Catalytic mechanism of yeast cytosine deaminase: An ONIOM computational study
Catalytic mechanism of yeast cytosine deaminase: An ONIOM computational study
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DOI：
10.1021/ja046462k
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发表时间：
2004-11-17
影响因子：
15
通讯作者：
Yan, HG
中科院分区：
文献类型：
--
作者：
Sklenak, S;Yao, LS;Yan, HG
酵母胞嘧啶脱氨酶（酵母胞嘧啶脱氨酶，一种具有重要生物医学意义的锌金属酶）催化的脱氨反应的完整路径已经用ONIOM方法进行了研究。胞嘧啶脱氨是通过一系列的机制进行的，包括N-3的质子化，锌配位氢氧化物对C-4的亲核攻击，以及C-4- n -4键的断裂。最后一步是锌结合尿嘧啶生成的速率决定步骤。尿嘧啶通过氧交换机制从锌原子中释放出来，该机制包括由锌结合的尿嘧啶和水分子形成宝石二醇中间体，C-4-O-Zn裂解，以及锌配位水的再生。氧交换的速率决定步骤是宝石二醇中间体的形成，这也是整个ycd催化脱氨反应的速率决定步骤。
The complete path for the deamination reaction catalyzed by yeast cytosine deaminase (yCD), a zinc metalloenzyme of significant biomedical interest, has been investigated using the ONIOM method. Cytosine deamination proceeds via a sequential mechanism involving the protonation of N-3, the nucleophilic attack of C-4 by the zinc-coordinated hydroxide, and the cleavage of the C-4-N-4 bond. The last step is the rate determining step for the generation of the zinc bound uracil. Uracil is liberated from the Zn atom by an oxygen exchange mechanism that involves the formation of a gem-diol intermediate from the Zn bound uracil and a water molecule, the C-4-O-Zn cleavage, and the regeneration of the Zn-coordinated water. The rate determining step in the oxygen exchange is the formation of the gem-diol intermediate, which is also the rate determining step for the overall yCD-catalyzed deamination reaction.