Direct and stereospecific interaction of amphidinol 3 with sterol in lipid bilayers.
Amphidinol 3 (AM3), a polyhydroxy-polyene metabolite from the dinoflagellate Amphidinium klebsii, possesses potent antifungal activity. Although AM3 permeabilizes phospholipid membranes only in the presence of sterol, the detailed molecular basis by which AM3 recognizes sterols in membranes remains unknown. Here, we investigated the molecular interaction between sterols and AM3 in membranes from the viewpoint of stereospecific molecular recognition using ergosterol, cholesterol, and epicholesterol, which is the 3-OH epimer of cholesterol. Dye leakage assays, surface plasmon resonance experiments, (2)H and (31)P NMR measurements, and microscopic observations revealed that AM3 directly interacts with membrane sterols through the strict molecular recognition of the stereochemistry of the sterol 3-OH group. The direct interaction enhances the membrane binding efficiency of AM3, which subsequently permeabilizes membranes without altering membrane integrity.
Department of Chemistry, Graduate School of Science, Osaka University , Osaka 560-0043, Japan.
Rafael Atillo
RA
Espiritu
Nobuaki
N
Matsumori
Masashi
M
Tsuda
Michio
M
Murata
D000475:Alkenes / Q000737:chemistry* / Q000378:metabolism*; D002478:Cells, Cultured; D004141:Dinoflagellida / Q000737:chemistry / Q000378:metabolism; D004347:Drug Interactions; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D011714:Pyrans / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D000095722:Amphidinols
D000475:Alkenes; D008051:Lipid Bilayers; D011714:Pyrans; C438973:amphidinol 3; D000095722:Amphidinols