Adenosine deaminase-like protein 1 (ADAL1): characterization and substrate specificity in the hydrolysis of N(6)- or O(6)-substituted purine or 2-aminopurine nucleoside monophosphates.

Human N6-methyl-AMP/dAMP aminohydrolase has been shown to be involved in metabolism of pharmacologically important N6-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 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 ...