Thioredoxin
Encyclopedia
Thioredoxin is a class of small redox
protein
s known to be present in all organism
s. It plays a role in many important biological process
es. In humans, it is encoded by the TXN gene
. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo
. Although not entirely understood, thioredoxin plays a central role in humans and is increasingly linked to medicine through their response to reactive oxygen species
(ROS). In plants, thioredoxins perform a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. It has also recently been found to play a role in cell-to-cell communication
.
s that act as antioxidants by facilitating the reduction
of other proteins by cysteine
thiol-disulfide exchange
. Thioredoxins are found in nearly all known organisms and are essential for life in mammal
s.
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test.
Thioredoxins are characterized at the level of their amino acid
sequence by the presence of two vicinal
cysteines in a CXXC motif
. These two cysteines are the key to the ability of thioredoxin to reduce other proteins. Thioredoxin proteins also have a characteristic tertiary structure
termed the thioredoxin fold
.
The thioredoxins are kept in the reduced state by the flavoenzyme thioredoxin reductase
, in a NADPH-dependent reaction. Thioredoxins act as electron donors to peroxidase
s and ribonucleotide reductase
. The related glutaredoxin
s share many of the functions of thioredoxins, but are reduced by glutathione
rather than a specific reductase.
The benefit of thioredoxins to reduce oxidative stress
is shown by transgenic
mice that overexpress thioredoxin, are more resistant to inflammation, and live 35% longer — supporting the free radical theory of aging
.
Plant
s have an unusually complex complement of Trxs composed of six well-defined types (Trxs f, m, x, y, h, and o) that reside in different cell compartments and function in an array of processes. Recently, it has been discovered for the first time that thioredoxin proteins are able to move from cell to cell
, representing a novel form of cellular communication in plants.
with TXNIP
, ASK1
, Collagen, type I, alpha 1 and Glucocorticoid receptor
.
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
protein
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...
s known to be present in all organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
s. It plays a role in many important biological process
Biological process
A biological process is a process of a living organism. Biological processes are made up of any number of chemical reactions or other events that results in a transformation....
es. In humans, it is encoded by the TXN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
. Although not entirely understood, thioredoxin plays a central role in humans and is increasingly linked to medicine through their response to reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
(ROS). In plants, thioredoxins perform a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. It has also recently been found to play a role in cell-to-cell communication
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
.
Function
Thioredoxins are proteinProtein
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...
s that act as antioxidants by facilitating the reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
of other proteins by 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...
thiol-disulfide exchange
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
. Thioredoxins are found in nearly all known organisms and are essential for life in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s.
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test.
Thioredoxins are characterized at the level of their amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence by the presence of two vicinal
Vicinal (chemistry)
In chemistry vicinal stands for any two functional groups bonded to two adjacent carbon atoms. For example the molecule 2,3-dibromobutane carries two vicinal bromine atoms and 1,3-dibromobutane does not....
cysteines in a CXXC motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
. These two cysteines are the key to the ability of thioredoxin to reduce other proteins. Thioredoxin proteins also have a characteristic tertiary structure
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
termed the thioredoxin fold
Thioredoxin fold
The thioredoxin fold is a protein fold common to enzymes that catalyze disulfide bond formation and isomerization. The fold is named for the canonical example thioredoxin and is found in both prokaryotic and eukaryotic proteins. It is an example of an alpha/beta protein fold that has oxidoreductase...
.
The thioredoxins are kept in the reduced state by the flavoenzyme 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...
, in a NADPH-dependent reaction. Thioredoxins act as electron donors to peroxidase
Peroxidase
Peroxidases are a large family of enzymes that typically catalyze a reaction of the form:For many of these enzymes the optimal substrate is hydrogen peroxide, but others are more active with organic hydroperoxides such as lipid peroxides...
s and ribonucleotide reductase
Ribonucleotide reductase
Ribonucleotide reductase is an enzyme that catalyzes the formation of deoxyribonucleotides from ribonucleotides. Deoxyribonucleotides in turn are used in the synthesis of DNA. The reaction catalyzed by RNR is strictly conserved in all living organisms...
. The related glutaredoxin
Glutaredoxin
Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no...
s share many of the functions of thioredoxins, but are reduced by glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
rather than a specific reductase.
The benefit of thioredoxins to reduce oxidative stress
Oxidative stress
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage...
is shown by transgenic
Transgenesis
thumb|300px|right|A diagram comparing the genetic changes achieved through conventional plant breeding, transgenesis and cisgenesisTransgenesis is the process of introducing an exogenous gene – called a transgene – into a living organism so that the organism will exhibit a new property and transmit...
mice that overexpress thioredoxin, are more resistant to inflammation, and live 35% longer — supporting the free radical theory of aging
Free-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
.
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 have an unusually complex complement of Trxs composed of six well-defined types (Trxs f, m, x, y, h, and o) that reside in different cell compartments and function in an array of processes. Recently, it has been discovered for the first time that thioredoxin proteins are able to move from cell to cell
Cell signaling
Cell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
, representing a novel form of cellular communication in plants.
Interactions
Thioredoxin has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with TXNIP
TXNIP
Thioredoxin-interacting protein is a protein that in humans is encoded by the TXNIP gene.-Interactions:TXNIP has been shown to interact with Thioredoxin and ZBTB32.-Related gene problems:*TAR syndrome*1q21.1 deletion syndrome...
, ASK1
ASK1
Apoptosis signal-regulating kinase 1 also known as mitogen-activated protein kinase kinase kinase 5 is a member of MAP kinase kinase kinase family and as such a part of mitogen-activated protein kinase pathway...
, Collagen, type I, alpha 1 and Glucocorticoid receptor
Glucocorticoid receptor
The glucocorticoid receptor also known as NR3C1 is the receptor to which cortisol and other glucocorticoids bind....
.