Oxidative stress protection of Trypanosomes requires selenophosphate synthase

Abstract

Selenoproteins are characterized by the incorporation of at least one amino acid selenocysteine (Sec-U) encoded by in-frame UGA stop codons. These proteins, as well as the components of the Sec synthesis pathway, are present in members of the bacteria, archaea and eukaryote domains. Although not a ubiquitous pathway in all organisms, it was also identified in several protozoa, including the Kinetoplastida. Genetic evidence has indicated that the pathway is non-essential to the survival of Trypanosoma growing in non-stressed conditions. By analyzing the effects of RNA interference of the Trypanosoma brucei selenophosphate synthetase SPS2, we found a requirement under sub-optimal growth conditions. The present work shows that SPS2 is involved in oxidative stress protection of the parasite and its absence severely hampers the parasite survival in the presence of an oxidizing environment that results in an apoptotic-like phenotype and cell death.

Biological Implications of Selenium and its Role in Trypanosomiasis Treatment

“…The insertion of selenium into Sec-dependent enzymes requires the formation of a highly reactive reduced selenium donor compound monoselenophosphate. Monoselenophosphate synthesis is catalyzed by SPS in a 1:1 ratio from selenide and ATP [5,[15][16][17].…”

“…Those results suggested that selenoproteins are dispensable for T. brucei metabolism. Costa et al (2011) [17] demonstrated that under stress conditions T. brucei cells lacking SPS presented growth deficiency in both the procyc- lic and bloodstream forms [17], indicating that selenoproteins are relevant for stress protection of the parasite cell, a condition it encounters during its life cycle, and therefore may even be a relevant drug target.…”

“…Three selenoproteins were proposed in Kinetoplastida, two of which are homologs of SelK and SelT, and the third is a novel selenoprotein with two rhodanese domains and one rubredoxin oxygen oxidoreductase domain that appears to be a Kinetoplastida-specific selenoprotein [5,27]. None of the functions of these selenoproteins are known, although new data suggest their participation in redox processes [17].…”

“…Other data showed that T. brucei cells with a silenced SPS2 gene exhibited growth deficiency under oxidative stress conditions caused by overgrowth or the presence of H 2 O 2 in the medium, suggesting that selenoproteins are required only under specific conditions, such as during oxidative stress [17]. Eze et al [51] and Tonin et al [52] suggested that the mechanism by which Se reduces T. evansi and T. brucei parasitemia may be attributed to the antioxidant function of enzymes such as glutathione peroxidase or other proteins that contain selenocysteine, which is involved in host oxidative stress defense.…”

Highlights on Trypanosomatid Aminoacyl-tRNA Synthesis

“…The human seryl-tRNA synthetase charges tRNA Ser tenfold more effi ciently than tRNA Sec and the E. coli enzyme shows a 100-fold difference in favor of tRNA Ser (Geslain et al 2006 ). Given the necessity of a more "specialized" serylation reaction for tRNA Sec , together with the observation that auranofi n, a highly specifi c inhibitor of eukaryotic selenoenzymes, is very toxic for bloodstream and procyclic stages of T. brucei (Lobanov et al 2006 ), and given the importance of SPS2 for protection against H 2 O 2 generated reactive oxygen species in bloodstream and procyclic T. brucei 29-13 cells (Costa et al 2011 ), one can deduce that the Kinetoplastida selenoprotein system is permeated with interesting facts that need to be better understood.…”