Mycosamine orientation of amphotericin B controlling interaction with ergosterol: Sterol-dependent activity of conformation-restricted derivatives with an amino-carbonyl bridge

Nobuaki Matsumori, Yuri Sawada, Michio Murata

研究成果: Contribution to journalArticle査読

73 被引用数 (Scopus)

抄録

Amphotericin B (AmB 1) is known to assemble together and form an ion channel across biomembranes. The antibiotic consists of mycosamine and macrolactone moieties, whose relative geometry is speculated to be determinant for the drug's channel activity and sterol selectivity. To better understand the relationship between the amino-sugar orientation and drug's activity, we prepared conformation-restricted derivatives 2-4, in which the amino and carboxyl groups were bridged together with various lengths of alkyl chains. K+ influx assays across the lipid-bilayer membrane revealed that ergosterol selectivity was markedly different among derivatives; short-bridged derivative 2 almost lost the selectivity, while 3 showed higher ergosterol preference than AmB itself. Monte Carlo conformational analysis of 2-4 based on NOE-derived distances indicated that the amino-sugar moiety of 2 comes close to C41 because of the short bridge, whereas those of 3 and 4 are pointing outward. The mutual orientation of the amino-sugar moiety and macrolide ring is so rigid in derivatives 2 and 3 that these conformations should be unchanged upon complex formation in lipid membranes. These results strongly suggest that the large difference in sterol preference between derivatives 2 and 3 is ascribed to the different orientation of amino-sugar moieties. These findings allowed us to propose a simple model accounting for AmB-sterol interactions, in which hydrogen bonding between 2′-OH of AmB and 3β-OH of ergosterol plays an important role.

本文言語英語
ページ(範囲)10667-10675
ページ数9
ジャーナルJournal of the American Chemical Society
127
30
DOI
出版ステータス出版済み - 8 3 2005
外部発表はい

All Science Journal Classification (ASJC) codes

  • 触媒
  • 化学 (全般)
  • 生化学
  • コロイド化学および表面化学

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