Theoretical Study on the Repair Mechanism of the (6−4) Photolesion by the (6−4) Photolyase

详细信息    查看全文

• 作者：Keyarash Sadeghian ; Marco Bocola ; Thomas Merz ; Martin Schtz
• 刊名：Journal of the American Chemical Society
• 出版年：2010
• 出版时间：November 17, 2010
• 年：2010
• 卷：132
• 期：45
• 页码：16285-16295
• 全文大小：514K
• 年卷期：v.132,no.45(November 17, 2010)
• ISSN：1520-5126

文摘

UV irradiation of DNA can lead to the formation of mutagenic (6−4) pyrimidine−pyrimidone photolesions. The (6−4) photolyases are the enzymes responsible for the photoinduced repair of such lesions. On the basis of the recently published crystal structure of the (6−4) photolyase bound to DNA [Maul et al. 2008] and employing quantum mechanics/molecular mechanics techniques, a repair mechanism is proposed, which involves two photoexcitations. The flavin chromophore, initially being in its reduced anionic form, is photoexcited and donates an electron to the (6−4) form of the photolesion. The photolesion is then protonated by the neighboring histidine residue and forms a radical intermediate. The latter undergoes a series of energy stabilizing hydrogen-bonding rearrangements before the electron back transfer to the flavin semiquinone. The resulting structure corresponds to the oxetane intermediate, long thought to be formed upon DNA−enzyme binding. A second photoexcitation of the flavin promotes another electron transfer to the oxetane. Proton donation from the same histidine residue allows for the splitting of the four-membered ring, hence opening an efficient pathway to the final repaired form. The repair of the lesion by a single photoexcitation was shown not to be feasible.