Information on EC 1.21.99.4 - thyroxine 5'-deiodinase and Organism(s) Homo sapiens

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The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.21.99.4
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RECOMMENDED NAME
GeneOntology No.
thyroxine 5'-deiodinase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
deiodination
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redox reaction
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-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
thyroid hormone metabolism I (via deiodination)
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thyroid hormone metabolism II (via conjugation and/or degradation)
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SYSTEMATIC NAME
IUBMB Comments
3,3',5-triiodo-L-thyronine,iodide:acceptor oxidoreductase (iodinating)
The enzyme activity has only been demonstrated in the direction of 5'-deiodination, which renders the thyroid hormone more active. The enzyme consists of type I and type II enzymes, both containing selenocysteine, but with different kinetics. For the type I enzyme the first reaction is a reductive deiodination converting the -Se-H group of the enzyme into an -Se-I group; the reductant then reconverts this into -Se-H, releasing iodide.
CAS REGISTRY NUMBER
COMMENTARY hide
70712-46-8
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3,3',5'-triiodo-L-thyronine + AH2
3,3'-diiodo-L-thyronine + iodide + A + H+
show the reaction diagram
3,3',5'-triiodothyronine + AH2
3,3'-diiodothyronine + iodide + A + H+
show the reaction diagram
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-
-
-
?
3,3',5-triiodothyronine + AH2
diiodothyronine + iodide + A + H+
show the reaction diagram
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rT3 ORD activity
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-
?
L-3,5',3'-triiodothyronine + AH2
L-3,3'-diiodothyronine + iodide + A + H+
show the reaction diagram
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5'-deionination by isozyme Dio1
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-
?
L-3,5'-diiodothyronine + AH2
L-3-iodothyronine + iodide + A + H+
show the reaction diagram
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-
-
-
?
L-3,5,3',5'-tetraiodothyronine + AH2
L-3,5,3'-triiodothyronine + iodide + A + H+
show the reaction diagram
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i.e. thyroxine
triiodothyrosine, a small 3,3'-T2 peak also occurs
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?
L-thyroxine + AH2
3,3',5-triiodo-L-thyronine + iodide + A + H+
show the reaction diagram
L-thyroxine + AH2
3,3',5-triiodothyronine + iodide + A + H+
show the reaction diagram
L-thyroxine + AH2
3,5,3'-triiodo-L-thyronine + iodide + A + H+
show the reaction diagram
L-thyroxine + reduced acceptor
3,3',5-triiodo-L-thyronine + iodide + acceptor + H+
show the reaction diagram
L-tyroxine + AH2
3,3',5'-triiodo-L-thyronine + iodide + A + H+
show the reaction diagram
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the reaction is catalyzed by the type 1 deiodinase
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?
additional information
?
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NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
3,3',5'-triiodo-L-thyronine + AH2
3,3'-diiodo-L-thyronine + iodide + A + H+
show the reaction diagram
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isozyme type I
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-
?
3,3',5'-triiodothyronine + AH2
3,3'-diiodothyronine + iodide + A + H+
show the reaction diagram
-
-
-
-
?
L-thyroxine + AH2
3,3',5-triiodo-L-thyronine + iodide + A + H+
show the reaction diagram
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from microsomal enzyme complex, 3,3',5-triiodo-L-thyronine is thyromimetically active
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?
L-thyroxine + AH2
3,5,3'-triiodo-L-thyronine + iodide + A + H+
show the reaction diagram
L-thyroxine + reduced acceptor
3,3',5-triiodo-L-thyronine + iodide + acceptor + H+
show the reaction diagram
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-
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-
?
additional information
?
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thyronines and thyronamines are two groups of endogenous iodine-containing signaling molecules that are substrates of three deiodinase isozymes, which catalyze the sequential reductive removal of iodine from the respective precursor molecule. Development of a analytical method applying liquid chromatography/tandem mass spectrometry, overview
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
dithioerythritol
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dithiothreitol
glutathione
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20 mM glutathione is used in assay conditions
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
selenium
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
3,3',5'-triiodo-L-thyronine
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aurothioglucose
gold thioglucose
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iodoacetate
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iopanoic acid
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both isozyme type I and type II
propylthiouracil
additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(Bu)2cAMP
DEX
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forskolin
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significantly stimulates deiodinating activity in TT cells
Se2+
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severe selenium deficiency leads to a decrease in activity of isozyme type I in liver, kidney, and several other organs, but not in the thyroid gland, the central nervous system, and several other endrocrine organs
additional information
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expression and function of the deiodinase isozymes are sensitive to thyroid hormone status, various cytokines and growth factors, severe illness, reactive oxygen species, a variety of hormones and signaling compounds, circadian rythm, and pharmacological agents
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.7
3,3',5'-triiodothyronine
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DTT 10 mM; type I, liver
0.003 - 0.57
L-3,5',3'-triiodothyronine
0.0000000017 - 0.0066
L-thyroxine
0.00000101 - 0.0000098
reverse triiodothyronine
0.00003
thyroxine
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additional information
additional information
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review on enzyme isoforms type I and II and 5-deiodinase, type III
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.00000000041
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medullary thyroid carcinoma
0.00000000043
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normal thyroid tissue
0.0000000058
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normal tissues
0.0000000286
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normal tissues
0.0000000429
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McCune-Albright syndrome patients
0.0000000543
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toxic adenoma patient
0.0000000714
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toxic adenoma patient
0.0000001857
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McCune-Albright syndrome patients
0.000001
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healthy control
0.0000025
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patient with mutation in thyroglobulin gene
0.0001
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isoenzyme type I
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.9
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activity assay
7.4
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assay at
8
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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hepatocellular carcinoma
Manually annotated by BRENDA team
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isozyme type I
Manually annotated by BRENDA team
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isozyme Dio3
Manually annotated by BRENDA team
expression of type 2 iodothyronine deiodinase D2, which converts T4 to T3, and TR1 in HUVECs
Manually annotated by BRENDA team
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thyroid tissue samples are collected from five patients, three affected by toxic nodule, and from areas of normal thyroid parenchyma from five patients undergoing total thyroidectomy for thyroid cancer
Manually annotated by BRENDA team
additional information
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severe selenium deficiency leads to a decrease in activity of isozyme type I in liver, kidney, and several other organs, but not in the thyroid gland, the central nervous system, and several other endrocrine organs
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
55000
x * 55000, SDS-PAGE, overexpressed enzyme can homodimerize probably through disulfide bridges. Monomeric form is also catalytically active
62000
x * 62000, SDS-PAGE, overexpressed enzyme can homodimerize probably through disulfide bridges. Monomeric form is also catalytically active
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
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x * 28000, SDS-PAGE
additional information
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substrate binding unit type I 31 kD
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Sephadex LH20 gel filtration
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
different splicing variants of DOI1 are cloned into the vector pGEM-T for sequencing, 11 variants are identified
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expression in COS cells
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expression in HEK-293 cells
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expression in HEK-293 cells; expression in HEK-293 cells
into a D10 vector
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isozyme type I, mapping on chromosome 1p32-p33, DNA sequence analysis
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the P135S mutant enzyme is expressed in HEK-293 cells
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transfection in HEK 293 cells; transfection in HEK 293 cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
3,5,3'-triiodothyronine decreases mRNA levels in TT cell, addition of thyroxine or 3,3',5'-triiodothyronine decreases the deiodinating activity
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5'-deiodinase is increased in McCune-Albright syndrome-associated hyperthyroidism pathogenesis
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an increase in enzyme expression is observed in Liver X receptor alpha-stimulated cells
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growth hormone significantly increases iodothyronine deiodinase D2 expression at the mRNA level in HTC/C3 cells
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substrate-dependent down-regulation, WSB-1-mediated ubiquitination inactivates the enzyme and targets it for proteasomal degradation, TEB4 interacts with the enzyme and mediates loss of activity and protein
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the enzymatic activity of type 1 iodothyronine deiodinase is low in liver hemangioma
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there is no significant difference between the thyroidal type 2 iodothyronine deiodinase mRNA level in patients with with 3,5,3'-triiodothyronine-predominant Graves' disease and that in patients with common type-Graves' disease
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thyroidal type 1 iodothyronine deiodinase mRNA level and activity in patients with 3,5,3'-triiodothyronine-predominant Graves' disease is significantly higher than that in patients with common type-Graves' disease
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ubiquitinated enzyme can be reactivated and rescued from proteosomal degradation by the von Hippel-Lindau protein-interacting deubiquitinating enzyme-1, TEB4 knockdown increases activity and protein level of iodothyronine deiodinase 2
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A131C
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similar Km-values for L-thyroxine and 3,3',5-triiodothyronine as the wild-type enzyme. Mutation improves the interaction with the reducing cofactor dithiothreitol
A131S
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similar Km-values for L-thyroxine and 3,3',5-triiodothyronine as the wild-type enzyme. Mutation improves the interaction with the reducing cofactor dithiothreitol
P135S
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the mutant type 2 iodothyronine deiodinase has many type 1 iodothyronine deiodinase-like properties, a Km (L-thyroxine) in the micromolar range, ping-pong kinetics with dithiothreitol, and sensitivity to 6n-propylthiouracil in vitro. When the P135S mutant is expressed in HEK-293 cells and exposed to 2-200 pM free L-thyroxine, the rate of L-thyroxine to 3,5,3'-triiodo-L-thyronine conversion is identical with type 2 iodothyronine deiodinase and conversion is insensitive to 6n-propylthiouracil. Using glutathione as a cofactor in vitro results in a marked decrease in the Km (L-thyroxine) (as also occurs for type 1 iodothyronine deiodinase), it shows sequential kinetics with L-thyroxine and is sensitive to 6n-propylthiouracil but is resistant when HEK-293 cytosol is used as a cofactor
SeC133A
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inactive mutant enzyme
SeC133C
SeC133C/A131C
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mutant enzyme with more than 1000fold increase in Km-value for L-thyroxine
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine