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MetaCyc Enzyme: type II iododthyronine deiodinase

Gene: DIO2 Accession Number: G-11350 (MetaCyc)

Synonyms: ITDI2, TXDI2, D2, type-II 5'-deiodinase, type 2 DI, DIOII, 5DII, type II idodthyronine selenodeiodinase, deiodinase, iodothyronine, type II

Species: Homo sapiens

Subunit composition of type II iododthyronine deiodinase = [DIO2]2
         type II idodthyronine deiodinase subunit = DIO2

Summary:
Three different types of deiodinases are primarily responsible for activation and inactivation of the thyroid hormones L-thyroxine and 3,5,3'-triiodo-L-thyronine. These deiodinases are selenoenzymes that contain selenocysteine as a key active site residue.

type I iododthyronine deiodinase can catalyze both 5'-deiodination (outer ring) and 5-deiodination (inner ring) of a variety of iodothyronines (including those shown here) and their derivatives (such as sulfate derivatives, see thyroid hormone metabolism II (via conjugation and/or degradation)). It has been found in liver, kidney, thyroid and pituitary.

Type II iodothyronine deiodinase (this enzyme) efficiently catalyzes 5'-deiodination of L-thyroxine to 3,5,3'-triiodo-L-thyronine, an activating reaction. This reaction contributes to systemic and serum 3,5,3'-triiodo-L-thyronine levels. Although L-thyroxine is the major secreted product of the thyroid gland, 3,5,3'-triiodo-L-thyronine is the major bioactive hormone and most circulating 3,5,3'-triiodo-L-thyronine is generated by type II deiodinase in peripheral tissues (in [Moreno94]). It also catalyzes 5'-deiodination of 3,3',5'-triiodo-L-thyronine (reverse triiodothyronine). It has been found in pituitary, brain, brown adipose tissue and in human thyroid, skeletal muscle, aortic smooth muscle cells and osteoblasts.

type III iododthyronine deiodinase produces inactive or less active metabolites by catalyzing the 5-deiodination of L-thyroxine to 3,3',5'-triiodo-L-thyronine (reverse triiodothyronine), and the 5-deiodination of 3,5,3'-triiodo-L-thyronine to 3,3'-diiodothyronine. It has an essential regulatory function during vertebrate development. It has been found in brain, skin, uterus, placenta and fetal tissues.

Although the roles of these enzymes in some physiological situations have been determined, their roles in others remain unclear. Reviewed in [St09, Peeters06, Kohrle02].

Human polymorphisms in the genes encoding the deiodinases have been described, although no inactivating mutations have been reported. Phenotypes of mice with targeted deletions of the deiodinase genes have been studied (reviewed in [Peeters06]). Although the three dimensional structures of these enzymes have not been determined, molecular models have been analyzed (reviewed in [Gereben08, St09]). Their homodimeric structure is critical for catalytic activity [Sagar08, CurcioMorelli03].

Gene Citations: [Ohba01, Buettner98, Croteau96, Salvatore96]

Locations: endoplasmic reticulum membrane

Map Position: [79,733,622 <- 79,748,278]

Molecular Weight of Polypeptide: 30.552 kD (from nucleotide sequence)

Unification Links: ArrayExpress:Q92813 , Entrez-gene:1734 , Pride:Q92813 , Protein Model Portal:Q92813 , String:9606.ENSP00000373490 , UniProt:Q92813

Relationship Links: InterPro:IN-FAMILY:IPR000643 , InterPro:IN-FAMILY:IPR008261 , InterPro:IN-FAMILY:IPR012336 , Panther:IN-FAMILY:PTHR11781 , Pfam:IN-FAMILY:PF00837 , Prosite:IN-FAMILY:PS01205

Gene-Reaction Schematic: ?

GO Terms:

Cellular Component: GO:0005789 - endoplasmic reticulum membrane [Baqui00]

Credits:
Created 08-Jun-2009 by Fulcher CA , SRI International
Revised 12-Jan-2011 by Fulcher CA , SRI International


Enzymatic reaction of: 3',5'-diiodothyronamine 5'-deiodinase (type II iododthyronine deiodinase)

3',5'-diiodothyronamine + a reduced electron acceptor <=> 3'-iodothyronamine + iodide + an oxidized electron acceptor + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: thyronamine and iodothyronamine metabolism


Enzymatic reaction of: 3,3',5'-triiodothyronamine 5'-deiodinase (type II iododthyronine deiodinase)

3,3',5'-triiodothyronamine + a reduced electron acceptor <=> 3,3'-diiodothyronamine + iodide + an oxidized electron acceptor + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: thyronamine and iodothyronamine metabolism

Kinetic Parameters:

Substrate
Km (μM)
Citations
3,3',5'-triiodothyronamine
0.63
[Piehl08a]


Enzymatic reaction of: 3',5'-diiodothyronine 5'-deiodinase (type II iododthyronine deiodinase)

EC Number: 1.97.1.10

3',5'-diiodothyronine + a reduced electron acceptor <=> 3'-monoiodothyronine + iodide + an oxidized electron acceptor + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: thyroid hormone metabolism I (via deiodination)


Enzymatic reaction of: 3,3',5'-triiodo-L-thyronine 5'-deiodinase (type II iododthyronine deiodinase)

EC Number: 1.97.1.10

3,3',5'-triiodo-L-thyronine + a reduced electron acceptor <=> 3,3'-diiodothyronine + iodide + an oxidized electron acceptor + H+

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the direction shown.

In Pathways: thyroid hormone metabolism I (via deiodination)


Enzymatic reaction of: L-thyroxine 5'-deiodinase (type II iododthyronine deiodinase)

EC Number: 1.97.1.10

3,5,3'-triiodo-L-thyronine + iodide + an oxidized electron acceptor + H+ <=> L-thyroxine + a reduced electron acceptor

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.

The reaction is favored in the opposite direction.

In Pathways: thyroid hormone metabolism I (via deiodination) , thyroid hormone metabolism II (via conjugation and/or degradation)

Summary:
Type II 5' deiodinase metabolizes L-thyroxine to 3,5,3'-triiodo-L-thyronine, the active metabolite in peripheral tissues. The type II 5' deiodinase is distinct from the type I iododthyronine deiodinase based on its insensitivity to propylthiouracil and iodoacetate inhibition, high affinity for both L-thyroxine and 3,3',5'-triiodo-L-thyronine as substrates, and its sequential two-substrate, rather than ping-pong, reaction mechanism. Unlike type I, the type II enzyme also cannot be affinity labeled by N-bromoacetyl derivatives of 3,5,3'-triiodo-L-thyronine or L-thyroxine. Another unique aspect if type II 5' deiodinase is its substrate-induced inactivation (by L-thyroxine and 3,3',5'-triiodo-L-thyronine) and translocation via actin-based endocytosis. Its expression and activity are modulated by a variety of metabolites including cyclic-AMP. Site-directed mutagenesis studies of the type II 5' deiodinase have led to a model of its catalytic mechanism. [Kuiper02] and reviewed in [Kohrle02].

Cofactors or Prosthetic Groups: selenide [Salvatore99], L-selenocysteine [Buettner00]

Kinetic Parameters:

Substrate
Km (μM)
Citations
L-thyroxine
0.0016
[Buettner00]


References

Baqui00: Baqui MM, Gereben B, Harney JW, Larsen PR, Bianco AC (2000). "Distinct subcellular localization of transiently expressed types 1 and 2 iodothyronine deiodinases as determined by immunofluorescence confocal microscopy." Endocrinology 141(11);4309-12. PMID: 11089566

Buettner00: Buettner C, Harney JW, Larsen PR (2000). "The role of selenocysteine 133 in catalysis by the human type 2 iodothyronine deiodinase." Endocrinology 141(12);4606-12. PMID: 11108274

Buettner98: Buettner C, Harney JW, Larsen PR (1998). "The 3'-untranslated region of human type 2 iodothyronine deiodinase mRNA contains a functional selenocysteine insertion sequence element." J Biol Chem 273(50);33374-8. PMID: 9837913

Croteau96: Croteau W, Davey JC, Galton VA, St Germain DL (1996). "Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues." J Clin Invest 98(2);405-17. PMID: 8755651

CurcioMorelli03: Curcio-Morelli C, Gereben B, Zavacki AM, Kim BW, Huang S, Harney JW, Larsen PR, Bianco AC (2003). "In vivo dimerization of types 1, 2, and 3 iodothyronine selenodeiodinases." Endocrinology 144(3);937-46. PMID: 12586771

Gereben08: Gereben B, Zeold A, Dentice M, Salvatore D, Bianco AC (2008). "Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences." Cell Mol Life Sci 65(4);570-90. PMID: 17989921

Kohrle02: Kohrle J (2002). "Iodothyronine deiodinases." Methods Enzymol 347;125-67. PMID: 11898402

Kuiper02: Kuiper GG, Klootwijk W, Visser TJ (2002). "Substitution of cysteine for a conserved alanine residue in the catalytic center of type II iodothyronine deiodinase alters interaction with reducing cofactor." Endocrinology 143(4);1190-8. PMID: 11897672

Moreno94: Moreno M, Kaptein E, Goglia F, Visser TJ (1994). "Rapid glucuronidation of tri- and tetraiodothyroacetic acid to ester glucuronides in human liver and to ether glucuronides in rat liver." Endocrinology 135(3);1004-9. PMID: 8070342

Ohba01: Ohba K, Yoshioka T, Muraki T (2001). "Identification of two novel splicing variants of human type II iodothyronine deiodinase mRNA." Mol Cell Endocrinol 172(1-2);169-75. PMID: 11165050

Peeters06: Peeters RP, van der Deure WM, Visser TJ (2006). "Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases." Eur J Endocrinol 155(5);655-62. PMID: 17062880

Piehl08: Piehl S, Heberer T, Balizs G, Scanlan TS, Kohrle J (2008). "Development of a validated liquid chromatography/tandem mass spectrometry method for the distinction of thyronine and thyronamine constitutional isomers and for the identification of new deiodinase substrates." Rapid Commun Mass Spectrom 22(20);3286-96. PMID: 18821722

Piehl08a: Piehl S, Heberer T, Balizs G, Scanlan TS, Smits R, Koksch B, Kohrle J (2008). "Thyronamines are isozyme-specific substrates of deiodinases." Endocrinology 149(6);3037-45. PMID: 18339710

Sagar08: Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeold A, Curcio-Morelli C, Harney JW, Luongo C, Mulcahey MA, Larsen PR, Huang SA, Bianco AC (2008). "The thyroid hormone-inactivating deiodinase functions as a homodimer." Mol Endocrinol 22(6);1382-93. PMID: 18356288

Salvatore96: Salvatore D, Bartha T, Harney JW, Larsen PR (1996). "Molecular biological and biochemical characterization of the human type 2 selenodeiodinase." Endocrinology 137(8);3308-15. PMID: 8754756

Salvatore99: Salvatore D, Harney JW, Larsen PR (1999). "Mutation of the Secys residue 266 in human type 2 selenodeiodinase alters 75Se incorporation without affecting its biochemical properties." Biochimie 81(5);535-8. PMID: 10403186

St09: St Germain DL, Galton VA, Hernandez A (2009). "Minireview: Defining the roles of the iodothyronine deiodinases: current concepts and challenges." Endocrinology 150(3);1097-107. PMID: 19179439


Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Fri Dec 19, 2014, BIOCYC13B.