Discovery of the ergothioneine transporter

Gründemann, Dirk; Harlfinger, Stephanie; Gölz, Stefan; Geerts, Andreas; Lazar, Andreas; Berkels, Reinhard; Jung, Norma; Rubbert, A.; Schömig, Edgar

doi:10.1073/pnas.0408624102

Cited by 479 publications

(514 citation statements)

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“…When mouse OCTN1 or OCTN2 was heterologously transfected in HEK293 cells, only OCTN1, but not OCTN2 efficiently transports ergothioneine as a substrate (Figure 2A), as previously reported for human and rat OCTN1 (3,19). The uptake of [ 3 H]ergothioneine by mouse OCTN1 was saturable with Km and Vmax values of 4.68 µM and 532 pmol/min/mg protein, respectively ( Figure 2B) and reduced by the replacement of Na + in the medium ( Figure 2C).…”

Section: Ergothioneine Is a Substrate Of Mouse Octn1mentioning

confidence: 54%

“…In addition, Gründemann et al have previously reported that ergothioneine is also the good substrate for OCTN1 in vitro, by utilizing cell biological and metabolomics approaches (3). Despite the previous identification of various substrates for OCTN1 in in vitro experimental systems, biologically important substrates for OCTN1 in vivo have not yet been clarified.…”

Section: Introductionmentioning

confidence: 99%

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Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

et al. 2010

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Purpose: Solute carrier, OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods:We first constructed octn1 gene knockout (octn1 -/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results:The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1 -/-mice among 112 metabolites examined.Pharmacokinetic analyses after oral administration revealed the highest distribution to small intestines and extensive renal reabsorption of [ 3 H]ergothioneine, both of which were much reduced in octn1 -/-mice.The octn1 -/-mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn's disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. 4Conclusions: These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine which could be important for protective effect against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases.

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Section: Ergothioneine Is a Substrate Of Mouse Octn1mentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

et al. 2010

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“…In humans, EGT is concentrated in erythrocyte progenitor cells, monocytes, the intestine and kidneys. EGT is cell membrane impermeable and recent human studies have identified a specific plasma membrane bound organic cation transporter known as OCTN1, which is encoded by the gene SLC22A4 (Grundemann et al, 2005). Polymorphisms in SLC22A4 have been associated with diabetes (Santiago et al, 2006) and susceptibility to chronic inflammatory diseases such as Crohn's disease (Fisher et al, 2006;Leung et al, 2006;Peltekova et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The evolutionary history of the genes involved in the biosynthesis of the antioxidant ergothioneine

Jones

Doyle

Fitzpatrick

2014

Gene

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Ergothioneine (EGT) is a histidine betaine derivative that exhibits antioxidant action in humans. EGT is primarily synthesized by fungal species and a number of bacterial species. A five-gene cluster (egtA, egtB, egtC, egtD & egtE) responsible for EGT production in Mycobacteria smegmatis has recently been identified. The first fungal biosynthetic EGT gene (NcEgt-1) has also been identified in Neurospora crassa. NcEgt-1 contains domains similar to those found in M. smegmatis egtB and egtD. EGT is biomembrane impermeable. Here we inferred the evolutionary history of the EGT cluster in prokaryotes as well as examining the phyletic distribution of Egt-1 in the fungal kingdom. A genomic survey of 2509 prokaryotes showed that the five-gene EGT cluster is only found in the Actinobacteria. Our survey identified more than 400 diverse prokaryotes that contain genetically linked orthologs of egtB and egtD. Phylogenetic analyses of Egt proteins show a complex evolutionary history and multiple incidences of horizontal gene transfer. Our analysis also identified two independent incidences of a fusion event of egtB and egtD in bacterial species. A genomic survey of over 100 fungal genomes shows that Egt-1 is found in all fungal phyla, except species that belong to the Saccharomycotina subphylum. This analysis provides a comprehensive analysis of the distribution of the key genes involved in the synthesis of EGT in prokaryotes and fungi. Our phylogenetic inferences illuminate the complex evolutionary history of the genes involved in EGT synthesis in prokaryotes. The potential to synthesize EGT is a fungal trait except for species belonging to the Saccharomycotina subphylum.

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“…OCTN1/SLC22A4 is multispecific transporter which accepts various types of therapeutic agents as substrates [5,6]. Metabolome analysis using cell lines transfected with SLC22A4 gene in vitro and octn1/slc22a4 gene knockout (octn1 -/-) mice in vivo have demonstrated that OCTN1 most efficiently transports a naturally occurring 5 food-derived antioxidant, ergothioneine (ERGO) [7,8]. ERGO is highly hydrophilic, and its uptake through plasma membranes is primarily mediated by OCTN1, as evidenced by the fact that food-derived ERGO is detected at µM to sub-mM level in almost all organs in wild-type mice, but minimally detected in octn1 -/-mice [8].…”

Section: Introductionmentioning

confidence: 99%

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

Tang

Masuo

Sakai

et al. 2016

Journal of Pharmaceutical Sciences

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3Xenobiotic transporters play key roles in disposition of a certain therapeutic agents although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1 -/-) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin

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Discovery of the ergothioneine transporter

Abstract: Variants of the

Cited by 479 publications

References 27 publications

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

The evolutionary history of the genes involved in the biosynthesis of the antioxidant ergothioneine

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

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