Selenoprotein
Encyclopedia
In molecular biology a selenoprotein is any protein
that includes a selenocysteine
(Se-Cys) amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidase
s (GPX) and three thioredoxin reductase
s, (TrxR/TXNRD) which both contain only one Se-Cys. Selenoprotein P is the most common selenoprotein found in the plasma. It is unusual because in humans it contains 10 Se-Cys residues, which are split into two domains, a longer N-terminal domain that contains 1 Se-Cys, and a shorter C-terminal domain that contains 9 Se-Cys. 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.
s, bacteria
and archaea
. Among eukaryote
s, selenoproteins appear to be common in animal
s, but rare or absent in other phyla (one has been identified in the green alga Chlamydomonas
, but none in other plant
s or in fungi). 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.
-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 dehydrogenase
s). 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 methionine
s 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.
is a vital nutrient in animal
s, including humans. About 25 different selenocysteine-containing selenoproteins have so far been observed in human cell
s and tissues. 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. In fact, three selenoproteins, TR1, TR3 and GPx4
, have been shown to be essential in mice knockout experiments. On the other hand, too much selenium in the diet causes toxic effects and leads to selenium poisoning. The threshold between essential and toxic concentrations of this element is rather narrow - the factor is in the range of 10-100.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that includes a selenocysteine
Selenocysteine
Selenocysteine is an amino acid that is present in several enzymes .-Nomenclature:...
(Se-Cys) amino acid residue. Among functionally characterized selenoproteins are five glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...
s (GPX) and three thioredoxin reductase
Thioredoxin reductase
Thioredoxin Reductases are the only known enzymes to reduce thioredoxin . Two classes of thioredoxin reductase have been identified: one class in bacteria and some eukaryotes and one in animals. Both classes are flavoproteins which function as homodimers...
s, (TrxR/TXNRD) which both contain only one Se-Cys. Selenoprotein P is the most common selenoprotein found in the plasma. It is unusual because in humans it contains 10 Se-Cys residues, which are split into two domains, a longer N-terminal domain that contains 1 Se-Cys, and a shorter C-terminal domain that contains 9 Se-Cys. 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.
Species distribution
Selenoproteins exist in all major forms of life, eukaryoteEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s, bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
. Among eukaryote
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
s, selenoproteins appear to be common in animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s, but rare or absent in other phyla (one has been identified in the green alga Chlamydomonas
Chlamydomonas
Chlamydomonas is a genus of green algae. They are unicellular flagellates. Chlamydomonas is used as a model organism for molecular biology, especially studies of flagellar motility and chloroplast dynamics, biogenesis, and genetics...
, but none in other plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s or in fungi). 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
Full genome sequencing
Full genome sequencing , also known as whole genome sequencing , complete genome sequencing, or entire genome sequencing, is a laboratory process that determines the complete DNA sequence of an organism's genome at a single time...
, which shows the presence or absence of selenoprotein genes and accessory genes for the synthesis of selenoproteins in the respective organism.
Types
Besides the selenocysteineSelenocysteine
Selenocysteine is an amino acid that is present in several enzymes .-Nomenclature:...
-containing selenoproteins, there are also some selenoproteins known from bacterial species, which have selenium
Selenium
Selenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...
bound noncovalently. Most of these proteins are thought to contain a selenide-ligand to a molybdopterin
Molybdopterin
Molybdopterins, when reacted with molybdenum or tungsten in the form of molybdate or tungstate, are a class of cofactors found in most molybdenum and all tungsten enzymes...
cofactor at their active sites (e.g. nicotinate dehydrogenase
Nicotinate dehydrogenase
In enzymology, a nicotinate dehydrogenase is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are nicotinate, H2O, and NADP+, whereas its 3 products are 6-hydroxynicotinate, NADPH, and H+....
of Eubacterium barkeri, or xanthine dehydrogenase
Xanthine dehydrogenase
Xanthine dehydrogenase, also known as XDH, is a protein that, in humans, is encoded by the XDH gene.-Function:Xanthine dehydrogenase belongs to the group of molybdenum-containing hydroxylases involved in the oxidative metabolism of purines. The enzyme is a homodimer...
s). 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
Selenomethionine
Selenomethionine is an amino acid containing selenium. The L-enantiomer of selenomethionine, known as Se-met and Sem, is a common natural food source of selenium. In vivo, selenomethionine is randomly incorporated instead of methionine and is readily oxidized. Its antioxidant activity arises from...
, which replaces methionine residues. Proteins containing such unspecifically incorporated selenomethionine residues are not regarded as selenoproteins. However, replacement of all methionine
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
s by selenomethionines is a widely used, recent technique in solving the phase problem during X-ray crystallographic structure determination of many proteins (MAD-phasing
Multi-wavelength anomalous dispersion
Multi-wavelength anomalous diffraction is a technique used in X-ray crystallography that facilitates the determination of the three-dimensional structure of biological macromolecules via solution of the phase problem...
). While the exchange of methionines by selenomethionines appears to be tolerated (at least in bacterial cells), unspecific incorporation of selenocysteine in lieu of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
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
SeleniumSelenium
Selenium is a chemical element with atomic number 34, chemical symbol Se, and an atomic mass of 78.96. It is a nonmetal, whose properties are intermediate between those of adjacent chalcogen elements sulfur and tellurium...
is a vital nutrient in animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s, including humans. About 25 different selenocysteine-containing selenoproteins have so far been observed in human cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s and tissues. 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. In fact, three selenoproteins, TR1, TR3 and GPx4
GPX4
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.- Function :...
, have been shown to be essential in mice knockout experiments. On the other hand, too much selenium in the diet causes toxic effects and leads to selenium poisoning. The threshold between essential and toxic concentrations of this element is rather narrow - the factor is in the range of 10-100.
Examples
Human selenoproteins include:- Iodothyronine deiodinases 1-3: DIO1, DIO2DIO2Type II iodothyronine deiodinase is an enzyme that in humans is encoded by the DIO2 gene.-Further reading:...
, DIO3 - Glutathione peroxidases: GPX1GPX1Glutathione peroxidase 1 is an enzyme that in humans is encoded by the GPX1 gene.-Further reading:...
, GPX2GPX2 (gene)Glutathione peroxidase 2 is an enzyme that in humans is encoded by the GPX2 gene.The antioxidant enzyme glutathione peroxidase 2 is one out of eight known glutathione peroxidases in humans...
, GPX3GPX3Glutathione peroxidase 3 , also known as plasma glutathione peroxidase or extracellular glutathione peroxidase is an enzyme that in humans is encoded by the GPX3 gene....
, GPX4GPX4Glutathione 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.- Function :...
, GPX6GPX6Glutathione peroxidase 6 is an enzyme that in humans is encoded by the GPX6 gene.This gene product belongs to the glutathione peroxidase family, which functions in the detoxification of hydrogen peroxide. It contains a selenocysteine residue at its active site. The selenocysteine is encoded by... - Selenoproteins: SelH, SelI, SelK, SelM, SelN, SelO, SelP, SelR, SelS, SelT, SelV, SelW, Sel15
- Selenophosphate synthetase 2 (SPS2)
- Thioredoxin reductases 1-3: TXNRD1TXNRD1Thioredoxin reductase 1, cytoplasmic is an enzyme that in humans is encoded by the TXNRD1 gene.-References:...
, TXNRD2, TXNRD3