The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus

Imber, Marcel; Loi, Vu Van; Reznikov, Sylvia; Fritsch, Verena Nadin; Pietrzyk‐Brzezinska, Agnieszka J.; Prehn, Janek; Hamilton, Chris J.; Wahl, Markus C.; Bronowska, Agnieszka K.; Antelmann, Haike

doi:10.1016/j.redox.2018.02.001

Cited by 37 publications

(31 citation statements)

References 75 publications

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“…In addition, the targets for S-thioallylations under allicin stress overlap with those proteins S-bacillithiolated under HOCl stress in B. subtilis and S. aureus. These data support that garlic compounds target mostly redox-sensitive active sites [19,27,30,31,35,70,71]. The conserved S-thiolated proteins by HOCl and garlic disulfides are mainly metabolic enzymes, such as MetE, YxjG, GuaB, AldA, PpaC, and SerA, that are most likely redox-regulated and protected by S-thioallylation at their active site Cys residues [31].…”

Section: Discussionsupporting

confidence: 62%

The Disulfide Stress Response and Protein S-thioallylation Caused by Allicin and Diallyl Polysulfanes in Bacillus subtilis as Revealed by Transcriptomics and Proteomics

et al. 2019

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Garlic plants (Allium sativum L.) produce antimicrobial compounds, such as diallyl thiosulfinate (allicin) and diallyl polysulfanes. Here, we investigated the transcriptome and protein S-thioallylomes under allicin and diallyl tetrasulfane (DAS4) exposure in the Gram-positive bacterium Bacillus subtilis. Allicin and DAS4 caused a similar thiol-specific oxidative stress response, protein and DNA damage as revealed by the induction of the OhrR, PerR, Spx, YodB, CatR, HypR, AdhR, HxlR, LexA, CymR, CtsR, and HrcA regulons in the transcriptome. At the proteome level, we identified, in total, 108 S-thioallylated proteins under allicin and/or DAS4 stress. The S-thioallylome includes enzymes involved in the biosynthesis of surfactin (SrfAA, SrfAB), amino acids (SerA, MetE, YxjG, YitJ, CysJ, GlnA, YwaA), nucleotides (PurB, PurC, PyrAB, GuaB), translation factors (EF-Tu, EF-Ts, EF-G), antioxidant enzymes (AhpC, MsrB), as well as redox-sensitive MarR/OhrR and DUF24-family regulators (OhrR, HypR, YodB, CatR). Growth phenotype analysis revealed that the low molecular weight thiol bacillithiol, as well as the OhrR, Spx, and HypR regulons, confer protection against allicin and DAS4 stress. Altogether, we show here that allicin and DAS4 cause a strong oxidative, disulfide and sulfur stress response in the transcriptome and widespread S-thioallylation of redox-sensitive proteins in B. subtilis. The results further reveal that allicin and polysulfanes have similar modes of actions and thiol-reactivities and modify a similar set of redox-sensitive proteins by S-thioallylation.

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Section: Discussionsupporting

confidence: 62%

The Disulfide Stress Response and Protein S-thioallylation Caused by Allicin and Diallyl Polysulfanes in Bacillus subtilis as Revealed by Transcriptomics and Proteomics

et al. 2019

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“…GapDH and AldA displayed both 29% increased oxidation under HOCl stress as revealed by the OxICAT approach in vivo [18] , [77] . Treatment of AldA with H 2 O 2 in the presence of BSH resulted in reversible S -bacillithiolation and loss of activity, which could be restored upon DTT reduction [77] . The purified AldA enzyme showed a broad substrate spectrum, catalyzing the oxidation of various aldehydes, including formaldehyde, methylglyoxal, acetaldehyde and glycolaldehyde.…”

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 89%

“…The aldehyde dehydrogenase AldA was identified as another target for S -bacillithiolation under HOCl stress in S. aureus ( Fig. 8 C ) [77] . Aldehyde dehydrogenases (ALDHs) catalyze the NAD + -dependent oxidation of aldehydes to their carboxylic acids in four steps ( Fig.…”

Section: Biosynthesis and Functions Of Mycothiol And Bacillithiol In mentioning

confidence: 99%

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Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

2019

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Low molecular weight (LMW) thiols play an important role as thiol-cofactors for many enzymes and are crucial to maintain the reduced state of the cytoplasm. Most Gram-negative bacteria utilize glutathione (GSH) as major LMW thiol. However, in Gram-positive Actinomycetes and Firmicutes alternative LMW thiols, such as mycothiol (MSH) and bacillithiol (BSH) play related roles as GSH surrogates, respectively. Under conditions of hypochlorite stress, MSH and BSH are known to form mixed disulfides with protein thiols, termed as S-mycothiolation or S-bacillithiolation that function in thiol-protection and redox regulation. Protein S-thiolations are widespread redox-modifications discovered in different Gram-positive bacteria, such as Bacillus and Staphylococcus species, Mycobacterium smegmatis, Corynebacterium glutamicum and Corynebacterium diphtheriae. S-thiolated proteins are mainly involved in cellular metabolism, protein translation, redox regulation and antioxidant functions with some conserved targets across bacteria. The reduction of protein S-mycothiolations and S-bacillithiolations requires glutaredoxin-related mycoredoxin and bacilliredoxin pathways to regenerate protein functions.In this review, we present an overview of the functions of mycothiol and bacillithiol and their physiological roles in protein S-bacillithiolations and S-mycothiolations in Gram-positive bacteria. Significant progress has been made to characterize the role of protein S-thiolation in redox-regulation and thiol protection of main metabolic and antioxidant enzymes. However, the physiological roles of the pathways for regeneration are only beginning to emerge as well as their interactions with other cellular redox systems. Future studies should be also directed to explore the roles of protein S-thiolations and their redox pathways in pathogenic bacteria under infection conditions to discover new drug targets and treatment options against multiple antibiotic resistant bacteria.

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“…S-bacillithiolated proteins are widespread and conserved across firmicutes and were discovered in many Bacillus and Staphylococcus species (Chi et al, 2013). Protein Sbacillithiolation functions in thiol-protection and redox regulation of redox-sensing regulators, metabolic enzymes and antioxidant enzymes (Chi et al, 2011;Chi et al, 2013;Loi et al, 2015;Imber et al, 2018a;Imber et al, 2018b;Imber et al, 2018c). In S. aureus, the glycolytic glyceraldehyde-3-phosphate dehydrogenase (GapDH) and the aldehyde dehydrogenase AldA were identified as most abundant proteins that are S-bacillithiolated under HOCl stress (Imber et al, 2018a;Imber et al, 2018b).…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureususes the bacilliredoxin (BrxAB)/ bacillithiol disulfide reductase (YpdA) redox pathway to defend against oxidative stress under infections

Linzner

Loi

Fritsch

et al. 2019

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Staphylococcus aureus is a major human pathogen and has to cope with reactive oxygen and chlorine species (ROS, RCS) during infections. The low molecular weight thiol bacillithiol (BSH) is an important defense mechanism of S. aureus for detoxification of ROS and HOCl stress to maintain the reduced state of the cytoplasm. Under HOCl stress, BSH forms mixed disulfides with proteins, termed as S-bacillithiolations, which are reduced by bacilliredoxins (BrxA and BrxB). The NADPH-dependent flavin disulfide reductase YpdA is phylogenetically associated with the BSH synthesis and BrxA/B enzymes and was proposed to function as BSSB reductase. Here, we investigated the role of the bacilliredoxin BrxAB/BSH/YpdA pathway in S. aureus COL under oxidative stress and macrophage infection conditions in vivo and in biochemical assays in vitro. Using HPLC thiol metabolomics, a strongly enhanced BSSB level and a decreased BSH/BSSB ratio were measured in the S. aureus COL ypdA deletion mutant under control and NaOCl stress. Monitoring the BSH redox potential (E BSH) using the Brx-roGFP2 biosensor revealed that YpdA is required for regeneration of the reduced EBSH upon recovery from oxidative stress. In addition, the ypdA mutant was impaired in H2O2 detoxification as measured with the novel H2O2-specific Tpx-roGFP2 biosensor. Phenotype analyses further showed that BrxA and YpdA are required for survival under NaOCl and H2O2 stress in vitro and inside murine J-774A.1 macrophages in infection assays in vivo. Finally, NADPH-coupled electron transfer assays provide evidence for the function of YpdA in BSSB reduction, which depends on the conserved Cys14 residue. YpdA acts together with BrxA and BSH in de-bacillithiolation of S-bacilithiolated GapDH. In conclusion, our results point to a major role of the BrxA/BSH/YpdA pathway in BSH redox homeostasis in S. aureus during recovery from oxidative stress and under infections. * *

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The aldehyde dehydrogenase AldA contributes to the hypochlorite defense and is redox-controlled by protein S-bacillithiolation in Staphylococcus aureus

Cited by 37 publications

References 75 publications

The Disulfide Stress Response and Protein S-thioallylation Caused by Allicin and Diallyl Polysulfanes in Bacillus subtilis as Revealed by Transcriptomics and Proteomics

The Disulfide Stress Response and Protein S-thioallylation Caused by Allicin and Diallyl Polysulfanes in Bacillus subtilis as Revealed by Transcriptomics and Proteomics

Redox regulation by reversible protein S-thiolation in Gram-positive bacteria

Staphylococcus aureususes the bacilliredoxin (BrxAB)/ bacillithiol disulfide reductase (YpdA) redox pathway to defend against oxidative stress under infections

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