Selenoprotein

In molecular biology a selenoprotein is any protein that includes a selenocysteine (Sec, U, Se-Cys) amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidases (GPX) and three thioredoxin reductases, (TrxR/TXNRD) which both contain only one Sec.^[1] 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.^[2]^[3]

Species distribution

Selenoproteins exist in all major domains of life, eukaryotes, bacteria and archaea. Among eukaryotes, selenoproteins appear to be common in animals, but rare or absent in other phyla—one has been identified in the green alga Chlamydomonas, but almost none in other plants or in fungi. The American cranberry (Vaccinium macrocarpon Ait.) is the only land plant known^[when?] to possess sequence-level machinery for producing selenocysteine in its mitochondrial genome, although its level of functionality is not yet determined.^[4] Among bacteria and archaea, selenoproteins are only present in some lineages, while they are completely absent in many other phylogenetic groups. These observations have now been confirmed by whole genome analysis, which shows the presence or absence of selenoprotein genes and accessory genes for the synthesis of selenoproteins in the respective organism.^[5]

Types

Besides the selenocysteine-containing selenoproteins, there are also some selenoproteins known from bacterial species,^[6] which have selenium bound noncovalently. Most of these proteins are thought to contain a selenide-ligand to a molybdopterin cofactor at their active sites (e.g. nicotinate dehydrogenase of Eubacterium barkeri, or xanthine dehydrogenases). Selenium is also specifically incorporated into modified bases of some tRNAs (as 2-seleno-5-methylaminomethyl-uridine).

In addition, selenium occurs in proteins as unspecifically incorporated selenomethionine, which replaces methionine residues. Proteins containing such unspecifically incorporated selenomethionine residues are not regarded as selenoproteins. However, replacement of all methionines by selenomethionines is a widely used, recent technique in solving the phase problem during X-ray crystallographic structure determination of many proteins (MAD-phasing). While the exchange of methionines by selenomethionines appears to be tolerated (at least in bacterial cells), unspecific incorporation of selenocysteine in lieu of cysteine seems to be highly toxic. This may be one reason for the existence of a rather complicated pathway of selenocysteine biosynthesis and specific incorporation into selenoproteins, which avoids the occurrence of the free amino acid as intermediate. Thus, even if a selenocysteine-containing selenoprotein is taken up in the diet and used as selenium source, the amino acid must be degraded prior to synthesising a new selenocysteine for incorporation into a selenoprotein.

Clinical significance

Selenium is a vital nutrient in animals,^[7] including humans. About 25 different selenocysteine-containing selenoproteins have so far been observed in human cells and tissues.^[8] Since lack of selenium deprives the cell of its ability to synthesize selenoproteins, many health effects of low selenium intake are believed to be caused by the lack of one or more specific selenoproteins. Three selenoproteins, TXNRD1 (TR1), TXNRD2 (TR3) and glutathione peroxidase 4 (GPX4), have been shown to be essential in mouse knockout experiments. On the other hand, too much dietary selenium causes toxic effects and can lead to selenium poisoning. The threshold between essential and toxic concentrations of this element is rather narrow with a factor in the range of 10-100.

Mutations in Selenoprotein N (SELENON, formerly SEPN1) in humans cause a subtype of congenital muscular dystrophy known as SELENON-related myopathy.^[9]^[10]

Examples

Human selenoproteins include:

Iodothyronine deiodinases 1-3: DIO1, DIO2, DIO3
Glutathione peroxidases: GPX1, GPX2, GPX3, GPX4, GPX6^[11]
Selenoproteins: SelH (C11orf31), SelI (EPT1), SelK, SelM, SelN (SEPN1), SelO, SelP (SEPP1), SelR (MSRB1), SelS, SelT, SelV, SelW (SEPW1), Sel15^[12]
Selenophosphate synthetase 2 (SEPHS2, SPS2)
Thioredoxin reductases 1-3: TXNRD1, TXNRD2, TXNRD3

Bacterial selenoproteins include:

Escherichia coli: FdhH-, FdhN- & FdhO-complex

References

^ Hatfield DL; Gladyshev VN (June 2002). "How selenium has altered our understanding of the genetic code". Mol. Cell. Biol. 22 (11): 3565–76. doi:10.1128/MCB.22.11.3565-3576.2002. PMC 133838. PMID 11997494.
^ Burk RF; Hill KE (2005). "Selenoprotein P: an extracellular protein with unique physical characteristics and a role in selenium homeostasis". Annu Rev Nutr. 25: 215–235. doi:10.1146/annurev.nutr.24.012003.132120. PMID 16011466.
^ Burk RF; Hill KE (2009). "Selenoprotein P-expression, functions, and roles in mammals". Biochim Biophys Acta. 1790 (11): 1441–1447. doi:10.1016/j.bbagen.2009.03.026. PMC 2763998. PMID 19345254.
^ Fajardo, Diego; Schlautman, Brandon; Steffan, Shawn; Polashock, James; Vorsa, Nicholi; Zalapa, Juan (2014-02-25). "The American cranberry mitochondrial genome reveals the presence of selenocysteine (tRNA-Sec and SECIS) insertion machinery in land plants". Gene. 536 (2): 336–343. doi:10.1016/j.gene.2013.11.104. PMID 24342657.
^ Tsuji, Petra A.; Santesmasses, Didac; Lee, Byeong J.; Gladyshev, Vadim N.; Hatfield, Dolph L. (2021-12-21). "Historical Roles of Selenium and Selenoproteins in Health and Development: The Good, the Bad and the Ugly". International Journal of Molecular Sciences. 23 (1): 5. doi:10.3390/ijms23010005. ISSN 1422-0067. PMC 8744743. PMID 35008430.
^ Sumner, Sarah E.; Markley, Rachel L.; Kirimanjeswara, Girish S. (November 2019). "Role of Selenoproteins in Bacterial Pathogenesis". Biological Trace Element Research. 192 (1): 69–82. Bibcode:2019BTER..192...69S. doi:10.1007/s12011-019-01877-2. ISSN 0163-4984. PMC 6801102. PMID 31489516.
^ Gu, Xin; Gao, Chun-qi (2022-07-05). "New horizons for selenium in animal nutrition and functional foods". Animal Nutrition. 11: 80–86. doi:10.1016/j.aninu.2022.06.013. ISSN 2405-6545. PMC 9464886. PMID 36157130.
^ Avery, JA & Hoffmann, PR (2018). "Selenium, selenoproteins, and immunity". Nutrients. 10 (9): 1203. doi:10.3390/nu10091203. PMC 6163284. PMID 30200430.
^ Moghadaszadeh, Behzad; Beggs, Alan H. (October 2006). "Selenoproteins and Their Impact on Human Health Through Diverse Physiological Pathways". Physiology. 21 (5): 307–315. doi:10.1152/physiol.00021.2006. ISSN 1548-9213. PMC 3372916. PMID 16990451.
^ "SELENON/SEPN1, Rigid Spine Muscular Dystrophy, RSMD". curecmd. Retrieved 2024-03-07.
^ G. V. Kryukov; S. Castellano; S. V. Novoselov; A. V. Lobanov; O. Zehtab; R. Guigó & V. N. Gladyshev (2003). "Characterization of mammalian selenoproteomes". Science. 300 (5624): 1439–1443. Bibcode:2003Sci...300.1439K. doi:10.1126/science.1083516. PMID 12775843. S2CID 10363908.
^ Reeves, MA & Hoffmann, PR (2009). "The human selenoproteome: recent insights into functions and regulation". Cell Mol Life Sci. 66 (15): 2457–78. doi:10.1007/s00018-009-0032-4. PMC 2866081. PMID 19399585.