Voltage-Switchable HCl Transport Enabled by Lipid Headgroup–Transporter Interactions
Access status:
Open Access
Type
ArticleAuthor/s
Wu, XinSmall, Jennifer R.
Cataldo, Alessio
Withecombe, Anne M.
Turner, Peter
Gale, Philip A.
Abstract
Synthetic anion transporters that facilitate transmembrane H+/Cl- symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have ...
See moreSynthetic anion transporters that facilitate transmembrane H+/Cl- symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low-to-modest H+/Cl- symport activity and their mechanism of action remains less well understood. We report a chloride-selective tetraurea macrocycle that has a record-high H+/Cl- symport activity similar to that of prodigiosin and most importantly demonstrates unprecedented voltage-switchable transport properties that are linked to the lack of uniport activity. By studying the anion binding affinity and transport mechanisms of four other anion transporters, we show that the lack of uniport and voltage-dependent H+/Cl@ symport originate from strong binding to phospholipid headgroups that hampers the diffusion of the free transporters through the membrane, leading to an unusualH+/Cl- symport mechanism that involves only charged species. Our work provides important mechanistic insights into different classes of anion transporters and a new approach to achieve voltage-switchability in artificial membrane transport systems.
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See moreSynthetic anion transporters that facilitate transmembrane H+/Cl- symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low-to-modest H+/Cl- symport activity and their mechanism of action remains less well understood. We report a chloride-selective tetraurea macrocycle that has a record-high H+/Cl- symport activity similar to that of prodigiosin and most importantly demonstrates unprecedented voltage-switchable transport properties that are linked to the lack of uniport activity. By studying the anion binding affinity and transport mechanisms of four other anion transporters, we show that the lack of uniport and voltage-dependent H+/Cl@ symport originate from strong binding to phospholipid headgroups that hampers the diffusion of the free transporters through the membrane, leading to an unusualH+/Cl- symport mechanism that involves only charged species. Our work provides important mechanistic insights into different classes of anion transporters and a new approach to achieve voltage-switchability in artificial membrane transport systems.
See less
Date
2019-08-30Publisher
Wiley-VCHLicence
This is the peer reviewed version of the following article: Wu, X., Small, J. R., Cataldo, A., Withecombe, A. M., Turner, P., & Gale, P. A. (2019). Voltage-Switchable HCl Transport Enabled by Lipid Headgroup-Transporter Interactions. Angewandte Chemie International Edition, 58(42), 15142–15147. https://doi.org/10.1002/anie.201907466, which has been published in final form at https://doi.org/10.1002/anie.201907466. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Citation
Angew. Chem. Int. Ed. 2019, 58, 15142 – 15147Share