title: Proximal ADP-ribose Hydrolysis in Trypanosomatids is Catalyzed by a Macrodomain.
abstract: ADP-ribosylation is a ubiquitous protein modification utilized by both prokaryotes and eukaryotes for several cellular functions, such as DNA repair, proliferation, and cell signaling. Higher eukaryotes, such as humans, utilize various enzymes to reverse the modification and to regulate ADP-ribose dependent signaling. In contrast, some lower eukaryotes, including trypanosomatids, lack many of these enzymes and therefore have a much more simplified ADP-ribose metabolism. Here we identified and characterized ADP-ribose hydrolases from Trypanosoma brucei and Trypanosoma cruzi, which are homologous to human O-acetyl-ADP-ribose deacetylases MacroD1 and MacroD2. The enzymes are capable for hydrolysis of protein linked ADP-ribose and a product of sirtuin-mediated lysine deacetylation, O-acetyl-ADP-ribose. Crystal structures of the trypanosomatid macrodomains revealed a conserved catalytic site with distinct differences to human MacroD1 and MacroD2.
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Haikarainen
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014 Oulu, Finland.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D055162:Biocatalysis; D002151:Calorimetry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D006801:Humans; D006867:Hydrolases / Q000737:chemistry / Q000378:metabolism; D006868:Hydrolysis; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D016415:Sequence Alignment; D037761:Sirtuins / Q000378:metabolism; D013816:Thermodynamics; D014346:Trypanosoma brucei brucei / Q000201:enzymology*; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D015800:Protozoan Proteins; D011994:Recombinant Proteins; D000246:Adenosine Diphosphate Ribose; D006867:Hydrolases; D036541:ADP-ribosyl Cyclase; D037761:Sirtuins