Deiodinase
Encyclopedia
Iodothyronine deiodinases ( and ) are a subfamily of deiodinase
enzyme
s important in the activation and deactivation of thyroid hormones. Thyroxine
(T4), the precursor of 3,5,3’-triiodothyronine
(T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor
, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium
, in the form of an otherwise rare amino acid
selenocysteine
.
Dionidase 2 activity can be regulated by ubiquitination:
including the rare selenocysteine amino acid and two histidine
residues.< Selenocysteine is coded by a UGA codon, which generally signifies termination of a peptide through a stop codon. In point mutation experiments with Deiodinase 1 changing UGA to the stop codon TAA resulted in a complete loss of function, while changing UGA to cysteine (TGT) caused the enzyme to operate at around 10% normal efficiency. In order for UGA to be read as a selenocysteine amino acid instead of a stop codon, it is necessary that a downstream stem loop sequence, the selenocysteine insertion sequence (SECIS), be present to bind with SECIS binding protein-2 (SBP-2), which binds with elongation factor EFsec. The translation of selenocysteine is not efficient, even though it is important to the functioning of the enzyme. Deiodinase 2 is localized to the ER membrane while Deinodase 1 and 3 are found in the plasma membrane.
The following is a list of the three human iodothyronine deiodinases:
, its function is less well understood than D2 or D3 Deiodinase 2, located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool. Deiodinase 3 prevents T4 activation and inactivates T3 D2 and D3 are important in homeostatic regulation in maintaining T3 levels at the plasma and cellular levels. In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T3, while in hypothyroidism
D2 is upregulated and D3 is downregulated to increase cytoplasmic T3 levels.
Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis
since T3 and T4 levels may vary by organ. Deiodinases also provide spatial and temporal developmental control of thyroid hormone levels. D3 levels are highest early in development and decrease over time, while D2 levels are high at moments of significant metamorphic change in tissues. Thus D2 enables production of sufficient T3 at necessary time points while D3 may shield tissue from overexposure to T3.
Deiodinase 2 also plays a significant role in thermogenesis
in brown adipose tissue
(BAT). In response to sympathetic stimulation, dropping temperature, or overfeeding BAT, increases oxidation of fatty acids and uncouples oxidative phosphorylation by UCP causing mitochondrial heat production. Deiodinase 2 increases during cold stress in BAT and increases intracellular T3 levels. In D2 deficient models, shivering is a behavioral adaptation to the cold. However, heat production is much less efficient than uncoupling lipid oxidation.
the heart reverts to a fetal gene programming due to the overload of the heart. Like during fetal development, thyroid hormone levels are low in the overloaded heart tissue in a local hypothyroid state, with low levels of Deiodinase 1 and Deiodinase 2. Although Deiodinase 3 levels in a normal heart are generally low, in cardiomyopathy Deiodinase 3 activity is increased to decrease energy turnover and oxygen consumption.
Deiodinase
Iodothyronine deiodinases are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine , the precursor of 3,5,3’-triiodothyronine is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor,...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s important in the activation and deactivation of thyroid hormones. Thyroxine
Thyroxine
Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(T4), the precursor of 3,5,3’-triiodothyronine
Triiodothyronine
Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
(T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor
Thyroid hormone receptor
The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.-Function:Amongst the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate...
, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain 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...
, in the form of an otherwise rare 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...
selenocysteine
Selenocysteine
Selenocysteine is an amino acid that is present in several enzymes .-Nomenclature:...
.
Activation and inactivation
In tissues, deiodinases can either activate or inactivate thyroid hormones:- Activation occurs by conversion of the prohormoneProhormoneA prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. The primary function of a prohormone is to enhance the strength of the hormone that already occurs in the...
thyroxineThyroxineThyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
(T4) to the active hormone triiodothyronineTriiodothyronineTriiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
(T3) through the removal of an iodineIodineIodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
atom on the outer ring. - Inactivation of thyroid hormones occurs by removal of an iodineIodineIodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
atom on the inner ring, which converts thyroxine to the inactive reverse triiodothyronineReverse triiodothyronineReverse triiodothyronine is a molecule that is an isomer of triiodothyronine . It is derived from thyroxine through the action of deiodinase....
(rT3), or which converts the active triiodothyronineTriiodothyronineTriiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate....
to the inactive diiodothyronine (T2). The major part of thyroxineThyroxineThyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:...
deiodination occurs within the cells.
Dionidase 2 activity can be regulated by ubiquitination:
- The covalent attachment of ubiquitinUbiquitinUbiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
inactivates D2 by disrupting dimerization and targets it to degradation in the proteosome. - Deubiquitination removing ubiquitin from D2 restores its activity and prevents proteosomal degradation.
- The Hedgehog cascade acts to increase D2 ubiquitination through WSB1WSB1WD repeat and SOCS box-containing protein 1 is a protein that in humans is encoded by the WSB1 gene.-Further reading:...
activity, decreasing D2 activity.
Reactions
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Enzyme structure
The three deiodinase enzymes share certain structural features in common although their sequence identity is lower than 50%. Each enzyme weighs between 29 and 33kDa. Deiodinases are dimeric integral membrane proteins with single transmembrane segments and large globular heads. They share a TRX fold that contains the active siteActive site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
including the rare selenocysteine amino acid and two histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
residues.< Selenocysteine is coded by a UGA codon, which generally signifies termination of a peptide through a stop codon. In point mutation experiments with Deiodinase 1 changing UGA to the stop codon TAA resulted in a complete loss of function, while changing UGA to cysteine (TGT) caused the enzyme to operate at around 10% normal efficiency. In order for UGA to be read as a selenocysteine amino acid instead of a stop codon, it is necessary that a downstream stem loop sequence, the selenocysteine insertion sequence (SECIS), be present to bind with SECIS binding protein-2 (SBP-2), which binds with elongation factor EFsec. The translation of selenocysteine is not efficient, even though it is important to the functioning of the enzyme. Deiodinase 2 is localized to the ER membrane while Deinodase 1 and 3 are found in the plasma membrane.
Types
In most vertebrates, there are three types of enzymes that can deiodinate thyroid hormones:| Type | Location | Function >- | type I (DI) |
is commonly found in the liver Liver The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion... and kidney Kidney The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and... |
>- | is found in the heart Heart The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions... , skeletal muscle, CNS, fat Fat Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure... and thyroid Thyroid The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage... |
prohormone Prohormone A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. The primary function of a prohormone is to enhance the strength of the hormone that already occurs in the... thyroxine Thyroxine Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:... (or the metabolically inactive reverse triiodothyronine Reverse triiodothyronine Reverse triiodothyronine is a molecule that is an isomer of triiodothyronine . It is derived from thyroxine through the action of deiodinase.... ) and is the major activating enzyme >- | type III deiodinase (DIII) |
found in the fetal tissue and the placenta Placenta The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and... |
DIII can only deiodinate the inner ring of thyroxine Thyroxine Thyroxine, or 3,5,3',5'-tetraiodothyronine , a form of thyroid hormones, is the major hormone secreted by the follicular cells of the thyroid gland.-Synthesis and regulation:... or triiodothyronine Triiodothyronine Triiodothyronine, C15H12I3NO4, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.... and is the major inactivating enzyme |
The following is a list of the three human iodothyronine deiodinases:
Biological function
Deiodinase 1 both activates T4 to produce T3 and inactivates T4. Besides its increased function in producing extrathyroid T3 in patients with hyperthyroidismHyperthyroidism
Hyperthyroidism is the term for overactive tissue within the thyroid gland causing an overproduction of thyroid hormones . Hyperthyroidism is thus a cause of thyrotoxicosis, the clinical condition of increased thyroid hormones in the blood. Hyperthyroidism and thyrotoxicosis are not synonymous...
, its function is less well understood than D2 or D3 Deiodinase 2, located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool. Deiodinase 3 prevents T4 activation and inactivates T3 D2 and D3 are important in homeostatic regulation in maintaining T3 levels at the plasma and cellular levels. In hyperthyroidism D2 is down regulated and D3 is upregulated to clear extra T3, while in hypothyroidism
Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland does not make enough thyroid hormone.Iodine deficiency is the most common cause of hypothyroidism worldwide but it can be caused by other causes such as several conditions of the thyroid gland or, less commonly, the pituitary gland or...
D2 is upregulated and D3 is downregulated to increase cytoplasmic T3 levels.
Serum T3 levels remain fairly constant in healthy individuals, but D2 and D3 can regulate tissue specific intracellular levels of T3 to maintain homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
since T3 and T4 levels may vary by organ. Deiodinases also provide spatial and temporal developmental control of thyroid hormone levels. D3 levels are highest early in development and decrease over time, while D2 levels are high at moments of significant metamorphic change in tissues. Thus D2 enables production of sufficient T3 at necessary time points while D3 may shield tissue from overexposure to T3.
Deiodinase 2 also plays a significant role in thermogenesis
Thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...
in brown adipose tissue
Brown adipose tissue
Brown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....
(BAT). In response to sympathetic stimulation, dropping temperature, or overfeeding BAT, increases oxidation of fatty acids and uncouples oxidative phosphorylation by UCP causing mitochondrial heat production. Deiodinase 2 increases during cold stress in BAT and increases intracellular T3 levels. In D2 deficient models, shivering is a behavioral adaptation to the cold. However, heat production is much less efficient than uncoupling lipid oxidation.
Disease relevance
In cardiomyopathyCardiomyopathy
Cardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
the heart reverts to a fetal gene programming due to the overload of the heart. Like during fetal development, thyroid hormone levels are low in the overloaded heart tissue in a local hypothyroid state, with low levels of Deiodinase 1 and Deiodinase 2. Although Deiodinase 3 levels in a normal heart are generally low, in cardiomyopathy Deiodinase 3 activity is increased to decrease energy turnover and oxygen consumption.