COMMENTARY

On the road to

Alan M. Diamond* Department of Human Nutrition, University of Illinois, Chicago, IL 60612

ecades ago, a mammalian purified PSTK established the substrate enzymes with antioxidant capabilities tRNA that exclusively bound specificity of this enzyme exclusively for (glutathione peroxidases) and those the UGA was both seryl-tRNA[Ser]Sec isoforms, which involved with the maintenance of the identified by using the triplet differ by only a single modified base (5). reduced cellular environment (thiore- bindingD assay that was instrumental in It is highly significant that the initial doxin reductases) and the maturation deciphering the (1). The method of detection, a computer- of thyroxin (thyroid hormone deiodi- possibility of a naturally occurring sup- assisted analysis of genomes that were nases). Other mammalian selenopro- pressor tRNA presented the dilemma known either to contain or to be miss- teins of known function include SelP, of explaining the biological function of ing the selenoprotein synthesis machin- which is involved with selenium trans- such a molecule. In the same year, an ery, was successful at all. The presence port; SPS2, which is required for Sec equally perplexing report indicated the of PSTK in archaeal and ge- synthesis; and SelR, a methionine sul- existence of tRNA from either rooster nomes that were known to translation- foxide reductase (reviewed in ref. 12). or rat liver that was aminoacylated ally synthesize selenoproteins, but its Although the biochemical properties with phosphoserine (2). That observa- absence in the genomes of organisms (i.e., cellular location and binding part- tion was verified several years later that do not, is consistent with the role ners) are known for several other sel- when phosphoseryl tRNA was also of PSTK indicated by Carlson et al. (8). enoproteins, their biological roles await identified from lactating bovine mam- This correlation also argues for a dedi- further investigation. Genetic data mary glands (3). Phosphoserine was cated role of this kinase in selenopro- have also implicated at least three sel- well established to be present in pro- tein synthesis and the absence of closely enoproteins in human disease: SelN1 teins at that time, but the synthesis of related, yet distinct, kinases. With the in muscular dystrophy (13) and GPX1 this amino acid was known to occur characterization of PSTK, the remark- (14–16) and Sep15 in cancer etiology posttranslationally, subsequent to the able list of cellular components whose (17, 18). It is also likely that multiple insertion of serine in response to one biological role is apparently restricted to biological roles for individual seleno- of the six serine codons. Not until sev- the synthesis of mammalian selenopro- will be identified: one of the eral years later was it discovered that teins is expanded. most interesting examples to date is these two tRNAs, that which recog- the dual role of GPX4 as a membrane- nized UGA and that which formed located antioxidant enzyme and as a phosphoseryl tRNA, were one and the Biosynthesis of major sperm structural (19). same (4), and that this tRNA was atyp- Just as there are clear evolutionary ical with respect to structure, size, and selenocysteine from differences among the functions of sel- modified base content (5). The mystery enoproteins, the results presented by as to the biological role this molecule serine in mammalian Carlson et al. (8) highlight the evolu- played was solved with the determina- tionary differences in the process of tion that this tRNA could support the cells is atypical among selenoprotein synthesis between pro- synthesis of the selenium-containing karyotes and . Although amino acid selenocysteine (Sec) (6), eukaryotic tRNAs. commonalities exist, such as the use of which addressed yet another perplexing UGA to encode Sec, the use of dedi- observation, the existence of Sec- cated tRNA[Ser]Sec, and translational containing proteins in which that Sec typically, but not exclusively, is elongation factors, differences, such as amino acid was encoded by the UGA present at the of selenium- the location of the SECIS element 3Ј codon, the first mammalian example containing enzymes across evolution. and adjacent to the Sec-encoding UGA being glutathione peroxidase (7). As There are several proteins in bacteria triplet in prokaryotes and in the 3Ј the pieces of the puzzle of selenopro- that contain UGA-encoded Sec, and UTR in eukaryotes and the need for tein biosynthesis fell into place, the these have been well characterized. an additional protein, SBP2, in eu- role of phosphoseryl-tRNA remained The list includes glycine and proline karyotes, also are apparent (reviewed obscure, its low relative abundance reductases, as well as formate and in ref. 12). In prokaryotes, an amino- raising the issue of whether it was an formylmethanofuran dehydrogenases acrylyl intermediate between the con- anomaly without physiological signifi- (for a review, see ref. 9). In fact, ge- version from serine to Sec was identified cance. In a recent issue of PNAS, Carl- netic analyses of bacterial mutants (20). Now, with the identification of son et al. (8) employed a clever com- unable to synthesize Sec-containing PSTK and the all-but-certain assign- parative genomics approach to identify formate dehydrogenases resulted in the ment of a phosphoserine intermediate a kinase that is most likely dedicated identification of the components of the in eukaryotic Sec synthesis, an addi- to Sec synthesis, providing the missing prokaryotic selenoprotein biosynthesis tional difference can be catalogued. link in the route from serine to Sec in machinery (10). The resolution of the biochemical eukaryotes and archaea, as well as In contrast to the relatively few pro- pathway by which serine is converted adding a new player to the translation karyotic selenoproteins, there are sev- to Sec in mammals is also a reminder ‘‘team’’ whose sole purpose is to pro- eral dozen selenoproteins in archaea duce selenoproteins. and eukaryotes, with a comprehensive Carlson et al. (8) provide data indicat- computational analysis of the human See companion article on page 12848 in issue 35 of volume ing that PSTK is the kinase that phos- genome identifying 25 selenoproteins 101. phorylates seryl-tRNA[Ser]Sec in vivo. (11). These include a diverse collection *E-mail: [email protected]. Studies using bacterially synthesized, of proteins, with families of related © 2004 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0405357101 PNAS ͉ September 14, 2004 ͉ vol. 101 ͉ no. 37 ͉ 13395–13396 Downloaded by guest on September 25, 2021 of the highly unusual dual role played As pointed out by Carlson et al. (8), the benefits of the selenoprotein bio- by tRNA[Ser]Sec. The biosynthesis of Sec the functional implications of a phos- synthesis machinery’s responsiveness to from serine via phosphoserine in mam- phoseryl-tRNA[Ser]Sec intermediate re- selenium availability, selenoprotein malian cells is certainly atypical among main to be determined. Did this path- synthesis is highly regulated, at the lev- eukaryotic tRNAs in that tRNA[Ser]Sec way evolve just to take advantage of els of both transcription and transla- serves as a scaffold for the synthesis of the chemistry of phosphorylation and tion. It will be particularly interesting an amino acid that ultimately and spe- serine activation, or are there other to determine whether PSTK activity is cifically finds its way into protein (this cellular benefits? Because of the chal- expressed in a tissue-specific manner is in addition to the role of tRNA[Ser- lenge created by UGA’s functioning as and whether it is influenced by cellular ]Sec as the UGA-recognizing adaptor). both a stop and Sec codon, as well as or environmental signals.

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