Selenoprotein

Last updated April 08, 2024

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 recently 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.^{[ citation needed ]}

Types

Besides the selenocysteine-containing selenoproteins, there are also some selenoproteins known from bacterial species, 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, including humans. About 25 different selenocysteine-containing selenoproteins have so far been observed in human cells and tissues.^[5] 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.^[6]^[7]

Examples

Human selenoproteins include:

Iodothyronine deiodinases 1-3: DIO1, DIO2, DIO3
Glutathione peroxidases: GPX1, GPX2, GPX3, GPX4, GPX6 ^[8]
Selenoproteins: SelH (C11orf31), SelI (EPT1), SelK, SelM, SelN (SEPN1), SelO, SelP (SEPP1), SelR (MSRB1), SelS, SelT, SelV, SelW (SEPW1), Sel15 ^[9]
Selenophosphate synthetase 2 (SEPHS2, SPS2)
Thioredoxin reductases 1-3: TXNRD1, TXNRD2, TXNRD3

Bacterial selenoproteins include:

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

Related Research Articles

<span class="mw-page-title-main">Selenium</span> Chemical element, symbol Se and atomic number 34

Selenium is a chemical element; it has the symbol Se and atomic number 34. It is a nonmetal with properties that are intermediate between the elements above and below in the periodic table, sulfur and tellurium, and also has similarities to arsenic. It seldom occurs in its elemental state or as pure ore compounds in Earth's crust. Selenium was discovered in 1817 by Jöns Jacob Berzelius, who noted the similarity of the new element to the previously discovered tellurium.

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

Selenocysteine 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.

<span class="mw-page-title-main">Glutathione peroxidase</span> Enzyme family protecting the organism from oxidative damages

Glutathione peroxidase (GPx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.

<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.

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

Selenomethionine (SeMet) is a naturally occurring amino acid. The L-selenomethionine enantiomer is the main form of selenium found in Brazil nuts, cereal grains, soybeans, and grassland legumes, while Se-methylselenocysteine, or its γ-glutamyl derivative, is the major form of selenium found in Astragalus, Allium, and Brassica species. In vivo, selenomethionine is randomly incorporated instead of methionine. Selenomethionine is readily oxidized.

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.

Glutathione peroxidase 4, also known as GPX4, is an enzyme that in humans is encoded by the GPX4 gene. GPX4 is a phospholipid hydroperoxidase that protects cells against membrane lipid peroxidation.

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

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

Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene.

Selenoprotein S, also known as SELS, is a human gene.

Selenoprotein N is a protein that in humans is encoded by the SEPN1 gene.

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.

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

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

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

Glutathione peroxidase 6 (GPx-6) is an enzyme that in humans is encoded by the GPX6 gene.

In molecular biology, the protein domain selenoprotein P (SelP) is the only known eukaryotic selenoprotein that contains multiple selenocysteine (Sec) residues. It is a secreted glycoprotein, often found in the plasma. Its precise function remains to be elucidated; however, it is thought to have antioxidant properties. This particular protein contains two domains: the C terminal and N terminal domain. The N-terminal domain is larger than the C terminal and the N-terminal is thought to be glycosylated.

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⁻).

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

References

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↑ 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.
↑ 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 | Cure CMD". 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.