Abstract
Selenocysteine (Sec) is cotranslationally inserted into protein in response to UGA codons and is the 21st amino acid in the genetic code. However, the means by which Sec is synthesized in eukaryotes is not known. Herein, comparative genomics and experimental analyses revealed that the mammalian Sec synthase (SecS) is the previously identified pyridoxal phosphate-containing protein known as the soluble liver antigen. SecS required selenophosphate and O-phosphoseryl-tRNA[Ser]Sec as substrates to generate selenocysteyl-tRNA[Ser]Sec. Moreover, it was found that Sec was synthesized on the tRNA scaffold from selenide, ATP, and serine using tRNA[Ser]Sec, seryl-tRNA synthetase, O-phosphoseryl-tRNA[Ser]Sec kinase, selenophosphate synthetase, and SecS. By identifying the pathway of Sec biosynthesis in mammals, this study not only functionally characterized SecS but also assigned the function of the O-phosphoseryl-tRNA[Ser]Sec kinase. In addition, we found that selenophosphate synthetase 2 could synthesize monoselenophosphate in vitro but selenophosphate synthetase 1 could not. Conservation of the overall pathway of Sec biosynthesis suggests that this pathway is also active in other eukaryotes and archaea that synthesize selenoproteins.
Highlights
Selenocysteine (Sec) is a selenium-containing amino acid that is cotranslationally inserted into protein and is recognized as the 21st amino acid in the genetic code [1,2,3]
Sec is incorporated into protein in all three lines of descent, eukaryota, archaea, and eubacteria, but unlike other amino acids, Sec synthesis occurs on its transfer RNA, designated tRNA[Ser]Sec [4,5]. tRNA[Ser]Sec is initially aminoacylated with serine by seryl-tRNA synthetase and the seryl moiety provides the backbone for Sec synthesis
We were able to characterize the activity of this synthase using selenophosphate and a tRNA aminoacylated with phosphoserine as substrates to generate selenocysteine
Summary
Selenocysteine (Sec) is a selenium-containing amino acid that is cotranslationally inserted into protein and is recognized as the 21st amino acid in the genetic code [1,2,3]. Bacterial Sec synthase (SecS) (E. coli selenocysteine synthase [SelA]) is a pyridoxal phosphate (PLP)-dependent protein that converts the serine attached to tRNA[Ser]Sec to Sec by initially removing the hydroxyl group from serine to form an aminoacrylyl intermediate. This intermediate serves as the acceptor for activated selenium, and when selenium is donated, selenocysteyl-tRNA[Ser]Sec is formed. The active selenium donor in bacteria is synthesized from selenide and ATP by E. coli selenophosphate synthetase (SelD), and the product of the reaction has been identified as monoselenophosphate (SeP) [9]
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