Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate

Song, Heng; Hu, Wentao; Naowarojna, Nathchar; Her, Ampon Sae; Wang, Shu; Desai, Rushil; Qin, Liqiang; Chen, Xiaoping; Liu, Pinghua

doi:10.1038/srep11870

Cited by 45 publications

(56 citation statements)

References 78 publications

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“…These results provide important insights into the role of EGT in Mtb virulence in addition to its role in drug susceptibility, both of which appear to be distinct from MSH (Vilcheze et al, 2008). The observation that egtA and egtD contribute to different degrees to intracellular survival is supported by the finding that different intermediates of EGT biosynthesis may perform antioxidant functions (Song et al, 2015) and feed into different pathways of central carbon metabolism. Consequently, disruption of different steps in the EGT biosynthetic pathway in the egtA and egtD mutants likely explains the differences in attenuation (Figure 7A–C, F, G).…”

Section: Discussionmentioning

confidence: 95%

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis

Cumming²,

et al. 2016

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SUMMARY The mechanisms by which Mycobacterium tuberculosis (Mtb) maintains metabolic equilibrium to survive during infection and upon exposure to antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) and mycothiol (MSH) are the major redox buffers present in Mtb, but the contribution of EGT to Mtb redox homeostasis and virulence remains unknown. We report that Mtb WhiB3, a 4Fe-4S redox sensor protein, regulates EGT production and maintains bioenergetic homeostasis. We show that central carbon metabolism and lipid precursors regulate EGT production and that EGT modulates drug sensitivity. Notably, EGT and MSH are both essential for redox and bioenergetic homeostasis. Transcriptomic analyses of EGT and MSH mutants indicate overlapping, but distinct functions of EGT and MSH. Lastly, we show that EGT is critical for Mtb survival in both macrophages and mice. This study has uncovered a dynamic balance between Mtb redox and bioenergetic homeostasis, which critically influences Mtb drug susceptibility and pathogenicity.

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Section: Discussionmentioning

confidence: 95%

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis

Cumming²,

et al. 2016

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“…However, as methionine can be converted into both S-adenosyl methionine and cysteine by yeast, increased levels of methionine in the medium by itself could be enough for increasing ERG titers. Pyridoxine is a precursor for pyridoxal 5’-phosphate (PLP), which binds to EgtE to facilitate the conversion of HCO to 2-(hydroxysulfanyl)hercynine in a PLP-dependent manner (Song et al, 2015). Since CpEgt2 is the fungal equivalent of EgtE, it is likely that pyridoxine has a positive effect on ERG production through CpEgt2.…”

Section: Resultsmentioning

confidence: 99%

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

Hoek

Darbani

Zugaj

et al. 2019

Preprint

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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

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“…The resulting N ‐α‐trimethylhistidine (TMH) is fused to either γ‐glutamylcysteine (in actinomycetes, EC 1.14.99.50) or cysteine (in fungi, EC 1.14.99.51) . The sulfoxide product ( 3 in Scheme ) is converted into ergothoneine by removal of the glutamyl and cysteinyl moieties …”

Section: Methodsmentioning

confidence: 99%

Convergent Evolution of Ergothioneine Biosynthesis in Cyanobacteria

Liao

Seebeck

2017

ChemBioChem

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Biosynthesis of N-α-trimethyl-2-thiohistidine (ergothioneine) is a frequent trait in cyanobacteria. This sulfur compound may provide essential relief from oxidative stress related to oxygenic photosynthesis. The central steps in ergothioneine biosynthesis are catalyzed by a histidine methyltransferase and an iron-dependent sulfoxide synthase. In this report, we present evidence that some cyanobacteria recruited and adapted a sulfoxide synthase from a different biosynthetic pathway to make ergothioneine. The discovery of a second origin of ergothioneine production underscores the physiological importance of this metabolite and highlights the evolutionary malleability of the thiohistidine biosynthetic machinery.

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Mechanistic studies of a novel C-S lyase in ergothioneine biosynthesis: the involvement of a sulfenic acid intermediate

Cited by 45 publications

References 78 publications

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis

Ergothioneine Maintains Redox and Bioenergetic Homeostasis Essential for Drug Susceptibility and Virulence of Mycobacterium tuberculosis

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

Convergent Evolution of Ergothioneine Biosynthesis in Cyanobacteria

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