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Large molecular assembly of amphotericin B formed in ergosterol-containing membrane evidenced by solid-state NMR of intramolecular bridged derivative
- Source :
- Journal of the American Chemical Society. 128(36)
- Publication Year :
- 2006
-
Abstract
- Amphotericin B (AmB 1) is known to assemble and form an ion channel across biomembranes. We have recently reported that conformation-restricted derivatives of AmB 2-4 show different ergosterol preferences in ion-channel assays, which suggested that the orientation of the mycosamine strongly affects the sterol selectivity of AmB. The data allowed us to assume that compound 3 showing the highest selectivity would reflect the active conformation of AmB in the channel assembly. In this study, to gain further insight into the active conformation of AmB, we prepared a new intramolecular-bridged derivative 5, where the linker encompassed a hydrophilic glycine moiety. The derivative has almost equivalent ion-channel activity to those of AmB and 3. The antifungal activity of 5 compared with 3 improves significantly, possibly because the increasing hydrophilicity in the linker enhances the penetrability through the fungal cell wall. Conformation of 5 was well converged and very similar to that of 3, thus further supporting the notion that the conformations of these derivatives reproduce the active structure of AmB in the channel complex. Then we used the derivative to probe the mobility of AmB in the membrane by solid-state NMR. To measure dipolar couplings and chemical shift anisotropies, we incorporated [1-(13)C,(15)N]glycine into the linker. The results indicate that 5 is mostly immobilized in ergosterol-containing DMPC bilayers, implying formation of large aggregates of 5. Meanwhile some fraction of 5 remains mobile in sterol-free DMPC bilayers, suggesting promotion of AmB aggregation by ergosterol.
- Subjects :
- Models, Molecular
Stereochemistry
Lipid Bilayers
Molecular Conformation
Biochemistry
Catalysis
Ion Channels
chemistry.chemical_compound
Colloid and Surface Chemistry
Amphotericin B
Ergosterol
Molecule
Moiety
Nuclear Magnetic Resonance, Biomolecular
technology, industry, and agriculture
Biological membrane
General Chemistry
Membrane
Solid-state nuclear magnetic resonance
chemistry
Liposomes
Potassium
Selectivity
Dimyristoylphosphatidylcholine
Linker
Subjects
Details
- ISSN :
- 00027863
- Volume :
- 128
- Issue :
- 36
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....7eee42a2307db7dccbfe6275bf9a16b1