Selenocysteine

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Selenocysteine [1]
L-selenocysteine-2D-skeletal.png
Selenocysteine-3D-vdW.png
Names
IUPAC name
Selenocysteine
Systematic IUPAC name
3-Selanyl-L-alanine (semisystematic name)
2-Amino-3-selanylpropanoic acid (fully systematic name)
Other names
L-Selenocysteine; Selenium-cysteine
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.236.386 OOjs UI icon edit-ltr-progressive.svg
KEGG
PubChem CID
UNII
  • InChI=1S/C3H7NO2Se/c4-2(1-7)3(5)6/h2,7H,1,4H2,(H,5,6)/t2-/m0/s1 Yes check.svgY
    Key: ZKZBPNGNEQAJSX-REOHCLBHSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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.

Contents

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

Selenocysteine is the Se-analogue of cysteine. It is rarely encountered outside of living tissue (and is not available commercially) because it is very susceptible 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

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

Selenocysteine has a lower reduction potential than cysteine. These properties make it very suitable in proteins that are involved in antioxidant activity. [12]

Although it is found in the three domains of life, it is not universal in all organisms. [13] Unlike other amino acids present in biological proteins, selenocysteine is not coded for directly in the genetic code. [14] 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 [15] and its efficiency depends on the selenoprotein being synthesized and on translation initiation factors. [16] 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. [17] 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. [18]

Unlike the other amino acids, no free pool of selenocysteine exists in the cell. Its high reactivity would cause damage to cells. [19] Instead, cells store selenium in the less reactive oxidized form, selenocystine, or in methylated form, selenomethionine. Selenocysteine synthesis occurs on a specialized tRNA, 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? ]

Rather, the tRNA-bound seryl residue is converted to a selenocysteine residue by the pyridoxal phosphate-containing enzyme selenocysteine synthase. In eukaryotes and archaea, two enzymes are required to convert tRNA-bound seryl residue into tRNA selenocysteinyl residue: PSTK (O-phosphoseryl-tRNA[Ser]Sec kinase) and selenocysteine synthase. [20] [21] Finally, the resulting Sec-tRNASec is specifically bound to an alternative translational elongation factor (SelB or mSelB (or eEFSec)), which delivers it in a targeted manner to the ribosomes translating mRNAs 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)[ Archaea? ] which bind to the corresponding RNA secondary structures formed by the SECIS elements in selenoprotein mRNAs.

Selenocysteine is decomposed by the enzyme selenocysteine lyase into L-alanine and selenide. [22]

As of 2021, 136 human proteins (in 37 families) are known to contain selenocysteine (selenoproteins). [23]

Selenocysteine derivatives γ-glutamyl-Se-methylselenocysteine and Se-methylselenocysteine occur naturally in plants of the genera Allium and Brassica . [24]

Applications

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

Related Research Articles

<span class="mw-page-title-main">Amino acid</span> Organic compounds containing amine and carboxylic groups

Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 appear in the genetic code of life.

<span class="mw-page-title-main">Stop codon</span> Codon that marks the end of a protein-coding sequence

In molecular biology, a stop codon is a codon that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the addition of an amino acid to a growing polypeptide chain, which may ultimately become a protein; stop codons signal the termination of this process by binding release factors, which cause the ribosomal subunits to disassociate, releasing the amino acid chain.

<span class="mw-page-title-main">Pyrrolysine</span> Chemical compound

Pyrrolysine is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group, a carboxylic acid group. Its pyrroline side-chain is similar to that of lysine in being basic and positively charged at neutral pH.

<span class="mw-page-title-main">Iodothyronine deiodinase</span> Class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

<span class="mw-page-title-main">SECIS element</span> RNA sequence directing the translation of UGA codons as selenocysteines

In biology, the SECIS element is an RNA element around 60 nucleotides in length that adopts a stem-loop structure. This structural motif directs the cell to translate UGA codons as selenocysteines. SECIS elements are thus a fundamental aspect of messenger RNAs encoding selenoproteins, proteins that include one or more selenocysteine residues.

In molecular biology a selenoprotein is any protein that includes a selenocysteine amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidases (GPX) and three thioredoxin reductases, (TrxR/TXNRD) which both contain only one Sec. Selenoprotein P is the most common selenoprotein found in the plasma. It is unusual because in humans it contains 10 Sec residues, which are split into two domains, a longer N-terminal domain that contains 1 Sec, and a shorter C-terminal domain that contains 9 Sec. The longer N-terminal domain is likely an enzymatic domain, and the shorter C-terminal domain is likely a means of safely transporting the very reactive selenium atom throughout the body.

<span class="mw-page-title-main">Proteinogenic amino acid</span> Amino acid that is incorporated biosynthetically into proteins during translation

Proteinogenic amino acids are amino acids that are incorporated biosynthetically into proteins during translation. The word "proteinogenic" means "protein creating". Throughout known life, there are 22 genetically encoded (proteinogenic) amino acids, 20 in the standard genetic code and an additional 2 that can be incorporated by special translation mechanisms.

<span class="mw-page-title-main">GPX1</span> Protein-coding gene in the species Homo sapiens

Glutathione peroxidase 1, also known as GPx1, is an enzyme that in humans is encoded by the GPX1 gene on chromosome 3. This gene encodes a member of the glutathione peroxidase family. Glutathione peroxidase functions in the detoxification of hydrogen peroxide, and is one of the most important antioxidant enzymes in humans.

The enzyme selenocysteine lyase (SCL) (EC 4.4.1.16) catalyzes the chemical reaction

<span class="mw-page-title-main">SEPP1</span> Protein-coding gene in the species Homo sapiens

Selenoprotein P is a protein that in humans is encoded by the SEPP1 gene.

<span class="mw-page-title-main">SECISBP2</span> Protein-coding gene in the species Homo sapiens

SECIS-binding protein 2 is a protein that in humans is encoded by the SECISBP2 gene.

<span class="mw-page-title-main">SEP15</span> Protein-coding gene in the species Homo sapiens

15 kDa selenoprotein is a protein that in humans is encoded by the SEP15 gene. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.

<span class="mw-page-title-main">SEPW1</span> Protein-coding gene in the species Homo sapiens

Selenoprotein W is a protein that in humans is encoded by the SEPW1 gene.

<span class="mw-page-title-main">SEPX1</span> Protein-coding gene in the species Homo sapiens

Methionine-R-sulfoxide reductase B1 is an enzyme that in humans is encoded by the SEPX1 gene.

<span class="mw-page-title-main">SELT</span> Protein-coding gene in the species Homo sapiens

Selenoprotein T, also known as SELT, is a protein that in humans is encoded by the SELT gene.

<span class="mw-page-title-main">Selenium in biology</span> Use of Selenium by organisms

Selenium is an essential micronutrient for animals, though it is toxic in large doses. In plants, it sometimes occurs in toxic amounts as forage, e.g. locoweed. Selenium is a component of the amino acids selenocysteine and selenomethionine. In humans, selenium is a trace element nutrient that functions as cofactor for glutathione peroxidases and certain forms of thioredoxin reductase. Selenium-containing proteins are produced from inorganic selenium via the intermediacy of selenophosphate (PSeO33−).

<span class="mw-page-title-main">Non-proteinogenic amino acids</span> Are not naturally encoded in the genome

In biochemistry, non-coded or non-proteinogenic amino acids are distinct from the 22 proteinogenic amino acids, which are naturally encoded in the genome of organisms for the assembly of proteins. However, over 140 non-proteinogenic amino acids occur naturally in proteins and thousands more may occur in nature or be synthesized in the laboratory. Chemically synthesized amino acids can be called unnatural amino acids. Unnatural amino acids can be synthetically prepared from their native analogs via modifications such as amine alkylation, side chain substitution, structural bond extension cyclization, and isosteric replacements within the amino acid backbone. Many non-proteinogenic amino acids are important:

O-phosphoseryl-tRNASec kinase is an enzyme with systematic name ATP:L-seryl-tRNASec O-phosphotransferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase</span>

O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase is an enzyme with systematic name selenophosphate:O-phospho-L-seryl-tRNASec selenium transferase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Selenoprotein o</span> Protein-coding gene in the species Homo sapiens

Selenoprotein O is a protein that in humans is encoded by the SELENOO gene.

References

  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.
  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. 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. 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 Crystallogr. E . 71 (6): 726–729. 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. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ Atkins, J. F. (2009). Recoding: Expansion of Decoding Rules Enriches Gene Expression. Springer. p. 31. ISBN   978-0-387-89381-5.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  24. ↑ Block, E. (2010). Garlic and Other Alliums: The Lore and the Science. Royal Society of Chemistry. ISBN   978-0-85404-190-9.

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