Iodothyronine deiodinase
Type I thyroxine 5'-deiodinase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Type II thyroxine 5-deiodinase | |||||||||
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Identifiers | |||||||||
ExPASy | NiceZyme view | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Type III thyroxine 5-deiodinase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Iodothyronine deiodinases (
These enzymes are not to be confused with the iodotyrosine deiodinases that are also deiodinases, but not members of the iodothyronine family. The iodotyrosine deiodinases (unlike the iodothyronine deiodinases) do not use selenocysteine or selenium. The iodotyrosine enzymes work on iodinated single tyrosine residue molecules to scavenge iodine, and do not use as substrates the double-tyrosine residue molecules of the various iodothyronines.
Activation and inactivation
In tissues, deiodinases can either activate or inactivate thyroid hormones:
- Activation occurs by conversion of thyroxine (T4) to the active hormone triiodothyronine (T3) through the removal of an iodineatom on the outer ring.
- Inactivation of thyroid hormones occurs by removal of an iodine atom on the inner ring, which converts thyroxine to the inactive reverse triiodothyronine (rT3), or which converts the active triiodothyronine to diiodothyronine (T2).
The major part of
Deiodinase 2 activity can be regulated by ubiquitination:
- The covalent attachment of proteosome.[7]
- Deubiquitination removing ubiquitin from D2 restores its activity and prevents proteosomal degradation.[7]
- The Hedgehog cascade acts to increase D2 ubiquitination through WSB1 activity, decreasing D2 activity.[7][8]
D-propranolol inhibits thyroxine deiodinase, thereby blocking the conversion of T4 to T3, providing some though minimal therapeutic effect.[citation needed]
Reactions
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.
The related catalytic domains of Deiodinases 1-3 feature a thioredoxine-related peroxiredoxin fold.[13] The enzymes catalyze a reductive elimination of iodine, thereby oxidizing themselves similar to Prx, followed by a reductive recycling of the enzyme.
Types
Type I iodothyronine deiodinase | |||||||
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Identifiers | |||||||
Symbol | DIO1 | ||||||
Alt. symbols | TXDI1 | ||||||
Chr. 1 p32-p33 | |||||||
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Chr. 14 q24.2-24.3 | |||||||
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Chr. 14 q32 | |||||||
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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 and kidney | DI can deiodinate both rings[14] |
type II deiodinase (DII) | is found in the pituitary[15] |
DII can only deiodinate the outer ring of the thyroxine and is the major activating enzyme (the already inactive reverse triiodothyronine is also degraded further by DII)
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type III deiodinase (DIII) | found in the fetal tissue and the placenta; also present throughout the brain, except in the pituitary[16] | DIII can only deiodinate the inner ring of thyroxine or triiodothyronine and is the major inactivating enzyme
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Function
Deiodinase 1 both activates T4 to produce T3 and inactivates T4. Besides its increased function in producing extrathyroid T3 in patients with hyperthyroidism, its function is less well understood than D2 or D3 [2][7] Deiodinase 2, located in the ER membrane, converts T4 into T3 and is a major source of the cytoplasmic T3 pool.[2] Deiodinase 3 prevents T4 activation and inactivates T3.[9] 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.[2][7]
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.[12]
Also, iodothyronine deiodinases (type 2 y 3; DIO2 and DIO3, respectively) respond to seasonal changes in photoperiod-driven melatonin secretion and govern peri-hypothalamic catabolism of the prohormone thyroxine (T4). In long summer days, the production of hypothalamic T3 increase due to DIO-2-mediated conversion of T4 to the biologically active hormone. This process allows to active anabolic neuroendocrine pathways that maintain reproductive competence and increase body weight. However, during the adaptation to reproductively inhibitory photoperiods, the levels of T3 decrease due to peri-hypothalamic DIO3 expression that catabolizes T4 and T3 into receptor inactive amines.[17][18]
Deiodinase 2 also plays a significant role in thermogenesis in brown adipose tissue (BAT). In response to sympathetic stimulation, dropping temperature, or overfeeding BAT, D2 increases oxidation of fatty acids and uncouples oxidative phosphorylation via uncoupling protein, causing mitochondrial heat production. D2 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.[19][20]
Disease relevance
In cardiomyopathy 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.[7]
Hypothyroidism is a disease diagnosed by decreased levels of serum thyroxine (T4). Presentation in adults leads to decreased metabolism, increased weight gain, and neuropsychiatric complications.
Quantifying enzyme activity
In vitro, including
In vivo, deiodination activity is estimated from
See also
- Iodotyrosine deiodinase
- Selenium, section Evolution in biology
References
- PMID 25002520.
- ^ PMID 17016550.
- S2CID 44602986.
- S2CID 42616219.
- S2CID 11333443.
- S2CID 40148034.
- ^ PMID 18815314.
- PMID 15965468.
- ^ a b Bianco AC. "Thyroid hormone action starts and ends by deiodination". Bianco Lab & The University of Miami. Retrieved 2011-05-08.
- PMID 9002998.
- S2CID 4338963.
- ^ PMID 9292958.
- PMID 25002520.
- PMID 8187873.
- ^ Holtorf K (2012). "Deiodinases". National Academy of Hypothyroidism.
- PMID 6371572.
- PMID 31189592.
- PMID 17478556.
- PMID 3793928.
- PMID 11696583.
- PMID 9461307.
- PMID 19812240.
- PMID 18978342.
- PMID 9835613.
- PMID 18259611.
- PMID 16982586.
- OL 24586469M. 3897228505.
- S2CID 25630198.
- PMID 27375554.
- PMID 28775711.
Further reading
- Heinrich P, Löffler G, Petrides PE (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (in German) (German ed.). Berlin: Springer. pp. 847–861. ISBN 978-3-540-32680-9.
External links
- Deiodinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)