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- Title
A model for enediyne antibiotic transport/release.
- Authors
Hariharan, Parameswaran; Shan-Ho Chou; Der-Hang Chin
- Abstract
The cytocidal activity of antibiotic chromoproteins such as neocarzinostatin critically relies on efficient dissociation of DNA-cleaving enediyne chromophore from the tightly bound carrier protein. However, the precise mode of chromophore release under physiological conditions is poorly understood. Here we demonstrate a novel hydrophobic-sensing mechanism for triggering the enediyne chromophore release from the chromoprotein complex using large unilammelar vesicles (LUVs) to mimic cellular membranes. Kinetics study monitored by fluorescence spectroscopy reveals a lipid concentration-dependent increase in antibiotic release rate. The results correlate well with the quantitative HPLC analyses. Circular dichroism analysis of neocarzinostatin in the presence of LUVs clearly shows that no major protein conformational changes are involved in the triggering process. Furthermore, the lipid-bilayer is shown to prevent the spontaneous-degradation of the released chromophore through hydrophobic interaction of the chromophore in the bilayer surface. Collectively, the above results lead to an antibiotic transport/release model, wherein we demonstrate how lipid bilayer membrane is likely to mediate the efficient dissociation of the chromophore, and to act as a protector and carrier until the chromophore is delivered for DNA cleavage. Our in vitro observations may be relevant to understanding the modus operandi of potential antitumor enediyne drugs.
- Subjects
ENEDIYNES; FLUORESCENCE spectroscopy; ANTIBIOTICS; PROTEINS; BILAYER lipid membranes
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA628
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fasebj.21.5.a628-b