Functional role of the 503F variant of the organic cation transporter OCTN1 in Crohn’s disease

Several susceptible gene loci were identified as being involved in the aetiology of Crohn’s disease (CD).1 Recently, a non-synonymous single nucleotide polymorphism in the SLC22A4 gene encoding the organic cation transporter OCTN1 has been linked with CD in Caucasian populations (a 1672CT transversion, resulting in the amino acid substitution L503F).2,3 However, the functional consequences of this alteration are unclear as yet. We have now discovered that L-ergothioneine (ET, 2-mercaptohistidine trimethylbetaine), a naturally occurring water soluble thiol compound of dietary origin, is the physiological substrate of OCTN1.4 Analysis of the concentration dependence of ET transport in OCTN1 transfected HEK293 fibroblasts by liquid chromatography tandem mass spectrometry revealed that the 503F variant was associated with a threefold higher substrate affinity (1/Km) and a twofold lower maximal transport velocity (Vmax), which resulted in a 50% higher initial transport capacity (Vmax/Km (503F) ≈ 1.5 × Vmax/Km (503L)) at low ET levels (⩽10 µmol/l) (fig 1A). Analysis of the time course of ET transport showed a higher clearance for …