Discovery of the Ergothioneine Transporter

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 102; no. 14; pp. 5256 - 5261
• Main Authors: Gründemann, Dirk, Harlfinger, Stephanie, Golz, Stefan, Geerts, Andreas, Lazar, Andreas, Berkels, Reinhard, Jung, Norma, Rubbert, Andrea, Schömig, Edgar, Cerami, Anthony
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.04.2005; National Acad Sciences
• Subjects: Animals; Base Sequence; Betaines; Biological Sciences; Biological Transport, Active; Blood cells; Bone marrow; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell lines; Complementary DNA; Crohns disease; DNA, Complementary - genetics; Ergothioneine - metabolism; Erythrocytes; Gene Expression Profiling; Genes; HEK293 cells; Humans; Inflammation - genetics; Inflammation - metabolism; Kinetics; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Monocytes; Neutrophils; Organic Cation Transport Proteins - genetics; Organic Cation Transport Proteins - metabolism; Proline - analogs & derivatives; Proline - metabolism; Rats; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rheumatoid arthritis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Solute Carrier Family 22 Member 5; Solute Carrier Proteins; Solutes; Symporters; Terminology as Topic; Tissue Distribution
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408624102

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 μl 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.