Adenosine Deaminase-like Protein 1 (ADAL1): Characterization and Substrate Specificity in the Hydrolysis of N6- or O6-Substituted Purine or 2-Aminopurine Nucleoside Monophosphates
Adenosine Deaminase-like Protein 1 (ADAL1): Characterization and Substrate Specificity in the Hydrolysis of N6- or O6-Substituted Purine or 2-Aminopurine Nucleoside Monophosphates
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DOI：
10.1021/jm200650j
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发表时间：
2011-08-25
影响因子：
7.3
通讯作者：
Furman, Phillip A.
中科院分区：
文献类型：
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作者：
Murakami, Eisuke;Bao, Haiying;Furman, Phillip A.
人类n -6-甲基amp /dAMP氨基水解酶已被证明参与了重要的n -6取代嘌呤核苷及其5'-单磷酸前药的代谢。该酶克隆并在大肠杆菌中表达，质谱分析和氨基酸序列分析表明该蛋白为腺苷脱氨酶样蛋白异构体1 （ADAL1）。广泛的构效关系研究表明，ADAL1不仅能催化去除n -6取代嘌呤或2-氨基嘌呤核苷单磷酸酯中的不同烷基，还能催化去除o -6取代化合物中的不同烷基。ADAL1的活性易受磷酸基修饰的影响，而不受糖基修饰的影响。总的来说，我们的数据表明ADAL1特异性作用于嘌呤和2-氨基嘌呤核苷单磷酸的6位。我们的结果可能有助于设计具有所需代谢谱的新的治疗性核苷/核苷酸前药。此外，氨基酸序列分析结合晶体学数据和金属分析表明，ADAL1含有催化锌离子。最后，讨论了ADAL1的潜在生理作用。
Human N-6-methyl-AMP/dAMP aminohydrolase has been shown to be involved in metabolism of pharmacologically important N-6-substituted purine nucleosides and 5'-monophosphate prodrugs thereof. This enzyme was cloned and expressed in E. coli, and mass spectroscopic analysis followed by amino acid sequence analyses indicated that the protein was adenosine deaminase-like protein isoform 1 (ADAL1). An extensive structure-activity relationship study showed that ADAL1 was able to catalyze removal of different alkyl groups not only from N-6-substituted purine or 2-aminopurine nucleoside monophosphates but also from O-6-substituted compounds. The ADAL1 activity was susceptible to modifications in the phosphate moiety but not to changes in the sugar moiety. Overall, our data indicated that ADAL1 specifically acts at the 6-position of purine and 2-aminopurine nucleoside monophosphates. Our results may help designing of new therapeutic nucleoside/nucleotide prodrugs with desired metabolic profiles. Furthermore, amino acid sequence analysis in conjunction with crystallographic data and metal analysis suggested that ADAL1 contains a catalytic zinc ion. Finally, a potential physiological role of ADAL1 is discussed.