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MetaCyc Enzyme: type III iododthyronine deiodinase

Gene: DIO3 Accession Number: G-11351 (MetaCyc)

Synonyms: ITDI3, TXDI3, D3, type III idodthyronine selenodeiodinase, type-III 5'-deiodinase, type 3 DI, DIOIII, 5DIII

Species: Homo sapiens

Subunit composition of type III iododthyronine deiodinase = [DIO3]2
         type III idodthyronine deiodinase subunit = DIO3

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 iododthyronine deiodinase 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 iodothyronine deiodinase (this enzyme) 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].

Type III 5-deiodinase is an integral membrane protein located in the plasma membrane. Most of the molecule is in the extracellular space where it can rapidly inactivate L-thyroxine and 3,5,3'-triiodo-L-thyronine. The enzyme is recycled between the plasma membrane and early endosomes. Changes in its activity both globally and locally modulate thyorid hormone levels in tissues. The recombinant human placental enzyme has been expressed and characterized [Baqui03].

Gene Citations: [Salvatore95]

Locations: plasma membrane

Map Position: [101,097,441 -> 101,099,542]

Molecular Weight of Polypeptide: 31.451 kD (from nucleotide sequence)

Unification Links: Entrez-gene:1735 , Pride:P55073 , Protein Model Portal:P55073 , String:9606.ENSP00000352273 , UniProt:P55073

Relationship Links: InterPro:IN-FAMILY:IPR000643 , InterPro:IN-FAMILY:IPR008261 , InterPro:IN-FAMILY:IPR012336 , InterPro:IN-FAMILY:IPR027252 , Panther:IN-FAMILY:PTHR11781 , Pfam:IN-FAMILY:PF00837 , Prosite:IN-FAMILY:PS01205

Gene-Reaction Schematic: ?

GO Terms:

Cellular Component: GO:0005886 - plasma membrane [Baqui03]

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


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

3,3',5'-triiodothyronamine + a reduced electron acceptor <=> 3',5'-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


Enzymatic reaction of: 3,5-diiodothyronamine 5-deiodinase (type III 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-iodothyronamine deiodinase (type III iododthyronine deiodinase)

3-iodothyronamine + a reduced electron acceptor <=> thyronamine + 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-iodothyronamine
1.2
[Piehl08a]


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

3,3'-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 III 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
0.017
[Piehl08a]


Enzymatic reaction of: 3,3',5,5'-tetraiodothyronamine 5-deiodinase (type III iododthyronine deiodinase)

3,3',5,5'-tetraiodothyronamine + a reduced electron acceptor <=> 3,3',5'-triiodothyronamine + 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-momoiodothyronine 3-deiodinase (type III iododthyronine deiodinase)

3-monoiodothyronine + a reduced electron acceptor <=> L-thyronine + 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: thyroid hormone metabolism I (via deiodination)


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

3,3'-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 direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: thyroid hormone metabolism I (via deiodination)


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

EC Number: 1.97.1.11

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 3-deiodinase (type III iododthyronine deiodinase)

3,3',5'-triiodo-L-thyronine + a reduced electron acceptor <=> 3',5'-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 direction in which it was curated.

The reaction is favored in the direction shown.

In Pathways: thyroid hormone metabolism I (via deiodination)


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

EC Number: 1.97.1.11

3,5,3'-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)

Cofactors or Prosthetic Groups: L-selenocysteine [Salvatore95], selenide [Salvatore95]

Kinetic Parameters:

Substrate
Km (μM)
Citations
3,5,3'-triiodo-L-thyronine
0.0012
[Salvatore95]


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

EC Number: 1.97.1.11

3,3',5'-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)

Summary:
Like the type II iododthyronine deiodinase, type III 5-deiodinase shows sequential reaction kinetics in which the substrate and a thiol-containing cosubstrate simultaneously interact with the enzyme. Site-directed mutagenesis studies have demonstrated the essentiality of the L-selenocysteine residue in catalysis [Kuiper03]. The enzyme is insensitive to inactivation by propylthiouracil and requires dithiothreitol as cosubstrate in vitro [Salvatore95].

Cofactors or Prosthetic Groups: L-selenocysteine [Salvatore95], selenide [Salvatore95]


References

Baqui03: Baqui M, Botero D, Gereben B, Curcio C, Harney JW, Salvatore D, Sorimachi K, Larsen PR, Bianco AC (2003). "Human type 3 iodothyronine selenodeiodinase is located in the plasma membrane and undergoes rapid internalization to endosomes." J Biol Chem 278(2);1206-11. PMID: 12419801

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

Kuiper03: Kuiper GG, Klootwijk W, Visser TJ (2003). "Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference." Endocrinology 144(6);2505-13. PMID: 12746313

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

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

Salvatore95: Salvatore D, Low SC, Berry M, Maia AL, Harney JW, Croteau W, St Germain DL, Larsen PR (1995). "Type 3 lodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme." J Clin Invest 96(5);2421-30. PMID: 7593630

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 Sun Nov 23, 2014, biocyc13.