Wikipedia

Selenocysteine

Selenocysteine (symbol Sec or U,[4] in older publications also as Se-Cys)[5] is the 21st proteinogenic amino acid. Selenoproteins contain selenocysteine residues. Selenocysteine is an analogue of the more common cysteine with selenium in place of the sulfur.

Selenocysteine[1]
Names
IUPAC name
Selenocysteine
Systematic IUPAC name
2-Amino-3-selanylpropanoic acid
Other names
L-Selenocysteine; Selenium-cysteine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.236.386 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C3H7NO2Se/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1 checkY
    Key: ZKZBPNGNEQAJSX-REOHCLBHSA-N checkY
  • InChI=1/C3H7NO2Se/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1
    Key: ZKZBPNGNEQAJSX-REOHCLBHBZ
  • O=C(O)[C@@H](N)C[SeH]
  • Zwitterion: O=C([O-])[C@@H]([NH3+])C[SeH]
Properties
C3H7NO2Se
Molar mass 168.065 g·mol−1
Properties
Acidity (pKa) 5.24,[2] 5.43[3]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)
Selenocysteine ball and stick model spinning

Selenocysteine is present in several enzymes (for example glutathione peroxidases, tetraiodothyronine 5′ deiodinases, thioredoxin reductases, formate dehydrogenases, glycine reductases, selenophosphate synthetase 2, methionine-R-sulfoxide reductase B1 (SEPX1), and some hydrogenases). It occurs in all three domains of life, including important enzymes (listed above) present in humans.[6]

Selenocysteine was discovered in 1974[7] by biochemist Thressa Stadtman at the National Institutes of Health.[8]

Chemistry

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Selenocysteine is the Se-analogue of cysteine. It is rarely encountered outside of living tissue (nor is it available commercially) because of its high susceptiblility to air-oxidation. More common is the oxidized derivative selenocystine, which has an Se-Se bond.[9] Both selenocysteine and selenocystine are white solids. The Se-H group is more acidic (pKa = 5.43[3]) than the thiol group; thus, it is deprotonated at physiological pH.[10]

Structure

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Selenocysteine has the same structure as cysteine, but with an atom of selenium taking the place of the usual sulfur; it has a selenol group. Like other natural proteinogenic amino acids, cysteine and selenocysteine have L chirality in the older D/L notation based on homology to D- and L-glyceraldehyde. In the newer R/S system of designating chirality, based on the atomic numbers of atoms near the asymmetric carbon, they have R chirality, because of the presence of sulfur or selenium as a second neighbor to the asymmetric carbon. The remaining chiral amino acids, having only lighter atoms in that position, have S chirality.)

Proteins which contain a selenocysteine residue are called selenoproteins. Most selenoproteins contain a single selenocysteine residue. Selenoproteins that exhibit catalytic activity are called selenoenzymes.[11]

Biology

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Unlike the other amino acids, no free pool of selenocysteine exists in the cell. Its high reactivity would cause damage to cells.[12] Instead, cells store selenium in the less reactive oxidized form, selenocystine, or in methylated form, selenomethionine.

Production

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Selenocysteine synthesis occurs on a specialized tRNA,[13] which also functions to incorporate it into nascent polypeptides. The primary and secondary structure of selenocysteine-specific tRNA, tRNASec, differ from those of standard tRNAs in several respects, most notably in having an 8-base-pair (bacteria) or 10-base-pair (eukaryotes)[Archaea?] acceptor stem, a long variable region arm, and substitutions at several well-conserved base positions. The selenocysteine tRNAs are initially charged with serine by seryl-tRNA ligase, but the resulting Ser-tRNASec is not used for translation because it is not recognised by the normal translation elongation factor (EF-Tu in bacteria, eEF1A in eukaryotes).[Archaea?]

Selenocysteine synthesis

Rather, the tRNA-bound seryl residue is converted to a selenocysteine residue by the pyridoxal phosphate-containing enzyme[14] selenocysteine synthase. In eukaryotes and archaea, two enzymes[15] are required to convert tRNA-bound seryl[16] residue into tRNA selenocysteinyl residue: PSTK (O-phosphoseryl-tRNA[Ser]Sec kinase) and selenocysteine synthase.[17][18] Finally, the resulting Sec-tRNASecis specifically bound to an alternative translational elongation factor (SelB[19] or mSelB (or eEFSec)), which delivers it in a targeted manner to the ribosomes[20] translating mRNAs[21][22] for selenoproteins. The specificity of this delivery mechanism is brought about by the presence of an extra protein domain (in bacteria, SelB) or an extra subunit (SBP2 for eukaryotic mSelB/eEFSec) which bind to the corresponding RNA secondary structures formed by the SECIS elements in selenoprotein mRNAs.

Selenoproteins

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Selenocysteine has a lower reduction potential than cysteine. These properties make it very suitable in proteins that are involved in antioxidant activity.[23]

Although it is found in the three domains of life, it is not universal in all organisms.[24] Unlike other amino acids present in biological proteins, selenocysteine is not coded for directly in the genetic code.[25] Instead, it is encoded in a special way by a UGA codon, which is normally the "opal" stop codon. Such a mechanism is called translational recoding[26] and its efficiency depends on the selenoprotein being synthesized and on translation initiation factors.[27] When cells are grown in the absence of selenium, translation of selenoproteins terminates at the UGA codon, resulting in a truncated, nonfunctional enzyme. The UGA codon is made to encode selenocysteine by the presence of a selenocysteine insertion sequence (SECIS) in the mRNA. The SECIS element is defined by characteristic nucleotide sequences and secondary structure base-pairing patterns. In bacteria, the SECIS element is typically located immediately following the UGA codon within the reading frame for the selenoprotein.[28] In Archaea and in eukaryotes, the SECIS element is in the 3′ untranslated region (3′ UTR) of the mRNA and can direct multiple UGA codons to encode selenocysteine residues.[29]

As of 2021, 136 human proteins (in 37 families) are known to contain selenocysteine (selenoproteins).[30]

Breakdown

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Selenocysteine is decomposed by the enzyme selenocysteine lyase into L-alanine and selenide. This probably helps with the safe recycling of Sec during degradation of selenoproteins.[31]

Toxicity

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Just as selenomethionine can be randomly incorporated into proteins, selenocystine can also be mistakenly attached to tRNACys by cysteinyl-tRNA synthetase and incorporated into proteins in lieu of cystine. This causes considerable toxicity. A variant synthase that can distinguish between Cys and Sec helps reduce toxicity.[32]

Derivatives

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Selenocysteine derivatives γ-glutamyl-Se-methylselenocysteine and Se-methylselenocysteine occur naturally in plants of the genera Allium and Brassica.[33]

Applications

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Biotechnological applications of selenocysteine include use of 73Se-labeled Sec (half-life of 73Se = 7.2 hours) in positron emission tomography (PET) studies and 75Se-labeled Sec (half-life of 75Se = 118.5 days) in specific radiolabeling, facilitation of phase determination by multiwavelength anomalous diffraction in X-ray crystallography of proteins by introducing Sec alone, or Sec together with selenomethionine (SeMet), and incorporation of the stable 77Se isotope, which has a nuclear spin of ⁠1/2⁠ and can be used for high-resolution NMR, among others.[6]

See also

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  • Pyrrolysine, another amino acid not in the basic set of 20.
  • Selenomethionine, another selenium-containing amino acid, which is randomly substituted for methionine.

References

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  1. ↑ Merck Index, 12th Edition, 8584
  2. ↑ Huber RE, Criddle RS (1967-10-01). "Comparison of the chemical properties of selenocysteine and selenocystine with their sulfur analogs". Archives of Biochemistry and Biophysics. 122 (1): 164–173. doi:10.1016/0003-9861(67)90136-1. ISSN 0003-9861. PMID 6076213.
  3. 1 2 Thapa B, Schlegel HB (2016-11-10). "Theoretical Calculation of p K a 's of Selenols in Aqueous Solution Using an Implicit Solvation Model and Explicit Water Molecules". The Journal of Physical Chemistry A. 120 (44): 8916–8922. Bibcode:2016JPCA..120.8916T. doi:10.1021/acs.jpca.6b09520. ISSN 1089-5639. PMID 27748600.
  4. ↑ "Nomenclature and Symbolism for Amino Acids and Peptides". IUPAC-IUB Joint Commission on Biochemical Nomenclature. 1983. Archived from the original on 9 October 2008. Retrieved 5 March 2018.
  5. ↑ "IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN) and Nomenclature Committee of IUBMB (NC-IUBMB)". European Journal of Biochemistry. 264 (2): 607–609. 17 August 1999. doi:10.1046/j.1432-1327.1999.news99.x.
  6. 1 2 Johansson L, Gafvelin G, Arnér ES (October 2005). "Selenocysteine in proteins—properties and biotechnological use". Biochimica et Biophysica Acta (BBA) - General Subjects. 1726 (1): 1–13. doi:10.1016/j.bbagen.2005.05.010. hdl:10616/39311. PMID 15967579.
  7. ↑ "Stadtman Pioneer of Selenium Biochemistry - Office of NIH History and Stetten Museum". history.nih.gov. Archived from the original on May 10, 2020. Retrieved 2023-04-06.
  8. ↑ Stadtman TC (March 1974). "Selenium biochemistry". Science. 183 (4128): 915–22. Bibcode:1974Sci...183..915S. doi:10.1126/science.183.4128.915. PMID 4605100. S2CID 84982102.
  9. ↑ Görbitz CH, Levchenko V, Semjonovs J, Sharif MY (2015). "Crystal structure of seleno-L-cystine dihydrochloride". Acta Crystallographica Section E. 71 (6): 726–729. Bibcode:2015AcCrE..71..726G. doi:10.1107/S205698901501021X. PMC 4459342. PMID 26090162.
  10. ↑ Reich HJ, Hondal RJ (April 2016). "Why nature chose selenium". ACS Chemical Biology. 11 (4): 821–841. doi:10.1021/acschembio.6b00031. PMID 26949981.
  11. ↑ Roy G, Sarma BK, Phadnis PP, Mugesh G (2005). "Selenium-containing enzymes in mammals: chemical perspectives" (PDF). Journal of Chemical Sciences. 117 (4): 287–303. doi:10.1007/BF02708441. S2CID 32351033.
  12. ↑ Spallholz JE (July 1994). "On the nature of selenium toxicity and carcinostatic activity". Free Radical Biology and Medicine. 17 (1): 45–64. doi:10.1016/0891-5849(94)90007-8. PMID 7959166.
  13. ↑ “NIH 3D - TRNA.” Nih.gov, 2017, 3d.nih.gov/entries/3DPX-008056. Accessed 5 Dec. 2025.
  14. ↑ “PDB101: Molecule of the Month: Selenocysteine Synthase.” RCSB: PDB-101, 2025, pdb101.rcsb.org/motm/104. Accessed 5 Dec. 2025.
  15. ↑ "NIH 3D - ATP Molecule." Nih.gov, 2023, https://3d.nih.gov/entries/3DPX-007805. Accessed 5 Dec. 2025.
  16. ↑ “NIH 3D – dl-O-Phosphoserine.” Nih.gov, 2017, https://3d.nih.gov/entries/5203. Accessed 5 Dec. 2025.
  17. ↑ Xu XM, Carlson BA, Mix H, Zhang Y, Saira K, Glass RS, Berry MJ, Gladyshev VN, Hatfield DL (January 2007). "Biosynthesis of selenocysteine on its tRNA in eukaryotes". PLOS Biology. 5 (1): e4. doi:10.1371/journal.pbio.0050004. PMC 1717018. PMID 17194211.
  18. ↑ Yuan J, Palioura S, Salazar JC, Su D, O'Donoghue P, Hohn MJ, Cardoso AM, Whitman WB, Söll D (December 2006). "RNA-dependent conversion of phosphoserine forms selenocysteine in eukaryotes and archaea". Proceedings of the National Academy of Sciences of the United States of America. 103 (50): 18923–7. Bibcode:2006PNAS..10318923Y. doi:10.1073/pnas.0609703104. PMC 1748153. PMID 17142313.
  19. ↑ "NIH 3D - Crystal structure of the selenocysteine synthase SelA and tRNASec complex." Nih.gov, 2023, https://3d.nih.gov/entries/2523. Accessed 5 Dec. 2025.
  20. ↑ “NIH 3D - Human 80S Ribosome.” Nih.gov, 2019, 3d.nih.gov/entries/3DPX-011099. Accessed 5 Dec. 2025.
  21. ↑ “NIH 3D - Y-MRNA.” Nih.gov, 2018, 3d.nih.gov/entries/3DPX-008683. Accessed 5 Dec. 2025.
  22. ↑ “BioArt.” Nih.gov, 2025, bioart.niaid.nih.gov/discover?q=+mRNA&sort=relevance. Accessed 5 Dec. 2025.
  23. ↑ Byun BJ, Kang YK (May 2011). "Conformational preferences and pK(a) value of selenocysteine residue". Biopolymers. 95 (5): 345–53. doi:10.1002/bip.21581. PMID 21213257. S2CID 11002236.
  24. ↑ Longtin R (April 2004). "A forgotten debate: is selenocysteine the 21st amino acid?". Journal of the National Cancer Institute. 96 (7): 504–5. doi:10.1093/jnci/96.7.504. PMID 15069108.
  25. ↑ Böck A, Forchhammer K, Heider J, Baron C (December 1991). "Selenoprotein synthesis: an expansion of the genetic code". Trends in Biochemical Sciences. 16 (12): 463–7. doi:10.1016/0968-0004(91)90180-4. PMID 1838215.
  26. ↑ Baranov PV, Gesteland RF, Atkins JF (March 2002). "Recoding: translational bifurcations in gene expression". Gene. 286 (2): 187–201. doi:10.1016/S0378-1119(02)00423-7. PMID 11943474. S2CID 976337.
  27. ↑ Donovan J, Copeland PR (July 2010). "The efficiency of selenocysteine incorporation is regulated by translation initiation factors". Journal of Molecular Biology. 400 (4): 659–64. doi:10.1016/j.jmb.2010.05.026. PMC 3721751. PMID 20488192.
  28. ↑ Atkins, J. F. (2009). Recoding: Expansion of Decoding Rules Enriches Gene Expression. Springer. p. 31. ISBN 978-0-387-89381-5.
  29. ↑ Berry MJ, Banu L, Harney JW, Larsen PR (August 1993). "Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons". The EMBO Journal. 12 (8): 3315–22. doi:10.1002/j.1460-2075.1993.tb06001.x. PMC 413599. PMID 8344267.
  30. ↑ Romagné F, Santesmasses D, White L, Sarangi GK, Mariotti M, Hübler R, Weihmann A, Parra G, Gladyshev VN, Guigó R, Castellano S (January 2014). "SelenoDB 2.0: annotation of selenoprotein genes in animals and their genetic diversity in humans". Nucleic Acids Research. 42 (Database issue): D437-43. doi:10.1093/nar/gkt1045. PMC 3965025. PMID 24194593.
  31. ↑ Labunskyy VM, Hatfield DL, Gladyshev VN (July 2014). "Selenoproteins: molecular pathways and physiological roles". Physiological Reviews. 94 (3): 739–77. doi:10.1152/physrev.00039.2013. PMC 4101630. PMID 24987004.
  32. ↑ Hoffman KS, Vargas-Rodriguez O, Bak DW, Mukai T, Woodward LK, Weerapana E, Söll D, Reynolds NM (23 August 2019). "A cysteinyl-tRNA synthetase variant confers resistance against selenite toxicity and decreases selenocysteine misincorporation". The Journal of Biological Chemistry. 294 (34): 12855–12865. doi:10.1074/jbc.RA119.008219. PMC 6709638. PMID 31296657.
  33. ↑ Block, E. (2010). Garlic and Other Alliums: The Lore and the Science. Royal Society of Chemistry. ISBN 978-0-85404-190-9.

Further reading

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