Gamma-glutamylcysteine protects ergothioneine-deficient Mycobacterium tuberculosis mutants against oxidative and nitrosative stress

Emani, Carine Sao; Williams, Monique J.; Helden, Paul D. van; Taylor, Malcolm; Wiid, Ian; Baker, Bienyameen

doi:10.1016/j.bbrc.2017.10.163

Cited by 28 publications

(72 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…M. smegmatis (29) and M. tuberculosis (10) ⌬egtD mutants are ERG deficient, while the M. tuberculosis ⌬egtB mutant is ERG deficient and the M. tuberculosis ⌬egtA mutant is GGC and ERG deficient (13). The MshA enzyme is essential for MSH biosynthesis in both M. tuberculosis (15) and M. smegmatis (30).…”

Section: Resultsmentioning

confidence: 99%

“…This indicates that the increased sensitivity of these strains to Ba is not associated with the lack of ERG. EgtE is involved in the final step of ERG biosynthesis; however, it is not essential for ERG biosynthesis, since the ⌬egtE M. tuberculosis mutant still produces a significant amount of ERG (13). Interestingly, the M. tuberculosis ⌬egtE mutant was more sensitive to Ba than the wild type ( implicated in the modulation of the lipid content of mycobacterial membranes (13,38).…”

Section: Resultsmentioning

confidence: 99%

“…Ergothioneine (ERG) (9,10), mycothiol (MSH) (11,12), and gamma-glutamylcysteine (GGC) (13) are low-molecular-weight thiols that protect M. tuberculosis against cellular stress. MSH is synthesized by a multistep process in mycobacteria, and several compounds targeted against enzymes involved in this process have been investigated.…”

mentioning

confidence: 99%

“…Among the enzymes involved in ERG biosynthesis, EgtD and EgtB were found to be essential for ERG biosynthesis, while EgtA is required for ERG biosynthesis and essential for GGC biosynthesis (13). Inhibitors of EgtD or EgtB have not yet been investigated, but buthionine sulfoximine (BSO) was shown to inhibit the activity of EgtA (23).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Compounds with Potential Activity against Mycobacterium tuberculosis

Emani

Williams

Wiid

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The high acquisition rate of drug resistance by necessitates the ongoing search for new drugs to be incorporated in the tuberculosis (TB) regimen. Compounds used for the treatment of other diseases have the potential to be repurposed for the treatment of TB. In this study, a high-throughput screening of compounds against thiol-deficient strains and subsequent validation with thiol-deficient strains revealed that and mutants had increased susceptibility to azaguanine (Aza) and sulfaguanidine (Su); and mutants had increased susceptibility to bacitracin (Ba); and, , and mutants had increased susceptibility to fusaric acid (Fu). Further analyses revealed that some of these compounds were able to modulate the levels of thiols and oxidative stress in This study reports the activities of Aza, Su, Fu, and Ba against and provides a rationale for further investigations.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Compounds with Potential Activity against Mycobacterium tuberculosis

Emani

Williams

Wiid

et al. 2018

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

show abstract

“…Ergothioneine is synthesized from one molecule of L-histidine ( 1 ), one molecule of L-cysteine ( 2 ), and 3 methyl groups donated by S-adenosyl-L-methionine (SAM, figure 1). In M. smegmatis , the reaction sequence is catalyzed by five enzymes, encoded by egtA-E genes arranged in an operon (Sao Emani et al, 2018). Four enzymes of the cluster EgtA, EgtB, EgtC, and EgtD catalyze four individual reactions that methylate L-histidine to form hercynine ( 3 ), convert L-cysteine to γ-L-glutamyl-L-cysteine ( 4 ), combine hercynine and γ-L-glutamyl-L-cysteine to generate γ-L-glutamyl-S-(hercyn-2-yl)-L-cysteine S-oxide ( 5 ) and produce the S-(hercyn-2-yl)-L-cysteine S-oxide ( 6 , HCO).…”

Section: Introductionmentioning

confidence: 99%

Engineering the yeastSaccharomyces cerevisiaefor the production of L-(+)-ergothioneine

Hoek

Darbani

Zugaj

et al. 2019

Preprint

View full text Add to dashboard Cite

20 cerevisiae, yeast, nutraceutical 21 22 Abbreviations: ERG L-(+)-ergothioneine, HCO S-(hercyn-2-yl)-L-cysteine S-oxide, PBS 23 phosphate-buffered saline, PI propidium iodide, PLP pyridoxal 5'-phosphate, SAM S-adenosyl-24 L-methionine 25 26Abstract 27 L-(+)-Ergothioneine is an unusual, naturally occurring antioxidant nutraceutical that has been 28 shown to help reduce cellular oxidative damage. Humans do not biosynthesise it, so can acquire 29 it only from their diet; it exploits a specific transporter (SLC22A4) for its uptake. ERG is 30 considered to be a nutraceutical and possible vitamin that is involved in the maintenance of 31 health, and seems to be at too low a concentration in several diseases in vivo. Ergothioneine is 32 thus a potentially useful dietary supplement. Present methods of commercial production rely on 33 extraction from natural sources or on chemical synthesis. Here we describe the engineering of 34 the baker's yeast Saccharomyces cerevisiae to produce ergothioneine by fermentation in defined 35 media. After integrating combinations of ERG biosynthetic pathways from different organisms, 36 we screened yeast strains for their production of ERG. The highest-producing strain was also 37 engineered with known ergothioneine transporters. The effect of amino acid supplementation of 38 the medium was investigated and the nitrogen metabolism of S. cerevisiae was altered by knock-39 out of TOR1 or YIH1. We also optimized the media composition using fractional factorial 40 methods. Our optimal strategy led to a titer of 598 ± 18 mg/L ergothioneine in fed-batch culture 41 in bioreactors. Because S. cerevisiae is a GRAS ('generally recognised as safe') organism that is 42 2 widely used for nutraceutical production, this work provides a promising process for the 43 biosynthetic production of ERG. 44 45

show abstract

Enzyme‐Catalyzed Oxidative Degradation of Ergothioneine

Nalivaiko,

Vasseur,

Seebeck

2024

Angewandte Chemie

View full text Add to dashboard Cite

Ergothioneine is a sulfur‐containing metabolite that is produced by bacteria and fungi, and is absorbed by plants and animals as a micronutrient. Ergothioneine reacts with harmful oxidants including singlet oxygen or hydrogen peroxide, and may therefore protect cells against oxidative stress. In this report we describe two enzymes from actinobacteria that cooperate in the specific oxidative degradation of ergothioneine. The first enzyme is an iron‐dependent thiol dioxygenase that produces ergothioneine sulfinic acid. A crystal structure of ergothioneine dioxygenase from Thermocatellispora tengchongensis reveals many similarities with cysteine dioxygenases, suggesting that the two enzymes share a common mechanism. The second enzyme is a metal‐dependent ergothioneine sulfinic acid desulfinase that produces Na‐trimethylhistidine and SO2. The discovery that certain actinobacteria contain the enzymatic machinery for O2‐dependent biosynthesis and O2‐dependent degradation of ergothioneine indicates that these organisms may actively manage their ergothioneine content

show abstract

Gamma-glutamylcysteine protects ergothioneine-deficient Mycobacterium tuberculosis mutants against oxidative and nitrosative stress

Cited by 28 publications

References 40 publications

Compounds with Potential Activity against Mycobacterium tuberculosis

Compounds with Potential Activity against Mycobacterium tuberculosis

Engineering the yeastSaccharomyces cerevisiaefor the production of L-(+)-ergothioneine

Enzyme‐Catalyzed Oxidative Degradation of Ergothioneine

Contact Info

Product

Resources

About