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Discovery of the ergothioneine transporter.
Proc Natl Acad Sci U S A. 2005 Apr 05; 102(14):5256-61.PN

Abstract

Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substrate of this transporter is in fact ergothioneine (ET). Human OCTN1 was expressed in 293 cells. A substrate lead, stachydrine (alias proline betaine), was identified by liquid chromatography MS difference shading, a new substrate search strategy. Analysis of transport efficiency of stachydrine-related solutes, affinity, and Na+ dependence indicates that the physiological substrate is ET. Efficiency of transport of ET was as high as 195 microl per min per mg of protein. By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all. Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1. ET, all of which is absorbed from food, is an intracellular antioxidant with metal ion affinity. Its particular purpose is unresolved. Cells with expression of ETT accumulate ET to high levels and avidly retain it. By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound. The real-time PCR expression profile of human ETT, with strong expression in CD71+ cells, is consistent with a pivotal function of ET in erythrocytes. Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders.

Authors+Show Affiliations

Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany. dirk.gruendemann@uni-koeln.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15795384

Citation

Gründemann, Dirk, et al. "Discovery of the Ergothioneine Transporter." Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 14, 2005, pp. 5256-61.
Gründemann D, Harlfinger S, Golz S, et al. Discovery of the ergothioneine transporter. Proc Natl Acad Sci U S A. 2005;102(14):5256-61.
Gründemann, D., Harlfinger, S., Golz, S., Geerts, A., Lazar, A., Berkels, R., Jung, N., Rubbert, A., & Schömig, E. (2005). Discovery of the ergothioneine transporter. Proceedings of the National Academy of Sciences of the United States of America, 102(14), 5256-61.
Gründemann D, et al. Discovery of the Ergothioneine Transporter. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5256-61. PubMed PMID: 15795384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discovery of the ergothioneine transporter. AU - Gründemann,Dirk, AU - Harlfinger,Stephanie, AU - Golz,Stefan, AU - Geerts,Andreas, AU - Lazar,Andreas, AU - Berkels,Reinhard, AU - Jung,Norma, AU - Rubbert,Andrea, AU - Schömig,Edgar, Y1 - 2005/03/28/ PY - 2005/3/30/pubmed PY - 2005/5/26/medline PY - 2005/3/30/entrez SP - 5256 EP - 61 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 102 IS - 14 N2 - Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substrate of this transporter is in fact ergothioneine (ET). Human OCTN1 was expressed in 293 cells. A substrate lead, stachydrine (alias proline betaine), was identified by liquid chromatography MS difference shading, a new substrate search strategy. Analysis of transport efficiency of stachydrine-related solutes, affinity, and Na+ dependence indicates that the physiological substrate is ET. Efficiency of transport of ET was as high as 195 microl per min per mg of protein. By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all. Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1. ET, all of which is absorbed from food, is an intracellular antioxidant with metal ion affinity. Its particular purpose is unresolved. Cells with expression of ETT accumulate ET to high levels and avidly retain it. By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound. The real-time PCR expression profile of human ETT, with strong expression in CD71+ cells, is consistent with a pivotal function of ET in erythrocytes. Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders. SN - 0027-8424 UR - https://www.unboundmedicine.com/medline/citation/15795384/Discovery_of_the_ergothioneine_transporter_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=15795384 DB - PRIME DP - Unbound Medicine ER -