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.
Highlights
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
In humans over 20 enzymes have been found to catalyze ADP-ribosylation and modification can be reversed by various enzymes: PARG (poly(ADP-ribose) glycohydrolase) and ARH3 (ADP-ribosylhydrolase 3), which can hydrolyze ADP-ribose polymer leaving the proximal ADP-ribose molecule attached to the modified protein; MacroD1 and MacroD2, which cleave the proximal mono-ADP-ribosyl; and OARD1 (O-acetyl-ADP-ribose deacetylase 1), which is capable of hydroxylation of the proximal mono-ADP-ribosylation and cleaving the entire PAR en bloc[4]
Ribose hydrolyzing enzymes of T. cruzi and T. brucei were searched from NCBI non-redundant database using known ADP-ribose hydrolases from human
Summary
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. 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. T. brucei is the causative agent of African trypanosomiasis or sleeping sickness and T. cruzi is responsible for South American trypanosomiasis or Chagas Disease These parasites seem to have a highly simplified ADP-ribose metabolism compared to higher eukaryotes, such as humans. They contain a single PARP opposed to 17 PARPs found in humans[10,11,12] and have two (T. cruzi) or three (T. brucei) sirtuins, while humans have seven ( not all have ADP-ribosylating activity)[13]. The crystal structures of the enzymes reveal highly conserved macrodomain folds containing conserved ADP-ribose binding sites
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