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Researchers have found a molecular link between selenium and cancer before that selenium was considered a toxin many years ago. According to these findings, Selenium has some of the most important roles in humans and other animals. Selenium acts through the formation of Selenoproteins. Selenocysteine is a Selenium-containing Cysteine residue that is found in some proteins of eukaryotes, Archaea, bacteria and some viruses. Proteins, like Glutathione Peroxidase, bacterial Selenoprotein A, contain Selenocysteine and the sequencing of Selenoproteins reveals that the UGA codon corresponded to the location of Selenocysteine.
Selenocysteine and proteins containing Selenocysteine
Human Selenoproteins are encoded by 25 genes and half of them are Oxidoreductase while the functions of others are still unclear. Examples of human Selenoproteins include Glutathione Peroxidases, Thioredoxin Reductases, Thyroid Hormone Deiodinases, and Methionine-R-Sulfoxide Reductase. In addition to these enzymes, Selenocysteine Synthetase 2 is a Selenoenzyme that catalyzes the ATP-dependent synthesis of Selenophosphate. Some other properties of Selenoproteins are pro- and anticancer activities, roles in the immune system, etc.
Selenocysteine tRNA and Biosynthesis of Selenocysteine
In genetic codon, UGA represents the codon of 21st amino acid Selenocysteine. Therefore, Selenocysteine has its own tRNA, playing a major role in incorporating Selenocysteine into the polypeptide. Initially, this tRNA is aminoacylated with Serine and therefore, it is designated as tRNA[Ser]Sec. It has two isoforms Mcm5U which are involved in the expression of housekeeping Selenoproteins and mcm5Um which involves the expression of both housekeeping and stress-related Selenoproteins.
Seryl-tRNA[ser]sec is converted to Phosphoseryl-tRNA[ser]sec catalyzed by Phosphoseryl-tRNA[ser]sec Kinase (PSTK) and ATP-dependent Selenophosphate Synthetase 2 catalyzes the conversion of Selenide to Selenophosphate. Thus formed Selenophosphate reacts with Phosphoseryl-tRNA[ser]sec catalyzed by Selenocysteine Synthase (secS) to form Selenocysteyl-tRNA[ser]sec. However, is some cases, Cysteine can also be found in place of the Selenocysteine which is incorporated in the same way as Selenocysteine.
Sulfide is converted into the Thiophosphate catalyzed by the Selenophosphate Synthetase 2. Thus formed Thiophosphate reacts with Phosphoseryl-tRNA[ser]sec, catalyzed by Selenocysteine Synthase to form cys-tRNA[ser]sec that inserts Cys at UGA codon of Selenoprotein mRNA.
Translation of Selenoprotein mRNA
Sec insertion sequence (SECIS) element, present in the 3′-Untranslated Region (UTR) of the Selenoprotein mRNA plays an important role in inserting Selenocysteine into then stop codon UGA. It reads the stop codon UGA as a Selenocysteine codon. It serves as an attachment site for the elongation factor, SelB which is brought to the ribosome in a complex with sec-tRNA[ser]sec.
While, in the case of Archaea and eukaryotes, additional factors are involved like specific Elongation Factor (EFsec) which forms a complex with Sec-tRNA[Ser]Sec (EFsec-Sec-tRNA[Ser]Sec) that binds to the SECIS Binding Protein-2 (SBP2)-SECIS complex and the ribosome. There are three more factors and these are Ribosomal Protein L30 which serves as part of the basic machinery responsible for Sec insertion, Nucleolin, and Eukaryotic Initiation Factor eIF4a3. Nucleolin and eIF4a3 have regulatory roles tempering Selenoprotein synthesis.
Reference: Hatfield, Dolph L., et al. “Selenium and selenocysteine: roles in cancer, health, and development.” Trends in biochemical sciences 39.3 (2014): 112-120.
Article DOI: 10.1016/j.tibs.2013.12.007