Abstract
Drosophila melanogaster is used as a model system in biomedical studies. Selenoprotein is the major biological form of selenium in eukaryotes. Selenoproteins are generally involved in catabolic pathways in bacteria and archaea, whereas it participates in anabolic and antioxidant processes in eukaryotic. In this study, anticancer potential of selenoprotein BthD of D. melanogaster was investigated using bioinformatics methods. Results showed that selenoprotein BthD of D. melanogaster may have dual properties as evident by its orthology with selenoprotein H (SelH) of Homo sapiens and conserved domain of fructokinase-like protein 2 of Vitis vinifera. These dual properties were also revealed in the phylogenetic analysis, while further structural modeling showed that selenoprotein BthD possibly exists as homotetramer in the native functional structure. The anticancer property of selenoprotein BthD was proposed to be by synergy of antioxidant or redox activities of thioredoxin and glutathione reductase (TGR) domain and the signaling function of fructokinase-like protein 2 domain both in Golgi apparatus and cytoplasm, through energy deprivation. The anticancer peptide CRSUR was identified from conserved region of selenoprotein BthD, of which its cyclic form showed potential anticancer properties predictively through E3 ubiquitin-protein ligase regulating NF-kappa-B signaling by unleashing cells for spontaneous formation of the ripoptosome.
Highlights
The homology alignment of BthD protein sequence (Uniprot ID: Q9VYB0) by Blastp confirmed 41.38 % similarity with human selenoprotein H (SelH) (C11orf31) selenoprotein (Uniprot ID: Q8IZQ5) which is located in the Golgi apparatus and cytoplasm
The conserved domain of selenoprotein BthD was found to be exceptional with no similarity in H. sapiens unlike the other three
The conserved protein domain of BthD was classified as kinase which belong to PLN02967 superfamily of fructokinase-like protein 2 (EC 2.7.1.4), and belong to protein clusters conserved in taxonomy of Mesangiospermae in eukaryotic plant
Summary
The human genome contains 25 selenoprotein genes (Kryukov et al 2003) and they are involved in a variety of functions, most notably redox homeostasis. Human selenoprotein enzymes with known functions such as thioredoxin reductases (TR1), glutathione peroxidases (Sep and GPx2) are important cellular redox-regulators needed by both normal and cancer cells, which result in anti- and protumorigenic effects at a tissue-specific cellular level (Hatfield et al 2014). In D. melanogaster, Ser/Thr kinase domain is found in the core kinases of Hippo signaling pathway, as well as in the fourjointed and discs overgrown of upstream regulatory components (Yin and Zhang 2011). The gene product with anticancer properties in an insect could be useful in the development of biologic agent for human cancer therapy
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