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词条 Iodothyronine deiodinase
释义

  1. Activation and inactivation

  2. Reactions

  3. Structure

  4. Types

  5. Function

  6. Disease relevance

  7. Quantifying enzyme activity

  8. See also

  9. References

  10. Further reading

  11. External links

{{enzyme
| Name = Type I thyroxine 5'-deiodinase
| EC_number = 1.21.99.4
| CAS_number =70712-46-8
| GO_code = 0004800
| image =
| width =
| caption =
}}{{enzyme
| Name = Type II thyroxine 5-deiodinase
| EC_number = 1.21.99.3
| CAS_number =74506-30-2
| GO_code = 0033798
| image =
| width =
| caption =
}}{{enzyme
| Name = Type III thyroxine 5-deiodinase
| EC_number = 1.97.1.11
| CAS_number =74506-30-2
| GO_code = 0033798
| image = File:4TR3.png
| width =
| caption = Mouse iodothyronine deiodinase 3 catalytic core rendered from PDB entry 4TR3 [1]
}}Iodothyronine deiodinases ({{EC number|1.21.99.4}} and {{EC number|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 the prohormone 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.

Deionidase 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|date=May 2014}}

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.[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

{{infobox protein
| Name = Type I iodothyronine deiodinase
| caption =
| image =
| width =
| HGNCid = 2883
| Symbol = DIO1
| AltSymbols = TXDI1
| EntrezGene = 1733
| OMIM = 147892
| RefSeq = NM_000792
| UniProt = P49895
| PDB =
| ECnumber = 1.21.99.3
| Chromosome = 1
| Arm = p
| Band = 32
| LocusSupplementaryData = -p33
}}{{infobox protein
| Name = Type II iodothyronine deiodinase
| caption =
| image =
| width =
| HGNCid = 2884
| Symbol = DIO2
| AltSymbols = TXDI2, SelY
| EntrezGene = 1734
| OMIM = 601413
| RefSeq = NM_000793
| UniProt = Q92813
| PDB =
| ECnumber = 1.21.99.4
| Chromosome = 14
| Arm = q
| Band = 24.2
| LocusSupplementaryData = -24.3
}}{{infobox protein
| Name = Type III iodothyronine deiodinase
| caption =
| image =
| width =
| HGNCid = 2885
| Symbol = DIO3
| AltSymbols = TXDI3
| EntrezGene = 1735
| OMIM = 601038
| RefSeq = NM_001362
| UniProt = P55073
| PDB = 4TR3
| ECnumber = 1.97.1.11
| Chromosome = 14
| Arm = q
| Band = 32
| LocusSupplementaryData =
}}

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]

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.[17][18]

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.[19] During development, hypothyroidism is considered more severe and leads to neurotoxicity as cretinism or other human cognitive disorders,[20] 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.[21]

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).[22][23]

In vivo, deiodination activity is estimated from equilibrium levels of free T3 and free T4. A simple approximation is T3/T4 ratio,[24] a more elaborate approach is calculating sum activity of peripheral deiodinases (GD) from free T4, free T3 and parameters for protein binding, dissociation and hormone kinetics.[25][26] 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. ^{{cite journal | vauthors = Schweizer U, Schlicker C, Braun D, Kohrle J, Steegborn C | title = Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism | journal = Proc. Natl. Acad. Sci. USA | volume = 111 | issue = 29 | pages = 10526–31 | pmid = 25002520 | doi = 10.1073/pnas.1323873111 | date=Jul 2014 | pmc=4115520}}
2. ^1 2 3 {{cite journal | vauthors = Bianco AC, Kim BW | title = Deiodinases: implications of the local control of thyroid hormone action | journal = J. Clin. Invest. | volume = 116 | issue = 10 | pages = 2571–9 | date = October 2006 | pmid = 17016550 | pmc = 1578599 | doi = 10.1172/JCI29812 }}
3. ^{{cite journal | vauthors = Wu Y, Koenig RJ | title = Gene regulation by thyroid hormone | journal = Trends Endocrinol. Metab. | volume = 11 | issue = 6 | pages = 207–11 | date = August 2000 | pmid = 10878749 | doi = 10.1016/s1043-2760(00)00263-0 }}
4. ^{{cite journal | vauthors = Köhrle J | title = The selenoenzyme family of deiodinase isozymes controls local thyroid hormone availability | journal = Rev Endocr Metab Disord | volume = 1 | issue = 1–2 | pages = 49–58 | date = January 2000 | pmid = 11704992 | doi = 10.1023/A:1010012419869 }}
5. ^{{cite journal | vauthors = Köhrle J | title = Local activation and inactivation of thyroid hormones: the deiodinase family | journal = Mol. Cell. Endocrinol. | volume = 151 | issue = 1–2 | pages = 103–19 | date = May 1999 | pmid = 10411325 | doi = 10.1016/S0303-7207(99)00040-4 }}
6. ^{{cite journal | vauthors = Köhrle J | title = The deiodinase family: selenoenzymes regulating thyroid hormone availability and action | journal = Cell. Mol. Life Sci. | volume = 57 | issue = 13–14 | pages = 1853–63 | date = December 2000 | pmid = 11215512 | doi = 10.1007/PL00000667 }}
7. ^1 2 3 4 5 6 7 8 9 {{cite journal | vauthors = Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeöld A, Bianco AC | title = Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling | journal = Endocr. Rev. | volume = 29 | issue = 7 | pages = 898–938 | date = December 2008 | pmid = 18815314 | pmc = 2647704 | doi = 10.1210/er.2008-0019 }}
8. ^{{cite journal | vauthors = Dentice M, Bandyopadhyay A, Gereben B, Callebaut I, Christoffolete MA, Kim BW, Nissim S, Mornon JP, Zavacki AM, Zeöld A, Capelo LP, Curcio-Morelli C, Ribeiro R, Harney JW, Tabin CJ, Bianco AC | title = The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate | journal = Nat. Cell Biol. | volume = 7 | issue = 7 | pages = 698–705 | date = July 2005 | pmid = 15965468 | pmc = 1761694 | doi = 10.1038/ncb1272 }}
9. ^1 {{cite web | url = http://deiodination.org/ | title = Thyroid hormone action starts and ends by deiodination | author = Bianco AC | date = | format = | website = | publisher = Bianco Lab & The University of Miami | pages = | archiveurl = | archivedate = | quote = | accessdate = 2011-05-08 }}
10. ^{{cite journal | vauthors = Valverde C, Croteau W, Lafleur GJ, Orozco A, Germain DL | title = Cloning and expression of a 5'-iodothyronine deiodinase from the liver of Fundulus heteroclitus | journal = Endocrinology | volume = 138 | issue = 2 | pages = 642–8 | date = February 1997 | pmid = 9002998 | doi = 10.1210/en.138.2.642 }}
11. ^{{cite journal | vauthors = Berry MJ, Banu L, Larsen PR | title = Type I iodothyronine deiodinase is a selenocysteine-containing enzyme | journal = Nature | volume = 349 | issue = 6308 | pages = 438–40 | date = January 1991 | pmid = 1825132 | doi = 10.1038/349438a0 }}
12. ^1 {{cite journal | vauthors = St Germain DL, Galton VA | title = The deiodinase family of selenoproteins | journal = Thyroid | volume = 7 | issue = 4 | pages = 655–68 | date = August 1997 | pmid = 9292958 | doi = 10.1089/thy.1997.7.655 }}
13. ^{{cite journal | vauthors = Schweizer U, Schlicker C, Braun D, Köhrle J, Steegborn C | title = Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism. | journal = Proc. Natl. Acad. Sci. USA | volume = 111 | issue = 29 | pages = 10526–31 | pmid = 25002520 | doi = 10.1073/pnas.1323873111 | date=Jul 2014 | pmc=4115520}}
14. ^{{cite journal | vauthors = Moreno M, Berry MJ, Horst C, Thoma R, Goglia F, Harney JW, Larsen PR, Visser TJ | title = Activation and inactivation of thyroid hormone by type I iodothyronine deiodinase | journal = FEBS Lett. | volume = 344 | issue = 2–3 | pages = 143–6 | date = May 1994 | pmid = 8187873 | doi = 10.1016/0014-5793(94)00365-3 }}
15. ^{{cite web | url = http://nahypothyroidism.org/deiodinases/ | title = Deiodinases | author = Holtorf K | year = 2012 | format = | website = | publisher = National Academy of Hypothyroidism }}
16. ^{{cite journal | vauthors = Kaplan MM | title = The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function | journal = Neuroendocrinology | volume = 38 | issue = 3 | pages = 254–60 | date = March 1984 | pmid = 6371572 | doi = 10.1159/000123900 }}
17. ^{{cite journal | vauthors = Bianco AC, Silva JE | title = Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue | journal = J. Clin. Invest. | volume = 79 | issue = 1 | pages = 295–300 | date = January 1987 | pmid = 3793928 | pmc = 424048 | doi = 10.1172/JCI112798 }}
18. ^{{cite journal | vauthors = de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, Larsen PR, Bianco AC | title = The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue | journal = J. Clin. Invest. | volume = 108 | issue = 9 | pages = 1379–85 | date = November 2001 | pmid = 11696583 | pmc = 209445 | doi = 10.1172/JCI13803 }}
19. ^{{cite journal | vauthors = Kirkegaard C, Faber J | title = The role of thyroid hormones in depression | journal = Eur J Endocrinol | volume = 138 | issue = 1 | pages = 1–9 | year = 1998 | pmid = 9461307 | doi = 10.1530/eje.0.1380001 }}
20. ^{{cite journal | vauthors = Berbel P, Navarro D, Ausó E, Varea E, Rodríguez AE, Ballesta JJ, Salinas M, Flores E, Faura CC, de Escobar GM | year = 2010 | title = Role of late maternal thyroid hormones in cerebral cortex development: an experimental model for human prematurity | url = http://cercor.oxfordjournals.org/cgi/reprint/20/6/1462 | journal = Cereb Cortex | volume = 20 | issue = 6| pages = 1462–75 | doi = 10.1093/cercor/bhp212 | pmid = 19812240 | pmc=2871377}}
21. ^{{cite journal | vauthors = Szabo DT, Richardson VM, Ross DG, Diliberto JJ, Kodavanti PR, Birnbaum LS | title = Effects of perinatal PBDE exposure on hepatic phase I, phase II, phase III, and deiodinase 1 gene expression involved in thyroid hormone metabolism in male rat pups | journal = Toxicol. Sci. | volume = 107 | issue = 1 | pages = 27–39 | date = January 2009 | pmid = 18978342 | pmc = 2638650 | doi = 10.1093/toxsci/kfn230 }}
22. ^{{cite journal | vauthors = Steinsapir J, Harney J, Larsen PR | title = Type 2 iodothyronine deiodinase in rat pituitary tumor cells is inactivated in proteasomes | journal = J. Clin. Invest. | volume = 102 | issue = 11 | pages = 1895–9 | date = December 1998 | pmid = 9835613 | pmc = 509140 | doi = 10.1172/JCI4672 }}
23. ^{{cite journal | vauthors = Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FW, Crescenzi A, da-Silva WS, Harney J, Engel FB, Obregon MJ, Larsen PR, Bianco AC, Huang SA | title = Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats | journal = J. Clin. Invest. | volume = 118 | issue = 3 | pages = 975–83 | date = March 2008 | pmid = 18259611 | pmc = 2230657 | doi = 10.1172/JCI32824 }}
24. ^{{cite journal | vauthors = Mortoglou A, Candiloros H | title = The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy | journal = Hormones (Athens) | volume = 3 | issue = 2 | pages = 120–6 | year = 2004 | pmid = 16982586 | doi = 10.14310/horm.2002.11120 }}
25. ^{{cite book | publisher = Logos-Verlag Berlin | isbn = 978-3-89722-850-4 | location = Berlin, Germany | title = Der Hypophysen-Schilddrüsen-Regelkreis | url = http://openlibrary.org/books/OL24586469M/Der_Hypophysen-Schilddrüsen-Regelkreis | author = Dietrich JW | year = 2002 | oclc = 50451543 | id = 3897228505 }}
26. ^{{cite journal | vauthors = Rosolowska-Huszcz D, Kozlowska L, Rydzewski A | title = Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure | journal = Endocrine | volume = 27 | issue = 3 | pages = 283–8 | date = August 2005 | pmid = 16230785 | doi = 10.1385/ENDO:27:3:283 }}

Further reading

{{refbegin}}
  • {{cite book |vauthors=Heinrich P, Löffler G, Petrides PE | title = Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition) | edition = | language = German | publisher = Springer | location = Berlin | year = 2006 | pages = 847–861 | isbn = 978-3-540-32680-9 }}
{{refend}}

External links

  • {{MeshName|Deiodinase}}
{{Thyroid hormone metabolism enzymes and transporters}}{{Other oxidoreductases}}{{Enzymes}}{{Thyroid hormone receptor modulators}}{{Portal bar|Molecular and Cellular Biology|border=no}}

2 : EC 1.21.99|Selenoproteins
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