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Vol. 302, Issue 3, 1286-1294, September 2002
Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa,
Japan (R.O., I.T., A. I., M.K., Y.S., A.T.); Chugai Pharmaceutical
Co. Inc., Ibaraki, Japan (J.N.); and Core Research for Evolutional
Science and Technology, Japan Science and Technology Corporation,
Kawaguchi, Japan (I.T., Y.S., A.T.)
The organic cation/carnitine transporter OCTN2 mediates transport of
carnitine and organic cations in Na+-dependent and
Na+-independent manners, respectively. However, the
mechanism of molecular recognition of different substrates has not been
clarified yet. We previously found a single amino acid change in OCTN2, Ser467Cys (S467C), in the Japanese population and observed a decreased carnitine transport but unchanged organic cation transport compared with wild type. Therefore, we conducted detailed kinetic and functional analyses of the substrate recognition sites of wild-type and
S467C-mutant OCTN2. The Km value for
carnitine of S467C-mutant was increased about 15-fold over that of the
wild type. Mutual inhibition kinetics of carnitine and
tetraethylammonium (TEA) were not completely competitive, suggesting
that the binding sites are very close to each other, but not identical.
Several organic anions such as valproate, as well as organic cations,
significantly inhibited carnitine and TEA uptake by OCTN2, and
valproate showed Na+-dependent inhibition of OCTN2-mediated
TEA uptake. The Na+-activation kinetics of the S467C mutant
was similar to that of the wild type. Furthermore, a significant
decrease of the TEA uptake-inhibitory potency of valproate was observed
in S467C-mutant OCTN2. These observations suggest that the
decrease in affinity of S467C-mutant OCTN2 for carnitine was caused by
functional alteration of the anion (carboxyl moiety of carnitine)
recognition site located in trans-membrane domain 11, which is closely related to the Na+-binding site, on OCTN2
protein. These results demonstrate that OCTN2 has functional sites for
carnitine and Na+ and that the carnitine-binding site is
involved, in part, in the recognition of organic cations.
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