Iodothyronine deiodinase

Type I thyroxine 5'-deiodinase
Identifiers
EC no.	1.21.99.4
CAS no.	70712-46-8
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Type II thyroxine 5-deiodinase
Identifiers
EC no.	1.21.99.3
CAS no.	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
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

Type III thyroxine 5-deiodinase
Mouse iodothyronine deiodinase 3 catalytic core rendered from PDB entry 4TR3 [1]
Identifiers
EC no.	1.97.1.11
CAS no.	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
Gene Ontology	AmiGO / QuickGO
Search PMC articles PubMed articles NCBI proteins

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. ^{[2] [3]} Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine. ^{[4] [5] [6]}

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 iodine atom 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 thyroxine deiodination occurs within the cells.

Deiodinase 2 activity can be regulated by ubiquitination:

• The covalent attachment of ubiquitin inactivates D2 by disrupting dimerization and targets it to degradation in the 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

Reactions catalyzed by specific deiodinase isoforms

Iodothyronine deiodinase activity and regulation

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. ^[7] Deiodinases are dimeric integral membrane proteins with single transmembrane segments and large globular heads (see below). ^[9] They share a TRX fold that contains the active site including the rare selenocysteine amino acid and two histidine residues. ^{[7] [10]} 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. ^[11] 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. ^[7] The translation of selenocysteine is not efficient, ^[12] even though it is important to the functioning of the enzyme. Deiodinase 2 is localized to the ER membrane while Deiodinase 1 and 3 are found in the plasma membrane. ^[7]

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
Identifiers
Symbol	DIO1
Alt. symbols	TXDI1
NCBI gene	1733
HGNC	2883
OMIM	147892
RefSeq	NM_000792
UniProt	P49895
Other data
EC number	1.21.99.3
Locus	Chr. 1 p32-p33
Search for Structures Swiss-model Domains InterPro

Type II iodothyronine deiodinase
Identifiers
Symbol	DIO2
Alt. symbols	TXDI2, SelY
NCBI gene	1734
HGNC	2884
OMIM	601413
RefSeq	NM_000793
UniProt	Q92813
Other data
EC number	1.21.99.4
Locus	Chr. 14 q24.2-24.3
Search for Structures Swiss-model Domains InterPro

Type III iodothyronine deiodinase
Identifiers
Symbol	DIO3
Alt. symbols	TXDI3
NCBI gene	1735
HGNC	2885
OMIM	601038
PDB	4TR3
RefSeq	NM_001362
UniProt	P55073
Other data
EC number	1.97.1.11
Locus	Chr. 14 q32
Search for Structures Swiss-model Domains InterPro

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 heart, skeletal muscle, CNS, fat, thyroid, and pituitary [15]	DII can only deiodinate the outer ring of the prohormone thyroxine and is the major activating enzyme (the already inactive reverse triiodothyronine is also degraded further by DII)
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

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. ^[21] During development, hypothyroidism is considered more severe and leads to neurotoxicity as cretinism or other human cognitive disorders, ^[22] altered metabolism and underdeveloped organs. Medication and environmental exposures can result in hypothyroidism with changes in deiodinase enzyme activity. The drug iopanoic acid (IOP) decreased cutaneous cell proliferation by inhibition of deiodinase enzyme type 1 or 2 reducing the conversion of T₄ to T₃. The environmental chemical DE-71, a PBDE pentaBDE brominated flame retardant decreased hepatic deiodinase I transcription and enzyme activity in neonatal rats with hypothyroidism. ^[23]

Quantifying enzyme activity

In vitro, including cell culture experiments, deiodination activity is determined by incubating cells or homogenates with high amounts of labeled thyroxine (T₄) and required cosubstrates. As a measure of deiodination, the production of radioactive iodine and other physiological metabolites, in particular T₃ or reverse T₃, are determined and expressed (e.g. as fmol/mg protein/minute). ^{[24] [25]}

In vivo, deiodination activity is estimated from equilibrium levels of free T₃ and free T₄. A simple approximation is T₃/T₄ ratio, ^[26] a more elaborate approach is calculating sum activity of peripheral deiodinases (SPINA-GD) from free T₄, free T₃ and parameters for protein binding, dissociation and hormone kinetics. ^{[27] [28] [29] [30]} In atypical cases, this last approach can benefit from measurements of TBG, but usually only requires measurement of TSH, fT3 and fT4, and as such has no added laboratory requirements besides the measurement of the same.

See also

• Iodotyrosine deiodinase
• Selenium, section Evolution in biology

References

1. Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C (July 2014). "Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism". Proceedings of the National Academy of Sciences of the United States of America. 111 (29): 10526–31. Bibcode:2014PNAS..11110526S. doi: 10.1073/pnas.1323873111 . PMC   4115520 . PMID   25002520.
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3. Wu Y, Koenig RJ (August 2000). "Gene regulation by thyroid hormone". Trends in Endocrinology and Metabolism. 11 (6): 207–11. doi:10.1016/s1043-2760(00)00263-0. PMID   10878749. S2CID   44602986.
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8. Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, et al. (July 2005). "The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate". Nature Cell Biology. 7 (7): 698–705. doi:10.1038/ncb1272. PMC   1761694 . PMID   15965468.
9. Bianco AC. "Thyroid hormone action starts and ends by deiodination". Bianco Lab & The University of Miami. Retrieved 2011-05-08.
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15. Holtorf K (2012). "Deiodinases". National Academy of Hypothyroidism.
16. Kaplan MM (March 1984). "The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function". Neuroendocrinology. 38 (3): 254–60. doi:10.1159/000123900. PMID   6371572.
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24. Steinsapir J, Harney J, Larsen PR (December 1998). "Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes". The Journal of Clinical Investigation. 102 (11): 1895–9. doi:10.1172/JCI4672. PMC   509140 . PMID   9835613.
25. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, et al. (March 2008). "Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats". The Journal of Clinical Investigation. 118 (3): 975–83. doi:10.1172/JCI32824. PMC   2230657 . PMID   18259611.
26. Mortoglou A, Candiloros H (2004). "The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy". Hormones. 3 (2): 120–6. doi:10.14310/horm.2002.11120. PMID   16982586.
27. Dietrich JW (2002). Der Hypophysen-Schilddrüsen-Regelkreis. Berlin, Germany: Logos-Verlag Berlin. ISBN   978-3-89722-850-4. OCLC   50451543. OL   24586469M. 3897228505.
28. Rosolowska-Huszcz D, Kozlowska L, Rydzewski A (August 2005). "Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure". Endocrine. 27 (3): 283–8. doi:10.1385/ENDO:27:3:283. PMID   16230785. S2CID   25630198.
29. Dietrich, JW; Landgrafe-Mende, G; Wiora, E; Chatzitomaris, A; Klein, HH; Midgley, JE; Hoermann, R (2016). "Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research". Frontiers in Endocrinology. 7: 57. doi: 10.3389/fendo.2016.00057 . PMID   27375554.
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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)