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標題: 新抑癌素蛋白D79殘基負電荷對引導生色團環化路徑之影響
Effect of D79 negative charge of neocarzinostatin protein on directing cyclization pathway of its chromophore
作者: 鄭靖修
Cheng, Ching-Hsiu
關鍵字: neocarzinostatin;新抑癌素;enediyne;antitumor;cycloaromatization mechanism;HSQC NMR;protein mutanttion;烯雙炔;環化機制;抗腫瘤;異種核磁共振;蛋白突變
出版社: 化學系所
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Neocarzinostatin is a natural potent antitumor antibiotic chromoprotein. It consists of a carrier protein, aponeocarzinostatin, and a biologically active enediyne chromophore. Without the protein, the enediyne nucleus of neocarzinostatin chromophore is cycloaromatized upon a thiolate attack to form product 1, and the radical precursor of which is responsible for DNA cleavage. Whereas in the holo form of neocarzinostatin, product 1 formation is highly suppressed as the protein diverts the major cycloaromatization path into a distinct one that produces product 2. How the protein directs such a chemical path is an interesting question. We produced recombinant aponeocarzinostatin that is identical to the natural one, and employed the alanine-scanning mutagenesis to probe the influence of residues around binding cleft on directing the enediyne cycloaromatization pathways. We found that mutant D79A significantly abolishes the protein directing power. In this study, we designed and performed several mutations focusing around D79. The circular dichroism spectra of all the mutants show a folded structure that is similar to that of the wild-type aponeocarzinostatin. Two-dimensional nuclear magnetic resonance spectra of purified 15N-labeled D79A and double mutant L77D/D79A demonstrate that most residues around binding site are not perturbed by mutations. The thiol-induced enediyne cycloaromatization reaction was then performed on each chromophore-reconstituted neocarzinostatin mutant, and the yield of product 1 was determined by high pressure liquid chromatographic analyses. Our results clearly show that negative charge of D79 is crucial for directing the chemical cyclization pathway of neocarzinostatin chromophore. Considering ring strain and hybrid orbitals of possible cyclized intermediates, we proposed a mechanism of formation of product 2.
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