Trypanosomatid selenophosphate synthetase structure, function and interaction with selenocysteine lyase

Abstract

Eukaryotes from the Excavata superphylum have been used as models to study the evolution of cellular molecular processes. Strikingly, human parasites of the Trypanosomatidae family ( T . brucei , T . cruzi and L . major ) conserve the complex machinery responsible for selenocysteine biosynthesis and incorporation in selenoproteins (SELENOK/SelK, SELENOT/SelT and SELENOTryp/SelTryp), although these proteins do not seem to be essential for parasite viability under laboratory controlled conditions. Selenophosphate synthetase (SEPHS/SPS) plays an indispensable role in selenium metabolism, being responsible for catalyzing the formation of selenophosphate, the biological selenium donor for selenocysteine synthesis. We solved the crystal structure of the L . major selenophosphate synthetase and confirmed that its dimeric organization is functionally important throughout the domains of life. We also demonstrated its interaction with selenocysteine lyase (SCLY) and showed that it is not present in other stable assemblies involved in the selenocysteine pathway, namely the phosphoseryl-tRNA Sec kinase (PSTK)-Sec-tRNA Sec synthase (SEPSECS) complex and the tRNA Sec -specific elongation factor (eEFSec) complex. Endoplasmic reticulum stress with dithiothreitol (DTT) or tunicamycin upon selenophosphate synthetase ablation in procyclic T . brucei cells led to a growth defect. On the other hand, only DTT presented a negative effect in bloodstream T . brucei expressing selenophosphate synthetase-RNAi. Furthermore, selenoprotein T (SELENOT) was dispensable for both forms of the parasite. Together, our data suggest a role for the T . brucei selenophosphate synthetase in the regulation of the parasite’s ER stress response.

Selenium and protozoan parasitic infections: selenocompounds and selenoproteins potential

“…It is well known that pathogenic trypanosomatids have conserved the machinery responsible for selenocysteine biosynthesis and its incorporation in selenoproteins (Manhas et al 2016). In addition, only three selenoproteins containing a redox center selenocysteine-based have been reported in trypanosomatids (da Silva et al 2020). However, regarding the African Trypanosoma, it seems that those selenoproteins were not required for infectivity and acute infection progression in mice, and null-mutants showed similar sensitivity to stress conditions and to drugs targeting these enzymes than wild-type strains (Aeby et al 2009;Bonilla et al 2016).…”

“…However, regarding the African Trypanosoma, it seems that those selenoproteins were not required for infectivity and acute infection progression in mice, and null-mutants showed similar sensitivity to stress conditions and to drugs targeting these enzymes than wild-type strains (Aeby et al 2009;Bonilla et al 2016). Moreover, the ablation of enzymes participating in selenoproteins synthesis caused a higher sensitivity to endoplasmic reticulum stressors, one of those selenoproteins containing selenocysteine in its redox domain demonstrated to be dispensable for T. brucei (da Silva et al 2020). Accordingly, since most selenoproteins are important redox enzymes containing a catalytic selenocysteine residue, the selenoproteome of the protozoan parasites could link with critical functions and vital mechanisms in these parasites (Lobanov et al 2006b).…”