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J Am Chem Soc. 2015 Dec 9;137(48):15102-4. doi: 10.1021/jacs.5b05766. Epub 2015 Nov 30.

C3-OH of Amphotericin B Plays an Important Role in Ion Conductance.

Author information

1
Howard Hughes Medical Institute, ‡Department of Chemistry, §Department of Biochemistry, ∥School of Chemical Sciences, ⊥National Center for Supercomputing Applications, University of Illinois at Urbana-Champaign , Urbana, Illinois 61801, United States.

Abstract

Amphotericin B (AmB) is the archetype for small molecules that form ion channels in living systems and has recently been shown to replace a missing protein ion transporter and thereby restore physiology in yeast. Molecular modeling studies predict that AmB self-assembles in lipid membranes with the polyol region lining a channel interior that funnels to its narrowest region at the C3-hydroxyl group. This model predicts that modification of this functional group would alter conductance of the AmB ion channel. To test this hypothesis, the C3-hydroxyl group was synthetically deleted, and the resulting derivative, C3deoxyAmB (C3deOAmB), was characterized using multidimensional NMR experiments and single ion channel electrophysiology recordings. C3deOAmB possesses the same macrocycle conformation as AmB and retains the capacity to form transmembrane ion channels, yet the conductance of the C3deOAmB channels is 3-fold lower than that of AmB channels. Thus, the C3-hydroxyl group plays an important role in AmB ion channel conductance, and synthetic modifications at this position may provide an opportunity for further tuning of channel functions.

PMID:
26580003
PMCID:
PMC4687485
DOI:
10.1021/jacs.5b05766
[Indexed for MEDLINE]
Free PMC Article

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