A microbial transporter of the dietary antioxidant ergothioneine

Dumitrescu, Daniel G.; Gordon, Elizabeth M.; Kovalyova, Yekaterina; Seminara, Anna B.; Duncan-Lowey, Brianna; Forster, Emily R.; Zhou, Wen; Booth, Carmen J.; Shen, Aimee; Kranzusch, Philip J.; Hatzios, Stavroula K.

doi:10.1016/j.cell.2022.10.008

Cited by 40 publications

(21 citation statements)

References 116 publications

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“…An important metabolite, DG (18:0/20:1(11Z)/0:0), may have the same mechanism of action. A recent study had shown that Helicobacter sustains lives by “competing” with the body for dietary antioxidants ( 61 ) and was closely related to redox, which was consistent with the findings of this study.…”

Section: Discussionsupporting

confidence: 92%

Integrating microbiome and metabolome revealed microbe-metabolism interactions in the stomach of patients with different severity of peptic ulcer disease

Wang

Xiao²,

Lin³

et al. 2023

Front. Immunol.

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BackgroundPeptic ulcer disease (PUD) is a multi-cause illness with an unknown role for gastric flora and metabolism in its pathogenesis. In order to further understand the pathogenesis of gastric flora and metabolism in PUD, this study used histological techniques to analyze the microbiome and metabolome of gastric biopsy tissue. In this paper, our work described the complex interactions of phenotype-microbial-metabolite-metabolic pathways in PUD patients at different pathological stages.MethodsGastric biopsy tissue samples from 32 patients with chronic non-atrophic gastritis, 24 patients with mucosal erosions, and 8 patients with ulcers were collected for the microbiome. UPLC-MS metabolomics was also used to detect gastric tissue samples. These datasets were analyzed individually and integrated using various bioinformatics methods.ResultsOur work found reduced diversity of gastric flora in patients with PUD. PUD patients at different pathological stages presented their own unique flora, and there were significant differences in flora phenotypes. Coprococcus_2, Phenylobacterium, Candidatus_Hepatoplasma, and other bacteria were found in the flora of people with chronic non-atrophic gastritis (HC). The representative flora of mucosal erosion (ME) had uncultured_bacterium_c_Subgroup_6, Sphingomonadaceae, Xanthobacteraceae, and uncultured_bacterium_f_Xanthobacteraceae. In comparison, the characteristic flora of the PUD group was the most numerous and complex, including Ruminococcus_2, Agathobacter, Alistipes, Helicobacter, Bacteroides and Faecalibacterium. Metabolomics identified and annotated 66 differential metabolites and 12 significantly different metabolic pathways. The comprehensive analysis correlated microorganisms with metabolites at different pathological stages and initially explored the complex interactions of phenotype-microbial-metabolite-metabolic pathways in PUD patients at different pathological stages.ConclusionOur research results provided substantial evidence to support some data on the analysis of the microbial community and its metabolism in the stomach, and they demonstrated many specific interactions between the gastric microbiome and the metabolome. Our study can help reveal the pathogenesis of PUD and indicate plausible disease-specific mechanisms for future studies from a new perspective.

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Section: Discussionsupporting

confidence: 92%

Integrating microbiome and metabolome revealed microbe-metabolism interactions in the stomach of patients with different severity of peptic ulcer disease

Wang

Xiao²,

Lin³

et al. 2023

Front. Immunol.

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“…This is not yet known with certainty since concentrations of ET itself have not been comprehensively mapped in a wide variety of tissues or cells in an infected host using the analytical approaches we describe here. However, bacteria found in either the intracellular or extracellular lifestyle may well be capable of capturing ET, given that ETT is reported to transport ET with a K m of 20 µM 23 , which is ≈500-fold weaker than the K d for bacterial EgtUC described here 58 . Of course, the K m for transport by EgtU may not correlate with the K d for substrate binding by EgtUC, and this is an important focus of future work.…”

Section: Discussionmentioning

confidence: 57%

“…It is well established that commensals resist colonization by pathogens in the gut by depleting essential nutrients and remodeling resource allocation in this niche 62 . It is also known that ET can be catabolized by various bacteria, impacting ET bioavailability in their respective niches 58,63 . The work reported here raises the possibility of a competition between commensals and pathogens for a nutrient that may well be protective against oxidative and antibiotic stressors, for which there is now evidence in Helicobacter pylori 58 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, Clostridioides difficile OpuF 56 in the middle subcluster and others may be specific for another QAC, or exhibit relaxed QAC specificity. Indeed, very recent work in Helicobacter pylori reveals that some SSN cluster 2 transporters contribute to cellular ET uptake, but are characterized by a significantly lower affinity for ET relative to SpEgtUC 58 .…”

Section: Egtu Homologs Are Widely Distributed Across the Genomes Of F...mentioning

confidence: 99%

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Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine

Zhang

González-Gutiérrez²,

Legg³

et al. 2022

Nat Commun

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L-Ergothioneine (ET), the 2-thioimidazole derivative of trimethylhistidine, is biosynthesized by select fungi and bacteria, notably Mycobacterium tuberculosis, and functions as a scavenger of reactive oxygen species. The extent to which ET broadly functions in bacterial cells unable to synthesize it is unknown. Here we show that spd_1642-1643 in Streptococcus pneumoniae, a Gram-positive respiratory pathogen, encodes an ET uptake ATP-binding cassette (ABC) transporter, designated EgtU. The solute binding domain (SBD) of EgtU, EgtUC, binds ET with high affinity and exquisite specificity in a cleft between the two subdomains, with cation-π interactions engaging the betaine moiety and a network of water molecules that surround the thioimidazole ring. EgtU is highly conserved among known quaternary amine compound-specific transporters and widely distributed in Firmicutes, including the human pathogens Listeria monocytogenes, as BilEB, Enterococcus faecalis and Staphylococcus aureus. ET increases the chemical diversity of the low molecular weight thiol pool in Gram-positive human pathogens and may contribute to antioxidant defenses in the infected host.

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“…L‐Ergothioneine (EGT: 1 ) is a histidine derivative in which the C2 carbon of the imidazole ring is substituted with a sulfhydryl group. Although 1 is biosynthesized only in cyanobacteria, actinomycetes, methylobacteria, and some fungi, [1–4] it has been found in a broad range of organisms, including plants and animals [5–8] . Since 1 plays a complementary role to that of glutathione in vivo, it has a broad range of biological activities such as anti‐inflammatory, antioxidant, and anti‐aging properties [9–11] …”

Section: Methodsmentioning

confidence: 99%

Structure‐Function Analysis of the S‐Glycosylation Reaction in the Biosynthesis of Lincosamide Antibiotics

et al. 2023

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The S‐glycosyltransferase LmbT, involved in the biosynthesis of lincomycin A, is the only known enzyme that catalyzes the enzymatic incorporation of rare amino acid L‐ergothioneine (EGT) into secondary metabolites. Here, we show the structure and function analyses of LmbT. Our in vitro analysis of LmbT revealed that the enzyme shows promiscuous substrate specificity toward nitrogenous base moieties in the generation of unnatural nucleotide diphosphate (NDP)‐D‐α‐D‐lincosamides. Furthermore, the X‐ray crystal structures of LmbT in its apo form and in complex with substrates indicated that the large conformational changes of the active site occur upon binding of the substrates, and that EGT is strictly recognized by salt‐bridge and cation‐π interactions with Arg260 and Trp101, respectively. The structure of LmbT in complex with its substrates, the docking model with the EGT‐S‐conjugated lincosamide, and the structure‐based site‐directed mutagenesis analysis revealed the structural details of the LmbT‐catalyzed SN2‐like S‐glycosylation reaction with EGT.

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A microbial transporter of the dietary antioxidant ergothioneine

Cited by 40 publications

References 116 publications

Integrating microbiome and metabolome revealed microbe-metabolism interactions in the stomach of patients with different severity of peptic ulcer disease

Integrating microbiome and metabolome revealed microbe-metabolism interactions in the stomach of patients with different severity of peptic ulcer disease

Discovery and structure of a widespread bacterial ABC transporter specific for ergothioneine

Structure‐Function Analysis of the S‐Glycosylation Reaction in the Biosynthesis of Lincosamide Antibiotics

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