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Publisher: Portland Press
Journal: Biochemical Journal
Languages: English
Types: Article
Subjects: Research Article, Xenopus oocytes, BCECF, 2?-7?-bis(carboxyethyl)-5(6)-carboxyfluorescein, monocarboxylate transporter (MCT), Life Sciences, MCT, monocarboxylate transporter, chimaeric transporter, TM, transmembrane, lactate transport, erythrocyte, DIDS, di-isothiocyanostilbene disulfonate
Abstract In this paper we characterise the properties of the potent MCT1 inhibitor, AR-C155858. Inhibitor titrations of L-lactate transport by MCT1 in rat erythrocytes were used to determine the Ki value and number of AR-C155858 binding sites (Et) on MCT1 and the transporter?s turnover number (Kcat). Derived values were 2.3 ? 1.4 nM, 1.29 ? 0.09 nmoles per ml packed cells and 12.2 ? 1.1 s-1 respectively. When expressed in Xenopus laevis oocytes MCT1 and MCT2 were potently inhibited by AR-C155858 whilst MCT4 was not. Inhibition of MCT1 was shown to be time-dependent, and the compound was also active when microinjected suggesting that AR-C155858 probably enters the cell before binding to an intracellular site on MCT1. Measurement of the inhibitor sensitivity of several chimeric transporters combining different domains of MCT1 and MCT4 revealed that the binding site for AR-C155858 is contained within the C-terminal half of MCT1, and involves transmembrane (TM) domains 7-10. This is consistent with previous data identifying F360 (in TM 10) and D302 plus R306 (TM 8) as key residues in substrate binding and translocation by MCT1. Measurement of the Km values of the chimeras for L-lactate and pyruvate demonstrate that both the C- and N-terminal halves of the molecule influence transport kinetics consistent with our proposed molecular model of MCT1 and its translocation mechanism that requires K38 in TM1 in addition to D302 and R306 in TM 8 (Wilson et al (2009) J. Biol. Chem. 284:20011-20021). (Halestrap, Andrew P) Department of Biochemistry, University of Bristol - UNITED KINGDOM (Halestrap, Andrew P) UNITED KINGDOM

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