Skip to main content
SpringerLink
Log in

Valinomycin as a Classical Anionophore: Mechanism and Ion Selectivity

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

In the present study, we use theory and modeling to investigate K+ carrier valinomycin (Vln) as a classical anionophore. We discuss formation of the ion pair VlnK+, Cl− versus encapsulation of the anion into VlnCl− complex as two alternative mechanisms that could account for surprisingly high anionophoretic activity of the cyclic peptide (Riddell and Zhou in J Inorg Biochem 55:55–279, 1994), meanwhile constructing kinetic models to help distinguish between the two. The study is guided by the idea to create “valinomycin for anions” and in this respect the selectivity problem is at the heart, as synthetic anionophores are expected to have the same issues with the counterion translocation as Vln has. The study helps to understand what Vln really is and so what “valinomycin for anions” has to be. Furthermore, using recent examples, we explore how Vln has been utilized as a tool for research in the two different fields, with an aim to illustrate advantages and potential of basic scientific methods over supramolecular way, celebrating victory of science over commonsense.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abbott BJ, Fukuda DS, Dorman DE, Occolowitz JL, Debono M, Farhner L (1979) Microbial transformation of A23187, a divalent cation ionophore antibiotic. Antimicrob Agents Chemother 16:808–812. doi:10.1128/aac.16.6.808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ayling AJ, Nieves Pérez-Payán M, Davis AP (2001) New “cholapod” anionophores; high-affinity halide receptors derived from cholic acid. J Am Chem Soc 123:12716–12717. doi:10.1021/ja016796z

    Article  CAS  PubMed  Google Scholar 

  • Berezin SK (2009) Catechols as membrane anion transporters. Ph. D. Thesis University of Maryland, Chemistry&Biochemistry Department

  • Berezin SK (2013) Theoretical modelling of anion transport in liposomes: electrogenic anion exchange as a new paradigm in supramolecular chemistry. Supramol Chem 25:323–334. doi:10.1080/10610278.2013.782099

    Article  CAS  Google Scholar 

  • Berezin SK (2014) Synthetic anionophores for basic anions as “presumably, OH−/Cl− antiporters”: from the synthetic ion channels to multi-ion hopping, anti-Hofmeister selectivity, and strong positive AMFE. J Membr Biol 247:651–665. doi:10.1007/s00232-014-9683-7

    Article  CAS  PubMed  Google Scholar 

  • Berezin SK, Davis JT (2007) Unpublished results. Department of Chemistry and Biochemistry, University of Maryland

  • Berezin SK, Davis JT (2009) Catechols as membrane anion transporters. J Am Chem Soc 131:2458–2459. doi:10.1021/ja809733c

    Article  CAS  PubMed  Google Scholar 

  • Berrocal MJ, Cruz A, Badr IH, Bachas LG (2000) Tripodal ionophore with sulfate recognition properties for anion-selective electrodes. Anal Chem 72:5295–5299. doi:10.1021/ac000241p

    Article  CAS  PubMed  Google Scholar 

  • Brett Kimbrell J, Hite JR, Skala KN, Crittenden CM, Richardson CN, Swamy Mruthinti S, Fujita M, Khan FA (2011) Direct binding of halide ions by valinomycin. Supramol Chem 23:782–789. doi:10.1080/10610278.2011.593627

    Article  Google Scholar 

  • Bühlmann P, Pretsch E, Bakker E (1998) Carrier-based ion-selective electrodes and bulk optodes. 2. Ionophores for potentiometric and optical sensors. Chem Rev 98:1593–1688. doi:10.1021/cr970113+

    Article  PubMed  Google Scholar 

  • Carmichael VE, Dutton PJ, Fyles TM, James TD, Swan JA, Zojaji M (1989) Biomimetic ion transport: a functional model of a unimolecular ion channel. J Am Chem Soc 111:767–769. doi:10.1021/ja00184a075

    Article  CAS  Google Scholar 

  • Davis JT (2010) Anion binding and transmembrane transport by prodigiosin analogs. In: Gale PA, Dehaen W (eds) Topics in heterocyclic chemistry, vol 24. Springer, New York, pp 145–176. doi:10.1007/7081_2010_29

    Google Scholar 

  • Davis JT, Gale PA, Okunola OA, Prados P, Iglesias-Sanchez JC, Torroba T, Quesada R (2009) Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes. Nat Chem 1:138–144. doi:10.1038/nchem.178

    Article  CAS  PubMed  Google Scholar 

  • Dawson DC, Smith SS, Mansoura MK (1999) CFTR: mechanism of anion conduction. Physiol Rev 79:S47–S75

    CAS  PubMed  Google Scholar 

  • Deng G, Dewa T, Regen SL (1996) A synthetic ionophore that recognizes negatively charged phospholipid membranes. J Am Chem Soc 118:8975–8976. doi:10.1021/ja961269e

    Article  CAS  Google Scholar 

  • El-Etri M, Cuppoletti J (1996) Metalloporphyrin chloride ionophores: induction of increased anion permeability in lung epithelial cells. Am J Physiol 270:L386–L392

    CAS  PubMed  Google Scholar 

  • Futai F, Wada Y, Kaplan JH (2006) Handbook of ATPases: biochemistry, cell biology, pathophysiology. Wiley, New York. doi:10.1002/3527606122

    Google Scholar 

  • Fyles TM, Loock D, van Straaten-Nijenhuis WF, Zojaji XZ (1996) Pores formed by bis-macrocyclic bola-amphiphiles in vesicle and planar bilayer membranes. J Org Chem 61:8866–8874

    Article  CAS  PubMed  Google Scholar 

  • Gale PA (2011) From anion receptors to transporters. Acc Chem Res 44:216–226. doi:10.1021/ar100134p

    Article  CAS  PubMed  Google Scholar 

  • Gale PA, Busschaert N, Haynes CJE, Karagiannidis LE, Kirby IL (2014) Anion receptor chemistry: highlights from 2011 and 2012. Chem Soc Rev 43:205–241. doi:10.1039/C3CS60316D

    Article  CAS  PubMed  Google Scholar 

  • Gokel GW, Barkey N (2009) Transport of chloride ion through phospholipid bilayers mediated by synthetic ionophores. New J Chem 33:947–963. doi:10.1039/B817245P

    Article  CAS  Google Scholar 

  • Gokel GW, Mukhopadhyay A (2001) Synthetic models of cation-conducting channels. Chem Soc Rev 30:274–286. doi:10.1039/B008667N

    Article  CAS  Google Scholar 

  • Gorden AEV, Xu J, Raymond KN, Durbin PW (2003) Chem Rev 103:4207–4282. doi:10.1021/cr990114xCCC

    Article  CAS  PubMed  Google Scholar 

  • Helsel AJ, Brown AL, Yamato K, Feng W, Yuan L, Clements AJ, Harding SV, Szabo G, Shao Z, Gong B (2008) Highly conducting transmembrane pores formed by aromatic oligoamide macrocycles. J Am Chem Soc 130:15784–15785. doi:10.1021/ja807078y

    Article  CAS  PubMed  Google Scholar 

  • Hille B (2001) Ionic channels of excitable membranes, 3rd edn. Sinauer Associates Inc, Sunderland

    Google Scholar 

  • Hu X-B, Chen Z, Tang G, Hou J-L, Li Z-T (2012) Single-molecular artificial transmembrane water channels. J Am Chem Soc 134:8384–8387. doi:10.1021/ja302292c

    Article  CAS  PubMed  Google Scholar 

  • Iglesias-Sanchez JC, Wang W, Ferdani R, Prados P, deMendoza J, Gokel GW (2008) Synthetic cation transporters incorporating crown ethers and calixarenes as headgroups and central relays: a comparison of sodium and chloride selectivity. New J Chem 32:878–890. doi:10.1039/B719235P

    Article  PubMed Central  PubMed  Google Scholar 

  • Jia C, Wu B, Li S, Huang X, Zhao Q, Li QS, Yang XJ (2011) Highly efficient extraction of sulfate ions with a tripodal hexaurea receptor. Angew Chem Int Ed Engl 50:486–490. doi:10.1002/anie.201004461

    Article  CAS  PubMed  Google Scholar 

  • Jiang C, Harris D, Lee ER, Cheng SH, Lane M (1998) Use of aminosterol derivatives as chloride ionphores. Google Patents

  • Karagiannidis LE, Haynes CJ, Holder KJ, Kirby IL, Moore SJ, Wells NJ, Gale PA (2014) Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas. Chem Commun 50:12050–12053. doi:10.1039/C4CC05519E

    Article  CAS  Google Scholar 

  • Kelkar DA, Chattopadhyay A (2007) The gramicidin ion channel: a model membrane protein. Biochim Biophys Acta 1768:2011–2025. doi:10.1016/j.bbamem.2007.05.011

    Article  CAS  PubMed  Google Scholar 

  • Ko SK, Kim SK, Share A, Lynch VM, Park J, Namkung W, Van Rossom W, Busschaert N, Gale PA, Sessler JL, Shin I (2014) Synthetic ion transporters can induce apoptosis by facilitating chloride anion transport into cells. Nat Chem 6:885–892. doi:10.1038/nchem.2021

    Article  CAS  PubMed  Google Scholar 

  • Koulov AV, Lambert TN, Shukla R, Jain M, Boon JM, Smith BD, Li H, Sheppard DN, Joos JB, Clare JP, Davis AP (2003) Chloride transport across vesicle and cell membranes by steroid-based receptors. Angew Chem Int Ed Engl 42:4931–4933. doi:10.1002/anie.200351957

    Article  CAS  PubMed  Google Scholar 

  • Li X, Shen B, Yao X-Q, Yang D (2007) A small synthetic molecule forms chloride channels to mediate chloride transport across cell membranes. J Am Chem Soc 129:7264–7265. doi:10.1021/ja071961h

    Article  CAS  PubMed  Google Scholar 

  • Li X, Shen B, Yao X-Q, Yang D (2009) Synthetic chloride channel regulates cell membrane potentials and voltage-gated calcium channels. J Am Chem Soc 131:13676–13680

    Article  CAS  PubMed  Google Scholar 

  • Licen S, Bagnacani V, Baldini L, Casnati A, Sansone F, Giannetto M, Pengo P, Tecilla P (2013) Anion transport across phospholipid bilayers promoted by a guanidinium calix[4]arene conjugate. Supramol Chem 25:631–640. doi:10.1080/10610278.2013.824576

    Article  CAS  Google Scholar 

  • Lim H-H, Shane T, Miller C (2012) Intracellular proton access in a Cl−/H+antiporter. PLoS Biol 10:e1001441. doi:10.1371/journal.pbio.1001441

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marinetti GV, Skarin A, Whitman P (1978) Transport of organic anions through the erythrocyte membrane as K + -valinomycin complexes. J Membr Biol 40:143–155. doi:10.1007/BF01871145

    Article  CAS  PubMed  Google Scholar 

  • Matile S, Sakai N (2007) The characterization of synthetic ion channels and pores. In: Schalley C (ed) Analytical methods in supramolecular chemistry. Wiley, Weinheim, pp 391–418. doi:10.1002/9783527610273

    Google Scholar 

  • Matile S, Sakai N (2012) The characterization of synthetic ion channels and pores. In: Schalley CA (ed) Analytical methods in supramolecular chemistry, 2nd edn. Wiley, Weinheim, pp 711–742. doi:10.1002/9783527644131

    Chapter  Google Scholar 

  • McNally BA, Koulov AV, Lambert TN, Smith BD, Joos JB, Sisson AL, Clare JP, Sgarlata V, Judd LW, Magro G, Davis AP (2008) Structure-activity relationships in cholapod anion carriers: enhanced transmembrane chloride transport through substituent tuning. Chem Eur J 14:9599–9606. doi:10.1002/chem.200801163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Meshcheryakov D, Böhmer V, Bolte M, Hubscher-Bruder V, Arnaud-Neu F, Herschbach H, Van Dorsselaer A, Thondorf I, Mögelin W (2006) Two chloride ions as a template in the formation of a cyclic hexaurea. Angew Chem Int Ed Engl 45:1648–1652. doi:10.1002/anie.200503766

    Article  CAS  PubMed  Google Scholar 

  • Meshcheryakov D, Arnaud-Neu F, Böhmer V, Bolte M, Cavaleri J, Hubscher-Bruder V, Thondorf I, Werner S (2008) Cyclic tetraureas with variable flexibility-synthesis, crystal structures and properties. Org Biomol Chem 6:3244–3255. doi:10.1039/b808773c

    Article  CAS  PubMed  Google Scholar 

  • Miller C (2000) Ion channels: doing hard chemistry with hard ions. Curr Opin Chem Biol 4:148–151

    Article  CAS  PubMed  Google Scholar 

  • Moore SJ, Fisher MG, Yano M, Tong CC, Gale PA (2011) A dual host approach to transmembrane transport of salts. Chem Commun 47:689–691. doi:10.1039/c0cc04430j

    Article  CAS  Google Scholar 

  • Moyer BA, Custelcean R, Hay BP, Sessler JL, Bowman-James K, Day VW, Kang S-O (2013) A case for molecular recognition in nuclear separations: sulfate separation from nuclear wastes. Inorg Chem 52:3473–3490. doi:10.1021/ic3016832

    Article  CAS  PubMed  Google Scholar 

  • Otis F, Racine-Berthiaume C, Voyer N (2011) How far can a sodium ion travel within a lipid bilayer? J Am Chem Soc 133:6481–6483. doi:10.1021/ja110336s

    Article  CAS  PubMed  Google Scholar 

  • Ovchinnikov YA, Ivanov VD, Shkrob AM (1974) Membrane active chelators. Nauka, Moscow

    Google Scholar 

  • Perez-Velasco A, Gorteau V, Matile S (2008) Rigid oligoperylenediimide rods: anion–pi slides with photosynthetic activity. Angew Chem 47:921–923. doi:10.1002/anie.200703749

    Article  CAS  Google Scholar 

  • Riddell FG, Zhou Z (1994) Mn2 + as a contrast reagent for NMR studies of 35Cl− and 81Br- transport through model biological membranes. J Inorg Biochem 55:279–293. doi:10.1016/0162-0134(94)85012-7

    Article  CAS  PubMed  Google Scholar 

  • Sakai N, Matile S (2002) Recognition of polarized lipid bilayers by p-oligophenyl ion channels: from push–pull rods to push–pull barrels. J Am Chem Soc 124:1184–1185. doi:10.1021/ja017497c

    Article  CAS  PubMed  Google Scholar 

  • Schlesinger PH, Ferdani R, Liu J, Pajewska J, Pajewski R, Saito M, Shabany H, Gokel GW (2002) SCMTR: a chloride-selective, membrane-anchored peptide channel that exhibits voltage gating. J Am Chem Soc 124:1848–1849

    Article  CAS  PubMed  Google Scholar 

  • Seganish JL, Santacroce PV, Salimian KJ, Fettinger JC, Zavalij P, Davis JT (2006) Regulating supramolecular function in membranes: calixarenes that enable or inhibit transmembrane Cl− transport. Angew Chem Int Ed Engl 45:3334–3338. doi:10.1002/ange.200504489

    Article  CAS  PubMed  Google Scholar 

  • Sekutor M, Mlinaric-Majerski K (2014) Adamantyl aminoguanidines as receptors for oxo-anions. Tetrahedron Lett 55:6665–6670. doi:10.1016/j.tetlet.2014.10.062

    Article  CAS  Google Scholar 

  • Selwin MJ (1976) Triorganotin compounds as ionophores and inhibitors of ion translocating ATPases. In: Zuckerman JJ (ed) Organotin compounds: new chemistry and applications, vol 157., Advances in ChemistryWashington, DC, pp 204–226. doi:10.1021/ba-1976-0157.ch015

    Chapter  Google Scholar 

  • Shen B, Li X, Wang F, Yao X, Yang D (2012) A synthetic chloride channel restores chloride conductance in human cystic fibrosis epithelial cells. PLoS ONE 7:e34694. doi:10.1371/journal.pone.0034694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sidorov V, Kotch FW, Abdrakhmanova G, Mizani R, Fettinger JC, Davis JT (2002) Ion channel formation from a calix[4]arene amide that binds HCl. J Am Chem Soc 124:2267–2278. doi:10.1021/ja012338e

    Article  CAS  PubMed  Google Scholar 

  • Sidorov V, Kotch FW, Kuebler JL, Lam YF, Davis J (2003) Chloride transport across lipid bilayers and transmembrane potential induction by an oligophenoxyacetamide. J Am Chem Soc 125:2840–2841. doi:10.1021/ja029372t

    Article  CAS  PubMed  Google Scholar 

  • Stark G, Ketterer B, Benz R, Läuger P (1971) The rate constants of valinomycin-mediated ion transport through thin lipid membranes. Biophys J 11:981–994. doi:10.1016/S0006-3495(71)86272-0

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tong CC, Quesada R, Sessler JL, Gale PA (2008) meso-Octamethylcalix[4]pyrrole: an old yet new transmembrane ion-pair transporter. Chem Commun 47:6321–6323. doi:10.1039/b814988g

    Article  Google Scholar 

  • Valkenier H, Davis AP (2013) Making a match for valinomycin: steroidal scaffolds in the design of electroneutral, electrogenic anion carriers. Acc Chem Res 46:2898–2909. doi:10.1021/ar4000345

    Article  CAS  PubMed  Google Scholar 

  • Watling-Payne AS, Selwyn MJ (1974) Inhibition and uncoupling of hotophosphorylation in isolated chloroplasts by organotin, organomercury and diphenyleneiodonium compounds.  Biochem J 142:65–74

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Weiss LA, Sakai N, Ghebremariam B, Ni C, Matile S (1997) Rigid rod-shaped polyols: functional nonpeptide models for transmembrane proton channels. J Am Chem Soc 119:12142–12149. doi:10.1021/ja973126d

    Article  CAS  Google Scholar 

  • Wenzel M, Light ME, Davis AP, Gale PA (2011) Thiourea isosteres as anion receptors and transmembrane transporters. Chem Commun 47:7641–7643. doi:10.1039/c1cc12439k

    Article  CAS  Google Scholar 

  • Wu X, Busschaert N, Wells NJ, Jiang YB, Gale PA (2015) Dynamic covalent transport of amino acids across lipid bilayer. J Am Chem Soc 137:1476–1484. doi:10.1021/ja510063n

    Article  CAS  PubMed  Google Scholar 

  • Wuthier U, Pham HV, Zuend R, Welti D, Funck RJJ, Bezegh A, Ammann D, Pretsch E, Simon W (1984) Tin organic compounds as neutral carriers for anion selective electrodes. Anal Chem 56:535–538. doi:10.1021/ac00267a052

    Article  CAS  Google Scholar 

  • Yang D, Qu J, Li W, Zhang Y-H, Ren Y, Wang D-P, Wu Y-D (2002) Cyclic hexapeptide of D, L-α-aminoxy acids as a selective receptor for chloride ion. J Am Chem Soc 124:12410–12411. doi:10.1021/ja027073y

    Article  CAS  PubMed  Google Scholar 

  • You L, Ferdani R, Li R, Kramer JP, Winter RE, Gokel GW (2008) Carboxylate anion diminishes chloride transport through a synthetic, self-assembled transmembrane pore. Chemistry 14:382–396. doi:10.1002/chem.200701071

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Zha HY, Shen B, Yau KH, Li ST, Yao XQ, Yang D (2014) A small synthetic molecule forms selective potassium channels to regulate cell membrane potential and blood vessel tone. Org Biomol Chem 12:8174–8179. doi:10.1039/c4ob01420k

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Financial support for the study is provided by Dr. Peter Berezin. While working on this draft I read this marvelous children book “Dr. Dyers Academy” by Prof. Russell Stannard (I shall suggest it for adults). I am the most grateful to the author for helping me to find right English words to sort out odds about science, technology and science education, or lack thereof. This keeps me positive and ensured that despite all the odds in the world, I can benefit society the most through my own writing efforts.

Author information

Authors and Affiliations

  1. Montreal, QC, Canada

    Sofya Kostina Berezin

Authors
  1. Sofya Kostina Berezin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sofya Kostina Berezin.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 24433 kb)

Supplementary material 2 (DOCX 158 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Berezin, S.K. Valinomycin as a Classical Anionophore: Mechanism and Ion Selectivity. J Membrane Biol 248, 713–726 (2015). https://doi.org/10.1007/s00232-015-9784-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-015-9784-y

Keywords

Search

Navigation