167ΔcopRSΔmshC copRSmshC deleted in RES167 This study RES167ΔcopRSΔmshD copRSmshD deleted in RES167 This study RES167ΔmshC+ RES167ΔmshC containing pXMJ19-mshC This study RES167ΔmshD+
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