Adenosine Deaminase-like Protein 1 (ADAL1): Characterization and Substrate Specificity in the Hydrolysis of N6- or O6-Substituted Purine or 2-Aminopurine Nucleoside Monophosphate

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• 作者：Eisuke Murakami ; Haiying Bao ; Ralph T. Mosley ; Jinfa Du ; Michael J. Sofia ; Phillip A. Furman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5902-5914
• 全文大小：1314K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

Human N⁶-methyl-AMP/dAMP aminohydrolase has been shown to be involved in metabolism of pharmacologically important N⁶-substituted purine nucleosides and 5鈥?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鈥揳ctivity relationship study showed that ADAL1 was able to catalyze removal of different alkyl groups not only from N⁶-substituted purine or 2-aminopurine nucleoside monophosphates but also from O⁶-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.