Abstract
Trypanosomiasis infects more than 21 million people and claims approximately 2 million lives annually. Due to the development of resistance against currently available anti-trypanosomal drugs, there is a growing need for specific inhibitors and novel drug targets. Of late, the proteins from the Ubiquitin Proteasome Pathway (UPP): ubiquitin ligases and deubiquitinase have received attention as potential drug targets in other parasites from the apicomplexan family. The completion of Trypanosoma cruzi (Tc) genome sequencing in 2005 and subsequent availability of database resources like TriTrypDB has provided a platform for the systematic study of the proteome of this parasite. Here, we present the first comprehensive survey of the UPP enzymes, their homologs and other associated proteins in trypanosomes and the UPPs from T. cruzi were explored in detail. After extensive computational analyses using various bioinformatics tools, we have identified 269 putative UPP proteins in the T. cruzi proteome along with their homologs in other Trypanosoma species. Characterization of T. cruzi proteome was done based on their predicted subcellular localization, domain architecture and overall expression profiles. Specifically, unique domain architectures of the enzymes and the UPP players expressed exclusively in the amastigote stage provide a rationale for designing inhibitors against parasite UPP proteins.
Highlights
Due to the development of resistance against currently available anti-trypanosomal drugs, there is a growing need for specific inhibitors and novel drug targets
We have used HMMer tool based on Hidden Markov Models (HMMs) for identifying the common domains (24 Pfam domains) present in Ubiquitin Proteasome Pathway (UPP) proteins such as Ubiquitin (Ub), Ubiquitin like modifiers (Ubls), Ubiquitin activating enzymes (E1s), Ubiquitin conjugating enzymes (E2s), Ubiquitin ligases (E3s) and Deubiquitinating enzymes (DUBs)
The analysis showed that 46 orthologous clusters were found commonly in T. cruzi, T. brucei gambiense, T. brucei brucei, T. cruzi marinkelli, T. congolense and T. rangeli
Summary
Due to the development of resistance against currently available anti-trypanosomal drugs, there is a growing need for specific inhibitors and novel drug targets. Ubiquitination is the post-translational addition of ubiquitin to target proteins to control their intracellular levels through proteasome-mediated proteolysis as well as to modulate their functions by proteasome independent processes Another class of proteins related to Ub called as ubiquitin like modifiers (Ubls), which shares high structural similarity with the Ub fold[1]. E2 transfers the Ub/Ubl to protein substrate with the assistance of target specific classes of ubiquitin ligases (E3s), accompanied by the formation of an isopeptide bond between carboxyl group of glycine and ε-amino group of a lysine residue on the substrate protein (see Fig. 1a). E3 ligases are classified into three major classes: HECT, RING and RBR based on their characteristic domains and mechanism of ubiquitin transfer to substrate. RBR have the presence of two predicted RING domains (RING1 and RING2)
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