Selenocysteine

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.{{ cite journal | title = Crystal structure of seleno-L-cystine dihydrochloride | first1 = C. H. | last1 = Görbitz | first2 = V. | last2 = Levchenko | first3 = J. | last3 = Semjonovs | first4 = M. Y. | last4 = Sharif | journal = Acta Crystallographica Section E | year = 2015 | volume = 71 | issue = 6 | pages = 726–729 | doi = 10.1107/S205698901501021X | pmid = 26090162 | pmc = 4459342 | bibcode = 2015AcCrE..71..726G }} Both selenocysteine and selenocystine are white solids. The Se-H group is more acidic (pK_a = 5.43) than the thiol group; thus, it is deprotonated at physiological pH.{{cite journal | vauthors = Reich HJ, Hondal RJ | title = Why nature chose selenium | journal = ACS Chemical Biology | volume = 11 | issue = 4 | pages = 821–841 | date = April 2016 | pmid = 26949981 | doi = 10.1021/acschembio.6b00031 }}

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 {{small|L}} chirality in the older {{small|D}}/{{small|L}} notation based on homology to {{small|D}}- and {{small|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.{{cite journal | vauthors = Roy G, Sarma BK, Phadnis PP, Mugesh G | title = Selenium-containing enzymes in mammals: chemical perspectives | journal = Journal of Chemical Sciences | year = 2005 | volume = 117 | issue = 4 | pages = 287–303 | doi = 10.1007/BF02708441 | s2cid = 32351033 |url=http://repository.ias.ac.in/79332/1/53-PUB.pdf | doi-access = free }}

Unlike the other amino acids, no free pool of selenocysteine exists in the cell. Its high reactivity would cause damage to cells.{{Cite journal |last=Spallholz |first=Julian E. |date=July 1994 |title=On the nature of selenium toxicity and carcinostatic activity |url=https://linkinghub.elsevier.com/retrieve/pii/0891584994900078 |journal=Free Radical Biology and Medicine |language=en |volume=17 |issue=1 |pages=45–64 |doi=10.1016/0891-5849(94)90007-8|pmid=7959166 |url-access=subscription }} Instead, cells store selenium in the less reactive oxidized form, selenocystine, or in methylated form, selenomethionine.

{{main|Selenoprotein#Production}}

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, tRNA^Sec, differ from those of standard tRNAs in several respects, most notably in having an 8-base-pair (bacteria) or 10-base-pair (eukaryotes){{fix|text=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-tRNA^Sec is not used for translation because it is not recognised by the normal translation elongation factor (EF-Tu in bacteria, eEF1A in eukaryotes).{{fix|text=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.{{cite journal | vauthors = Xu XM, Carlson BA, Mix H, Zhang Y, Saira K, Glass RS, Berry MJ, Gladyshev VN, Hatfield DL | title = Biosynthesis of selenocysteine on its tRNA in eukaryotes | journal = PLOS Biology | volume = 5 | issue = 1 | pages = e4 | date = January 2007 | pmid = 17194211 | pmc = 1717018 | doi = 10.1371/journal.pbio.0050004 | doi-access = free }}{{cite journal | vauthors = Yuan J, Palioura S, Salazar JC, Su D, O'Donoghue P, Hohn MJ, Cardoso AM, Whitman WB, Söll D | title = RNA-dependent conversion of phosphoserine forms selenocysteine in eukaryotes and archaea | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 50 | pages = 18923–7 | date = December 2006 | pmid = 17142313 | pmc = 1748153 | doi = 10.1073/pnas.0609703104 | bibcode = 2006PNAS..10318923Y | doi-access = free }} Finally, the resulting Sec-tRNA^Sec 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) which bind to the corresponding RNA secondary structures formed by the SECIS elements in selenoprotein mRNAs.

Selenocysteine has a lower reduction potential than cysteine. These properties make it very suitable in proteins that are involved in antioxidant activity.{{cite journal | vauthors = Byun BJ, Kang YK | title = Conformational preferences and pK(a) value of selenocysteine residue | journal = Biopolymers | volume = 95 | issue = 5 | pages = 345–53 | date = May 2011 | pmid = 21213257 | doi = 10.1002/bip.21581 | s2cid = 11002236 }}

Although it is found in the three domains of life, it is not universal in all organisms.{{cite journal | vauthors = Longtin R | title = A forgotten debate: is selenocysteine the 21st amino acid? | journal = Journal of the National Cancer Institute | volume = 96 | issue = 7 | pages = 504–5 | date = April 2004 | pmid = 15069108 | doi = 10.1093/jnci/96.7.504}} Unlike other amino acids present in biological proteins, selenocysteine is not coded for directly in the genetic code.{{cite journal | vauthors = Böck A, Forchhammer K, Heider J, Baron C | title = Selenoprotein synthesis: an expansion of the genetic code | journal = Trends in Biochemical Sciences | volume = 16 | issue = 12 | pages = 463–7 | date = December 1991 | pmid = 1838215 | doi = 10.1016/0968-0004(91)90180-4 }} 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{{cite journal | vauthors = Baranov PV, Gesteland RF, Atkins JF | title = Recoding: translational bifurcations in gene expression | journal = Gene | volume = 286 | issue = 2 | pages = 187–201 | date = March 2002 | pmid = 11943474 | doi = 10.1016/S0378-1119(02)00423-7 | s2cid = 976337 }} and its efficiency depends on the selenoprotein being synthesized and on translation initiation factors.{{cite journal | vauthors = Donovan J, Copeland PR | title = The efficiency of selenocysteine incorporation is regulated by translation initiation factors | journal = Journal of Molecular Biology | volume = 400 | issue = 4 | pages = 659–64 | date = July 2010 | pmid = 20488192 | pmc = 3721751 | doi = 10.1016/j.jmb.2010.05.026 }} 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.{{cite book | author = Atkins, J. F. | title = Recoding: Expansion of Decoding Rules Enriches Gene Expression | year = 2009 | page = 31 | publisher = Springer | isbn = 978-0-387-89381-5 | url = https://books.google.com/books?id=8cSZpPWXoqIC&pg=PA31 }} 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.{{cite journal | vauthors = Berry MJ, Banu L, Harney JW, Larsen PR | title = Functional characterization of the eukaryotic SECIS elements which direct selenocysteine insertion at UGA codons | journal = The EMBO Journal | volume = 12 | issue = 8 | pages = 3315–22 | date = August 1993 | pmid = 8344267 | pmc = 413599 | doi = 10.1002/j.1460-2075.1993.tb06001.x }}

{{As of|2021}}, 136 human proteins (in 37 families) are known to contain selenocysteine (selenoproteins).{{cite journal |vauthors=Romagné F, Santesmasses D, White L, Sarangi GK, Mariotti M, Hübler R, Weihmann A, Parra G, Gladyshev VN, Guigó R, Castellano S |date=January 2014 |title=SelenoDB 2.0: annotation of selenoprotein genes in animals and their genetic diversity in humans |journal=Nucleic Acids Research |volume=42 |issue=Database issue |pages=D437-43 |doi=10.1093/nar/gkt1045 |pmc=3965025 |pmid=24194593}} [http://selenodb.crg.eu/cgi-perl/advanced_search.pl?feature=protein&species=Homo+sapiens]

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.{{cite journal | vauthors = Labunskyy VM, Hatfield DL, Gladyshev VN | title = Selenoproteins: molecular pathways and physiological roles | journal = Physiological Reviews | volume = 94 | issue = 3 | pages = 739–77 | date = July 2014 | pmid = 24987004 | pmc = 4101630 | doi = 10.1152/physrev.00039.2013 }}

Just as selenomethionine can be randomly incorporated into proteins, selenocystine can also be mistakenly attached to tRNA^Cys 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.{{cite journal |last1=Hoffman |first1=KS |last2=Vargas-Rodriguez |first2=O |last3=Bak |first3=DW |last4=Mukai |first4=T |last5=Woodward |first5=LK |last6=Weerapana |first6=E |last7=Söll |first7=D |last8=Reynolds |first8=NM |title=A cysteinyl-tRNA synthetase variant confers resistance against selenite toxicity and decreases selenocysteine misincorporation. |journal=The Journal of Biological Chemistry |date=23 August 2019 |volume=294 |issue=34 |pages=12855–12865 |doi=10.1074/jbc.RA119.008219 |doi-access=free |pmid=31296657}}

Selenocysteine derivatives γ-glutamyl-Se-methylselenocysteine and Se-methylselenocysteine occur naturally in plants of the genera Allium and Brassica.{{cite book|author=Block, E.|title=Garlic and Other Alliums: The Lore and the Science|url=https://books.google.com/books?id=6AB89RHV9ucC|publisher=Royal Society of Chemistry|year=2010|isbn=978-0-85404-190-9}}

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 {{sfrac|1|2}} and can be used for high-resolution NMR, among others.

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

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• {{cite journal | vauthors = Zinoni F, Birkmann A, Stadtman TC, Böck A | title = Nucleotide sequence and expression of the selenocysteine-containing polypeptide of formate dehydrogenase (formate-hydrogen-lyase-linked) from Escherichia coli | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 13 | pages = 4650–4 | date = July 1986 | pmid = 2941757 | pmc = 323799 | doi = 10.1073/pnas.83.13.4650 | bibcode = 1986PNAS...83.4650Z | doi-access = free }}
• {{cite journal | vauthors = Zinoni F, Birkmann A, Leinfelder W, Böck A | title = Cotranslational insertion of selenocysteine into formate dehydrogenase from Escherichia coli directed by a UGA codon | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 10 | pages = 3156–60 | date = May 1987 | pmid = 3033637 | pmc = 304827 | doi = 10.1073/pnas.84.10.3156 | bibcode = 1987PNAS...84.3156Z | doi-access = free }}
• {{cite journal | vauthors = Cone JE, Del Río RM, Davis JN, Stadtman TC | title = Chemical characterization of the selenoprotein component of clostridial glycine reductase: identification of selenocysteine as the organoselenium moiety | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 73 | issue = 8 | pages = 2659–63 | date = August 1976 | pmid = 1066676 | pmc = 430707 | doi = 10.1073/pnas.73.8.2659 | bibcode = 1976PNAS...73.2659C | doi-access = free }}
• {{cite journal | vauthors = Fenyö D, Beavis RC | title = Selenocysteine: Wherefore Art Thou? | journal = Journal of Proteome Research | volume = 15 | issue = 2 | pages = 677–8 | date = February 2016 | pmid = 26680273 | doi = 10.1021/acs.jproteome.5b01028 }}

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• [https://ciencia.ladiaria.com.uy/articulo/2019/2/cientifico-uruguayo-halla-por-primera-vez-en-hongos-el-aminoacido-selenocisteina/ For the first time a Uruguayan scientist finds selenocysteine in fungi] {{Webarchive|url=https://web.archive.org/web/20190222133330/https://ciencia.ladiaria.com.uy/articulo/2019/2/cientifico-uruguayo-halla-por-primera-vez-en-hongos-el-aminoacido-selenocisteina/ |date=2019-02-22 }} {{in lang|es}}

{{Amino acids}}

{{selenium compounds}}

Category:Alpha-Amino acids

Category:Proteinogenic amino acids

Category:Selenols