Thyroxine 5-deiodinase

Last updated
DIO3
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DIO3 , 5DIII, D3, DIOIII, TXDI3, deiodinase, iodothyronine, type III, iodothyronine deiodinase 3, Dio3 Gene
External IDs OMIM: 601038 MGI: 1306782 HomoloGene: 1044 GeneCards: DIO3
Gene location (Human)
Ideogram human chromosome 14.svg
Chr. Chromosome 14 (human) [1]
Human chromosome 14 ideogram.svg
HSR 1996 II 3.5e.svg
Red rectangle 2x18.png
Band 14q32.31Start101,561,351 bp [1]
End101,563,452 bp [1]
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001362

NM_172119

RefSeq (protein)

NP_001353

NP_742117

Location (UCSC) Chr 14: 101.56 – 101.56 Mb Chr 12: 110.28 – 110.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Thyroxine 5-deiodinase also known as type III iodothyronine deiodinase (EC number 1.21.99.3) is an enzyme that in humans is encoded by the DIO3 gene. [5] [6] This enzyme catalyses the following chemical reaction

Contents

3,3',5'-triiodo-L-thyronine + iodide + A + H+ L-thyroxine + AH2

The protein encoded by this intronless gene belongs to the iodothyronine deiodinase family. It catalyzes the inactivation of thyroid hormone by inner ring deiodination of the prohormone thyroxine (T4) and the bioactive hormone 3,3',5-triiodothyronine (T3) to inactive metabolites, 3,3',5'-triiodothyronine (RT3) and 3,3'-diiodothyronine (T2), respectively. This enzyme is highly expressed in the pregnant uterus, placenta, fetal and neonatal tissues, suggesting that it plays an essential role in the regulation of thyroid hormone inactivation during embryological development. [7]

Discovery

The gene was mapped to chromosome 14q32 using fluorescence in situ hybridization (FISH) in 1998. [8]

Structure

This protein contains a selenocysteine (Sec) residue, which is essential for efficient enzyme activity. The selenocysteine is encoded by the UGA codon, which normally signals translation termination. The 3' UTR of Sec-containing genes have a common stem-loop structure, the sec insertion sequence (SECIS), which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. [7]

Function

Thyroxine 5-deiodinase
Identifiers
EC number 1.21.99.3
CAS number 74506-30-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

The DIO3 gene codes for type 3 iodothyronine deiodinase (D3), an enzyme that inactivates thyroid hormones and is highly expressed throughout fetal development, peaking early and decreasing towards the end of gestation. Part of the DLK1-Dio3 imprinting control region, this gene is one involved in the epigenetic process that causes a subset of genes to be regulated based on their parental origin . [9] Such imprinted genes are required for the formation of the placenta as well as the development of cellular lineages such as those derived from the mesoderm and ectoderm. [10] D3 is found in the pregnant uterus, placenta, and mammalian fetal tissues where it is thought to be involved in the transfer of thyroid hormone between the mother and fetus. [11] Expression of D3 contributes to the development of the brain, skin, liver, bone, ovary, testis, intestine, and brown adipose tissue. Introductory observations of D3-deficient mice indicate growth retardation and even some neonatal death. Due to its ability to activate or inactivate thyroid hormone, Dio3 coding of D3 could be a target for therapeutic intervention in insulin-related illness such as diabetes. In addition, an abnormal amount of Dio3 related to insufficient thyroid hormone levels could be responsible for the disruption of brain development in conjunction with alcohol exposure. [12] Many factors modify genetic imprinting of Dio3, making it a potential aid in understanding prenatal insults and their production of spectrum disorders.

Related Research Articles

Hypothyroidism Endocrine disease

Hypothyroidism, also called underactive thyroid or low thyroid, is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Iodothyronine deiodinase class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes 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.

Proopiomelanocortin mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 285-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 44-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

Thyroxine-binding globulin mammalian protein found in Homo sapiens

Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the SERPINA7 gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.

Triiodothyronine chemical compound

Triiodothyronine, 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.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

Hypothalamic–pituitary–thyroid axis part of the neuroendocrine system responsible for the regulation of metabolism.

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

Reverse triiodothyronine pair of enantiomers

Reverse triiodothyronine (3,3’,5’-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3’ triiodothyronine, T3).

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamsus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences and impaired assay characteristics in critical illness.

Growth-hormone-releasing hormone receptor protein-coding gene in the species Homo sapiens

The growth-hormone-releasing hormone receptor (GHRHR) is a G-protein-coupled receptor that binds growth hormone-releasing hormone. The GHRHR activates a Gs protein that causes a cascade of cAMP via Adenylate cyclase.

DLK1 Protein-coding gene in the species Homo sapiens

Protein delta homolog 1 is a protein that in humans is encoded by the DLK1 gene.

SECISBP2 protein-coding gene in the species Homo sapiens

SECIS-binding protein 2 is a protein that in humans is encoded by the SECISBP2 gene.

USP33 protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 33 is an enzyme that in humans is encoded by the USP33 gene.

CRYM protein-coding gene in the species Homo sapiens

Mu-crystallin homolog also known as NADP-regulated thyroid-hormone-binding protein (THBP) is a protein that in humans is encoded by the CRYM gene. Multiple alternatively spliced transcript variants have been found for this gene.

USP20 protein-coding gene in the species Homo sapiens

Ubiquitin carboxyl-terminal hydrolase 20 is an enzyme that in humans is encoded by the USP20 gene.

DIO2 protein-coding gene in the species Homo sapiens

Type II iodothyronine deiodinase is an enzyme that in humans is encoded by the DIO2 gene.

Thyroid hormones hormones produced by the thyroid gland

Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre. The major form of thyroid hormone in the blood is thyroxine (T4), which has a longer half-life than T3. In humans, the ratio of T4 to T3 released into the blood is approximately 14:1. T4 is converted to the active T3 (three to four times more potent than T4) within cells by deiodinases (5′-iodinase). These are further processed by decarboxylation and deiodination to produce iodothyronamine (T1a) and thyronamine (T0a). All three isoforms of the deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 production.

Iopanoic acid chemical compound

Iopanoic acid is an iodine-containing radiocontrast medium used in cholecystography. Both iopanoic acid and ipodate sodium are potent inhibitors of thyroid hormone release from thyroid gland, as well as of peripheral conversion of thyroxine (T4) to triiodothyronine (T3). These compounds inhibit 5'deiodinase (5'DID-1 and 5'DID-2) enzymes, which catalyse T4-T3 conversion in the thyroid cell, liver, kidney, skeletal muscle, heart, brain, pituitary. This accounts for the dramatic improvement in both subjective and objective symptoms of hyperthyroidism, particularly when they are used as an adjunctive therapy with thioamides (propylthiouracil, carbimazole). They can be used in the treatment of patients with severe thyrotoxicosis (thyroid storm) and significant morbidity (e.g., myocardial infarction, or stroke) for rapid control of elevated plasma triiodothyronine concentrations. The use of iopanoic acid for treatment of thyrotoxicosis has been discontinued in the United States.

Iodotyrosine deiodinase protein-coding gene in the species Homo sapiens

Iodotyrosine deiodinase, also known as iodotyrosine dehalogenase 1, is a type of deiodinase enzyme that scavenges iodide by removing it from iodinated tyrosine residues in the thyroid gland. These iodinated tyrosines are produced during thyroid hormone biosynthesis. The iodide that is scavenged by iodotyrosine deiodinase is necessary to again synthesize the thyroid hormones. After synthesis, the thyroid hormones circulate through the body to regulate metabolic rate, protein expression, and body temperature. Iodotyrosine deiodinase is thus necessary to keep levels of both iodide and thyroid hormones in balance.

Deiodinase is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000197406 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000075707 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Chopra IJ, Chua Teco GN (Jan 1982). "Characteristics of inner ring (3 or 5) monodeiodination of 3,5-diiodothyronine in rat liver: evidence suggesting marked similarities of inner and outer ring deiodinases for iodothyronines". Endocrinology. 110 (1): 89–97. doi:10.1210/endo-110-1-89. PMID   7053997.
  6. Köhrle J (2002). Iodothyronine deiodinases. Methods in Enzymology. 347. pp. 125–167. doi:10.1016/s0076-6879(02)47014-0. ISBN   9780121822484. PMID   11898402.
  7. 1 2 "Entrez Gene: Deiodinase, iodothyronine, type III".
  8. Hernandez A, Park JP, Lyon GJ, Mohandas TK, St Germain DL (Oct 1998). "Localization of the type 3 iodothyronine deiodinase (DIO3) gene to human chromosome 14q32 and mouse chromosome 12F1". Genomics. 53 (1): 119–121. doi:10.1006/geno.1998.5505. PMID   9787088.
  9. Lin SP, Coan P, da Rocha ST, Seitz H, Cavaille J, Teng PW, Takada S, Ferguson-Smith AC (Jan 2007). "Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region". Development. 134 (2): 417–426. doi: 10.1242/dev.02726 . PMID   17166925.
  10. Hernandez A, Fiering S, Martinez E, Galton VA, St Germain D (Nov 2002). "The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts". Endocrinology. 143 (11): 4483–4486. doi: 10.1210/en.2002-220800 . PMID   12399446.
  11. Medina MC, Molina J, Gadea Y, Fachado A, Murillo M, Simovic G, Pileggi A, Hernández A, Edlund H, Bianco AC (Oct 2011). "The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion". Endocrinology. 152 (10): 3717–3727. doi:10.1210/en.2011-1210. PMC   3176649 . PMID   21828183.
  12. Sittig LJ, Shukla PK, Herzing LB, Redei EE (Jul 2011). "Strain-specific vulnerability to alcohol exposure in utero via hippocampal parent-of-origin expression of deiodinase-III". FASEB Journal. 25 (7): 2313–2324. doi:10.1096/fj.10-179234. PMC   3114527 . PMID   21429942.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.