Pathways in De Novo Biosynthesis of Selenocysteine and Cysteine in Eukaryotes
A distinct feature of selenocysteine (Sec) biosynthesis is that this amino acid is synthesized on its tRNA, designated tRNA[Ser]Sec. Sec is then inserted into protein in response to the codon, UGA, as the 21st proteinogenic amino acid. In eukaryotes and a
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Pathways in De Novo Biosynthesis of Selenocysteine and Cysteine in Eukaryotes Vadim N. Gladyshev, Bradley A. Carlson, and Dolph L. Hatfield
Abstract A distinct feature of selenocysteine (Sec) biosynthesis is that this amino acid is synthesized on its tRNA, designated tRNA[Ser]Sec. Sec is then inserted into protein in response to the codon, UGA, as the 21st proteinogenic amino acid. In eukaryotes and archaea, Sec biosynthesis involves several steps. Transfer RNA[Ser]Sec is first aminoacylated by seryl-tRNA synthetase with serine. O-PhosphoseryltRNA[Ser]Sec kinase phosphorylates seryl-tRNA[Ser]Sec forming O-phosphoseryltRNA[Ser]Sec that in turn reacts with Sec synthase (SEPSECS) in the presence of selenophosphate yielding Sec-tRNA[Ser]Sec. Selenophosphate is generated by selenophosphate synthetase 2 (SPS2) from selenide and/or other selenium metabolites and ATP. Interestingly, sulfide can replace selenide in the reaction involving SPS2 yielding thiophosphate which can then form cysteine- (Cys)-tRNA[Ser]Sec in the presence of SEPSECS. The Cys moiety on Cys-tRNA[Ser]Sec can donate Cys to protein in response to UGA codons at internal positions of mammalian selenoprotein mRNAs. Cys/Sec replacement occurs naturally in vivo and the amount of replacement is dependent on the level of selenium in the diet. Keywords Codon UGA • Cysteine • De novo biosynthesis • Selenocysteine • Selenocysteine tRNA • Selenoprotein biosynthesis • Selenoproteins
4.1
Introduction
The selenium-containing amino acid, selenocysteine (Sec), is biosynthesized unlike any other known amino acid in eukaryotes in that it is synthesized on its tRNA, designated tRNA[Ser]Sec. Transfer RNA[Ser]Sec has many unique features that distinguish it from all canonical tRNAs as detailed in Chap. 1. Other than seryl-tRNA
V.N. Gladyshev Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA B.A. Carlson • D.L. Hatfield (*) Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA e-mail: hatfi[email protected] © Springer Science+Business Media, LLC 2016 D.L. Hatfield et al. (eds.), Selenium, DOI 10.1007/978-3-319-41283-2_4
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synthetase (SERS), which initiates the biosynthesis of Sec by aminoacylating tRNA[Ser]Sec with serine, all enzymes involved in the synthesis of this amino acid are exclusive to the Sec pathway (see [1, 2] and references therein). Interestingly, cysteine (Cys) may replace Sec on tRNA[Ser]Sec, and Cys may be incorporated into protein in place of Sec as discussed below. Replacement of Cys with Sec or Sec with Cys in cellular metabolism is not too surprising, since the structures of these two amino acids are so similar, differing only in the presence of a selenium versus a sulfur atom. Furthermore, these two amino acids have similar chemical properties and, when present in active sites of enzymes, may catalyze some of the same reactions. An exam
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