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Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes


Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl/HCO3 exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems.

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Figure 1: Structures of the bicarbonate transporters studied in this work.
Figure 2: Comparison of chloride efflux, measured using a chloride-selective electrode, from synthetic vesicles mediated by compounds 1–4 in nitrate and sulfate solution.
Figure 3: Results of chloride transport (measured using a chloride-selective electrode) that commenced when a bicarbonate pulse was added to the external solution.
Figure 4: 13C-NMR spectroscopy experiments demonstrated that both natural products and synthetic receptors are able to facilitate Cl/HCO3 antiport by allowing bicarbonate to enter the vesicles.
Figure 5: 13C-NMR experiments demonstrate that both natural products and synthetic receptors are able to facilitate chloride/bicarbonate antiport.


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J.T.D. and P.A.G. thank the NSF/EPSRC for funding this research through the International Collaboration in Chemistry program. R.Q. thanks the Spanish Ministerio de Educación y Ciencia for support with the Jose Castillejo mobility grant and Ramon y Cajal contract. T.T. thanks DGI of Spain for funding. O.A.O thanks the University of Maryland Graduate School for the Mabel Spencer Fellowship award. P.A.G. thanks C.C. Tong for the mass spectrometry study with prodigiosin and M.G. Fisher for fitting the NMR titration data with prodigiosin.

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J.T.D., P.A.G. and R.Q conceived this project, experiments, analysed data and prepared the manuscript; O.A.O. and R.Q. conducted experiments and analysed data; P.P. and T.T. contributed reagents, materials, analysis tools and supervized the synthesis; J.C.I.S. and R.Q. synthesized new compounds.

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Correspondence to Jeffery T. Davis, Philip A. Gale or Roberto Quesada.

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Davis, J., Gale, P., Okunola, O. et al. Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes. Nature Chem 1, 138–144 (2009).

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