Axial Hydrogen at C7 Position and Bumpy Tetracyclic Core Markedly Reduce Sterol鈥檚 Affinity to Amphotericin B in Membrane

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• 作者：Yasuo Nakagawa ; Yuichi Umegawa ; Kenichi Nonomura ; Naohiro Matsushita ; Tetsuro Takano ; Hiroshi Tsuchikawa ; Shinya Hanashima ; Tohru Oishi ; Nobuaki Matsumori ; Michio Murata
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：January 20, 2015
• 年：2015
• 卷：54
• 期：2
• 页码：303-312
• 全文大小：498K
• ISSN：1520-4995

文摘

The interaction of amphotericin B (AmB) with fungal ergosterol (Erg) is stronger than its interaction with mammalian cholesterol (Cho), and this property of AmB as an antifungal drug is thought to be responsible for its selective toxicity toward fungi. However, the mechanism by which AmB recognizes the structural differences between sterols, particularly minor difference in the sterol alicyclic portion, is largely unknown. Thus, to investigate the mode of interaction between AmB and the sterol core, we assessed the affinity of AmB to various sterols with different alicyclic structures. Ion flux assays and UV spectral measurements clearly revealed the importance of the 螖7-double bond of the sterol B-ring for interaction with the drug. AmB showed lower affinity for triene sterols, which have double bonds at the 螖5, 螖7, and 螖9 positions. Intermolecular distance measurements by ¹³C{¹⁹F} rotational echo double resonance (REDOR) revealed that the AmB macrolide ring is in closer contact with the steroid core of Erg than it is with the Cho core in the membrane. Conformational analysis suggested that an axial hydrogen atom at C7 of 螖5-sterol (2, 6) and the protruded A-ring of 螖5,7,9-sterol (4, 8) sterically hampered face-to-face contact between the van der Waals surface of the sterol core and the macrolide of AmB. These results further suggest that the 伪-face of sterol alicycle interacts with the flat macrolide structure of AmB.