Selenium and selenocysteine: roles in cancer, health, and development

Abstract

The many biological and biomedical effects of selenium are relatively unknown outside the selenium field. This fascinating element, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid-1990s selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results. However, basic research on selenium continued to move at a rapid pace, elucidating its many roles in health, development, and in cancer prevention and promotion. Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions.

Keywords: cancer; selenium; selenocysteine; selenoproteins.

Figure 1

Human selenoproteome. The names, designations, protein size and location of Sec in human selenoproteins are shown. The length (blue panels) and location of Sec (red mark) in proteins are shown schematically on the right.

Figure 2

Biosynthesis of Sec and de novo biosynthesis of cysteine. The biosynthesis of Sec occurs on its tRNA and the pathway begins with the attachment of serine to Sec tRNA^[Ser]Sec by seryl-tRNA synthetase (SerS) in the presence of ATP. Phosphoseryl-tRNA kinase (PSTK) phosphorylates the serine moiety to form an intermediate, phosphoseryl-tRNA^[Ser]Sec, that in turn is acted upon by Sec synthase (SecS), converting the phosphoserine moiety to an intermediate, likely aminoacrylyl-tRNA^[Ser]Sec. SecS accepts selenophosphate (H₂SePO₃⁻; upper pathway), converting the intermediate to Sec-tRNA^[Ser]Sec. Selenophosphate synthetase 2 (SPS2) synthesizes selenophosphate from selenide in the presence of ATP. In the lower pathway, sulfide can replace selenide in the reaction with SPS2, generating thiophosphate (H₂SPO₃⁻) that in turn can interact with SecS and PSer-tRNA^[Ser]Sec to yield Cys-tRNA^[Ser]Sec.

Figure 3

Incorporation of Sec into protein in mammals. The incorporation of Sec into protein involves a multifarious complex containing the Sec insertion sequence (SECIS) binding protein 2, SBP2, bound to the SECIS element that occurs in the selenoprotein mRNA 3’-untranslated region and the Sec elongation factor, EFsec, bound with Sect-RNA^[Ser]Sec that is decoded at the ribosomal acceptor site. The other factors, L30, eIF4a3 and nucleolin, have regulatory roles in governing the insertion process. The decoded Sec-tRNA^[Ser]Sec will be transferred to the peptidyl site, wherein the growing polypeptide will be covalently bound to Sec-tRNA^[Ser]Sec.