The ARH and Macrodomain Families of α-ADP-ribose-acceptor Hydrolases Catalyze α-NAD + Hydrolysis

作者：Linda A. Stevens, Jiro Kato, Atsushi Kasamatsu, Hirotake Oda, Duck‐Yeon Lee, Joel Moss · 发表于：ACS Chemical Biology · 年份：2019 · DOI：10.1021/acschembio.9b00429 · 被引用次数：26 · 研究领域：PARP inhibition in cancer therapy、Calcium signaling and nucleotide metabolism、Toxin Mechanisms and Immunotoxins

ADP-ribosyltransferases transfer ADP-ribose from β-NAD + to acceptors; ADP-ribosylated acceptors are cleaved by ADP-ribosyl-acceptor hydrolases (ARHs) and proteins containing ADP-ribose-binding modules termed macrodomains. On the basis of the ADP-ribosyl-arginine hydrolase 1 (ARH1) stereospecific hydrolysis of α-ADP-ribosyl-arginine and the hypothesis that α-NAD + is generated as a side product of β-NAD + / NADH metabolism, we proposed that α-NAD + was a substrate of ARHs and macrodomain proteins. Here, we report that ARH1, ARH3, and macrodomain proteins (i.e., MacroD1, MacroD2, C6orf130 (TARG1), Af1521, hydrolyzed α-NAD + but not β-NAD + . ARH3 had the highest α-NADase specific activity. The ARH and macrodomain protein families, in stereospecific reactions, cleave ADP-ribose linkages to N- or O- containing functional groups; anomerization of α- to β-forms (e.g., α-ADP-ribosyl-arginine to β-ADP-ribose- (arginine) protein) may explain partial hydrolysis of ADP-ribosylated acceptors with an increase in content of ADP-ribosylated substrates. Af1521 and ARH3 crystal structures with bound ADP-ribose revealed similar ADP-ribose-binding pockets with the catalytic residues of the ARH and macrodomain protein families in the N-terminal helix and loop. Although the biological roles of the ARHs and macrodomain proteins differ, they share enzymatic and structural properties that may regulate metabolites such as α-NAD + .