PMID- 25517013
OWN - NLM
STAT- MEDLINE
DCOM- 20150408
LR  - 20150120
IS  - 1520-4995 (Electronic)
IS  - 0006-2960 (Linking)
VI  - 54
IP  - 2
DP  - 2015 Jan 20
TI  - Axial hydrogen at C7 position and bumpy tetracyclic core markedly reduce sterol's 
      affinity to amphotericin B in membrane.
PG  - 303-12
LID - 10.1021/bi5012942 [doi]
AB  - 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 Delta7-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 Delta5, Delta7, and Delta9 positions. 
      Intermolecular distance measurements by (13)C(19)F 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 Delta5-sterol 
      (2, 6) and the protruded A-ring of Delta5,7,9-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 alpha-face of sterol 
      alicycle interacts with the flat macrolide structure of AmB.
FAU - Nakagawa, Yasuo
AU  - Nakagawa Y
AD  - Department of Chemistry, Graduate School of Science, Osaka University , 1-1 
      Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
FAU - Umegawa, Yuichi
AU  - Umegawa Y
FAU - Nonomura, Kenichi
AU  - Nonomura K
FAU - Matsushita, Naohiro
AU  - Matsushita N
FAU - Takano, Tetsuro
AU  - Takano T
FAU - Tsuchikawa, Hiroshi
AU  - Tsuchikawa H
FAU - Hanashima, Shinya
AU  - Hanashima S
FAU - Oishi, Tohru
AU  - Oishi T
FAU - Matsumori, Nobuaki
AU  - Matsumori N
FAU - Murata, Michio
AU  - Murata M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150105
PL  - United States
TA  - Biochemistry
JT  - Biochemistry
JID - 0370623
RN  - 0 (Antifungal Agents)
RN  - 0 (Liposomes)
RN  - 0 (Sterols)
RN  - 7XU7A7DROE (Amphotericin B)
SB  - IM
MH  - Amphotericin B/*chemistry/*pharmacology
MH  - Antifungal Agents/*chemistry/*pharmacology
MH  - Cell Membrane/chemistry/drug effects/metabolism
MH  - Fungi/cytology/drug effects/metabolism
MH  - Humans
MH  - Liposomes/chemistry/*metabolism
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - Mycoses/drug therapy/microbiology
MH  - Sterols/chemistry/*metabolism
EDAT- 2014/12/18 06:00
MHDA- 2015/04/09 06:00
CRDT- 2014/12/18 06:00
PHST- 2014/12/18 06:00 [entrez]
PHST- 2014/12/18 06:00 [pubmed]
PHST- 2015/04/09 06:00 [medline]
AID - 10.1021/bi5012942 [doi]
PST - ppublish
SO  - Biochemistry. 2015 Jan 20;54(2):303-12. doi: 10.1021/bi5012942. Epub 2015 Jan 5.