Halide-selective, proton-coupled anion transport by phenylthiosemicarbazones

• Published in: Biochimica et biophysica acta. Biomembranes Vol. 1864; no. 2; p. 183828
• Main Authors: Howe, Ethan N.W., Chang, Vai-Vai Tiffany, Wu, Xin, Fares, Mohamed, Lewis, William, Macreadie, Lauren K., Gale, Philip A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2022
• Subjects: Anion transport; Anions - chemistry; Anions - metabolism; Chlorides - chemistry; Chlorides - metabolism; Crystallography, X-Ray; Hydrogen bonding; Hydrogen-Ion Concentration; Ion Transport; Kinetics; Nitrates - chemistry; Nitrates - metabolism; Protons; Switchable receptors; Thiosemicarbazones; Thiosemicarbazones - chemistry; Switchable receptors; Anion transport; Hydrogen bonding; Thiosemicarbazones
• ISSN: 0005-2736; 1879-2642; 1879-2642
• DOI: 10.1016/j.bbamem.2021.183828

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon imine protonation at pH 4.5. The rate-determining process of the pH switch, however, was not examined. We here develop a new series of PTSCs and demonstrate their conformational behaviour by X-ray crystallographic analysis and pH-switchable anion transport properties by liposomal assays. We report the surprising finding that the protonated PTSCs are extremely selective for halides over oxyanions in membrane transport. Owing to the high chloride over nitrate selectivity, the pH-dependent chloride/nitrate exchange of PTSCs originates from the rate-limiting nitrate transport process being inhibited at neutral pH. [Display omitted] •A new class of phenylthiosemicarbazones (PTSCs) function as pH-switchable transmembrane anion transporters.•Chloride/nitrate exchange is switched OFF at pH 7.2 due to an intramolecular hydrogen bond and ON at pH 4.5.•Anion transport selectivity analysis reveals strong halide over oxyanion preference exhibited by protonated PTSCs.•The pH-switchable chloride/nitrate exchange originates from inhibition of rate-limiting nitrate transport at pH 7.2.