Information on EC 1.21.1.1 - iodotyrosine deiodinase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
1.21.1.1
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RECOMMENDED NAME
GeneOntology No.
iodotyrosine deiodinase
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REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
3-iodo-L-tyrosine + NADP+ + iodide = 3,5-diiodo-L-tyrosine + NADPH + H+
show the reaction diagram
(1b)
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L-tyrosine + 2 NADP+ + 2 iodide = 3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
show the reaction diagram
overall reaction
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L-tyrosine + NADP+ + iodide = 3-iodo-L-tyrosine + NADPH + H+
show the reaction diagram
(1a)
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SYSTEMATIC NAME
IUBMB Comments
NADP+:L-tyrosine oxidoreductase (iodinating)
The enzyme activity has only been demonstrated in the direction of 3-deiodination. Present in a transmembrane flavoprotein. Requires FMN.
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
gene sup-18
UniProt
Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
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Manually annotated by BRENDA team
female
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Manually annotated by BRENDA team
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UniProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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domain swaps at each N and C terminus consistent with the nitro-FMN reductase superfamily
malfunction
metabolism
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
3,5-diiodo-L-tyrosine + dithionite
3-iodo-L-tyrosine + ? + I-
show the reaction diagram
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
show the reaction diagram
3-bromo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + Br-
show the reaction diagram
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-
-
-
?
3-chloro-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + Cl-
show the reaction diagram
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-
-
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?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
show the reaction diagram
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + iodide
show the reaction diagram
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-
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r
L-tyrosine + 2 NADP+ + 2 bromide
3,5-dibromo-L-tyrosine + 2 NADPH + 2 H+
show the reaction diagram
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halide elimination does not appear to limit reactions of bromo- and iodotyrosine since both fully oxidize the reduced enzyme with nearly equivalent second-order rate constants despite the differing strength of their carbon-halogen bonds
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r
L-tyrosine + 2 NADP+ + 2 chloride
3,5-dichloro-L-tyrosine + 2 NADPH + 2 H+
show the reaction diagram
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chlorotyrosine reacts with the reduced enzyme approximately 20fold more slowly than bromo- and iodotyrosine and reveals a spectral intermediate that forms at approximately the same rate as the bromo- and iodotyrosine reactions
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r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
show the reaction diagram
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
show the reaction diagram
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r
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
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
show the reaction diagram
Q9DCX8
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-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
show the reaction diagram
Q9DCX8
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-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
show the reaction diagram
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
FAD
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Ferredoxin
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-
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flavin
NADPH
additional information
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the cofactors form a redox electron transport chain, overview
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2,2'-dipyridyl
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2,3,6-tribromo-4-(2,4-dibromophenoxy)phenol
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2,3-dibromo-4-(2,4-dibromophenoxy)phenol
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2,5-dibromo-4-(2,4-dibromophenoxy)phenol
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3,5-diiodo-L-tyrosine
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pronounced substrate inhibition above 5 microM
3-bromo-4-(2,4-dibromophenoxy)phenol
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3-hydroxy-2,2',5,5'-tetrachlorobiphenyl
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4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether
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4'-hydroxy-2,2',4-tribromodiphenyl ether
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4,4'-dihydroxy-3,3',5,5'-tetrachlorobiphenyl
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4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl
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4-hydroxy-2',3,4',5,6'-pentachlrobiphenyl
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4-hydroxy-2',3,4',6'-tetrachlrobiphenyl
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4-hydroxy-2,2',3,4',5-pentabromodiphenyl ether
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4-hydroxy-2,2',5,5'-tetrachlorobiphenyl
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4-hydroxy-2,3,3',4'-tetrabromodiphenyl ether
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5-bromo-2-(2,4-dibromophenoxy)phenol
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5-bromo-2-(4-bromophenoxy)phenol
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benzbromarone
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Bithionol
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bromoxynil
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closantel
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erythrosine B
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N-ethylmaleimide
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nitroxynil
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o-phenanthroline
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oxyclozanide
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phloxine B
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Rose bengal
tribromsalan
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triclosan
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additional information
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-mercaptoethanol
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maximal activity at 50 mM
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0011 - 0.44
3,5-diiodo-L-tyrosine
0.001 - 0.05
3-iodo-L-tyrosine
0.027
NADPH
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method 125I release, pH 7.4, 37C
additional information
additional information
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.11 - 10
3,5-diiodo-L-tyrosine
0.07 - 18
3-iodo-L-tyrosine
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.5 - 6
3,5-diiodo-L-tyrosine
3597
6 - 58.3
3-iodo-L-tyrosine
2332
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.017
4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl
Homo sapiens
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pH 7.4, 25C
0.011
benzbromarone
Homo sapiens
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pH 7.4, 25C
0.0008
erythrosine B
0.0002
Rose bengal
Homo sapiens
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pH 7.4, 25C
0.019
triclosan
Homo sapiens
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pH 7.4, 25C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
4
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stage 42, tail
6.1
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stage 44, lower jaw
6.6
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stage 46, lower jaw
9.2
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stage 44, brain
17.9
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stage 42, lower jaw
24.01
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stage 44, lower jaw
28.4
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stage 46, lower jaw
65.8
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stage 42, brain
109
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stage 42, brain
118.6
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stage 44, tail
125
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stage 46, brain
138.5
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stage 42, tail
157.7
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stage 44, brain
3100
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pH 7.4, 25C
7800
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pH 7.4, 38C
additional information
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activity ranges from 0.0001 to 0.0003 microg/min/mg of tissue
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6.3
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7.6
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assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
6 - 9
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pH dependence of IYD binding and turnover, tightest binding was measured near a neutral pH of 7.67.7
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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during metamorphosis, DEHAL1 enzyme activity is higher on diiodotyrosine as compared to monoiodotyrosine. Using diiodotyrosine as a substrate, maximal activity is detected at stage 44 in the brain, while it is higher at stage 42 in the tail. With monoiodotyrosine as a substrate, highest activity is detected in the brain at stage 42
Manually annotated by BRENDA team
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tadpole tail fin. During metamorphosis, DEHAL1 enzyme activity is higher on diiodotyrosine as compared to monoiodotyrosine. Using diiodotyrosine as a substrate, maximal activity is detected at stage 44 in the brain, while it is higher at stage 42 in the tail (138.5 U/mg protein). With monoiodotyrosine as a substrate, highest activity is detected in the brain at stage 42
Manually annotated by BRENDA team
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ventricular lining of the fourth ventricle
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
42000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
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2 * 22300, SDS-PAGE
heterodimer
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two identical subunits of human IYD form an alphabeta fold, 2 * 30000, recombinant enzyme, SDS-PAGE
additional information
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the enzyme contains three domains: an N-terminal transmembrane region, an intermediate domain, and a catalytic domain
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
putative signal peptide with a possible cleavage site between Ala23 and Asp24
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
purified enzyme in complex with substrate 3-iodo-L-tyrosine, method optimization, hanging drop diffusion method, mixing of 0.001 ml of 12 mg/ml protein in 50mM sodium phosphate, pH 7.4, 100 mM NaCl, 1 mM DTT, and 10% glycerol with 0.001 ml of precipitant solution containing 0.05 M ammonium sulfate, 50 mM BisTris, pH 6.5, and 25% pentaerythritol ethoxylate, 2 days, 20C. To generate co-crystals the enzyme is treated with 1.5 mM 3-iodo-L-tyrosine overnight and then subjected to the same hanging drop procedure using a well solution of 0.15 M sodium acetate, 85mM Tris-HCl, pH 8.5, 25.5% w/v PEG 4000, and 15% glycerol at 20 C, 24 h, X-ray diffraction structure determination and analysis at 2.45-2.65 A resolution, molecular replacement
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hanging dop vapor diffusion method, using 0.2 M ammonium acetate, 0.1 M BisTris (pH 6.5), and 45% v/v 2-methyl-2,4-pentanediol; structure of a truncated derivative lacking the membrane domain, residues 2-33, at its N-terminal, and its complex with substrate monoiodotyrosine. In the absence of substrate, the active site appears very accessible to solvent due to a lack of detectable structure in two surrounding regions of the polypeptide. In the presence of substrate, an active site lid comprised of a helix and loop is detected from the diffraction data. This lid effectively sequesters the substrate-flavin complex from solvent
structures of soluble enzyme lacking codons for amino acids 2-33 and two co-crystals containing substrates, mono- and diiodotyrosine, alternatively, at resolutions of 2.0 A, 2.45 A, and 2.6 A, respectively. Substrate coordination induces formation of an additional helix and coil that act as an active site lid to shield the resulting substrateflavin complex from solvent. This complex is stabilized by aromatic stacking and extensive hydrogen bonding between the substrate and flavin. The carbon-iodine bond of the substrate is positioned directly over the C-4a/N-5 region of the flavin to promote electron transfer
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-15 to -20C in 10 mM phosphate buffer, stable for months
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0 to 4C in 10 mM phosphate buffer, stable for weeks
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
HiTrap column chromatography
purification of stable aporptoein
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recombinant SUMO-tagged enzyme from Escherichia coli strain Rosetta 2(DE3) by nickel affinity chromatography, tag removal, and gel filtration
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solubilization by 0.1% CHAPS
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Sf9 insect cells and in Escherichia coli
expression in HEK-293 cell
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expression in HEK-293T cell
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expression of a derivative lacking codons for amino acids 233 to gain a soluble protein
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gene DEHAL1, DNA and amino acid sequence determination and analysis, genotyping of healthy and iodotyrosine deiodinase deficiency samples
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gene DEHAL1, recombinant expression of N-terminally SUMO-tagged enzyme in Escherichia coli strain Rosetta 2(DE3)
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gene sup-18, genotyping, encodes the Caenorhabditis elegans orthologue of mammalian iodotyrosine deiodinase (IYD)
quantitative RT-PCR enzyme expression analysis, overview
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transfection of HEK-293 cells results in active protein, but not of CHO cells
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
DEHAL12 is upregulated by cAMP
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iodine deficiency results in an increased enzyme expression in thyroid
study on enzyme expression in thyroid pathology. The highest DEHAL1 mRNA levels are found in Graves' disease thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurrs in papillary thyroid carcinomas and anaplastic thyroid carcinomas. DEHAL1 protein is overexpressed in toxic thyroid nodules and Graves' disease thyroids with predominant apical staining in all samples. A weaker and patchy staining pattern is found in benign cold thyroid nodules and normal thyroids. In differentiated thyroid cancers such as follicular thyroid carcinomas and papillary thyroid carcinomas, a diffuse cytoplasmic DEHAL1 expression is found. In partially differentiated thyroid cancers and anaplastic thyroid carcinomas, DEHAL1 expression is faint or absent
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the enzyme is suppressed in liver and kidney by iodine intake. Excess iodine decreases the expression of thyroidal enzyme
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
G258D
a naturally occuring sup-18 loss-of-function mutation
G258S
a naturally occuring sup-18 loss-of-function mutation
G280R
a naturally occuring sup-18 loss-of-function mutation
R289K
a naturally occuring sup-18 loss-of-function mutation
S137N
a naturally occuring sup-18 loss-of-function mutation
T271I
a naturally occuring sup-18 loss-of-function mutation
T322P
a naturally occuring sup-18 loss-of-function mutation
A220T
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naturally occuring mutation involved in iodotyrosine deiodinase
I116T
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naturally occuring mutation involved in iodotyrosine deiodinase deficiency, the mutant shows highly reduced activity compared to te wild-type enzyme
R101W
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naturally occuring mutation involved in iodotyrosine deiodinase deficiency, the mutant shows highly reduced activity compared to te wild-type enzyme
E153Q
mutation reduces the deiodinase activity to an undetectable level. Mutant exhibits no measurable binding affinity for the substrate; the mutant exhibits no measurable binding affinity for 3-chloro-L-tyrosine
K178Q
upon expression in Escherichia coli, inactive and insoluble
Y157F
lack of the phenolic -OH of Y157F increases the kcat and KM values for deiodination by more than sevenfold and decreases the kcat/KM value more modestly by less than 40%; the mutation weakens the binding of 3-chloro-L-tyrosine by 20fold
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
activation of purified enzyme by dithionite, methyl viologen, or ferredoxin, but not by photo-reduced FMN or by reducing agents having more positive oxidation-reduction potentials than the ferredoxin-NADP system
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apoprotein binds FMN with an almost complete restoration of enzymatic activity. It can also bind FAD with partial restoration of activity, but does not bind riboflavin
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
diagnostics
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improvement of pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time
medicine
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study on enzyme expression in thyroid pathology. The highest DEHAL1 mRNA levels are found in Graves' disease thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurrs in papillary thyroid carcinomas and anaplastic thyroid carcinomas. DEHAL1 protein is overexpressed in toxic thyroid nodules and Graves' disease thyroids with predominant apical staining in all samples. A weaker and patchy staining pattern is found in benign cold thyroid nodules and normal thyroids. In differentiated thyroid cancers such as follicular thyroid carcinomas and papillary thyroid carcinomas, a diffuse cytoplasmic DEHAL1 expression is found. In partially differentiated thyroid cancers and anaplastic thyroid carcinomas, DEHAL1 expression is faint or absent
synthesis
high expression of a truncated derivative lacking the membrane domain, residues 2-33, at its N-terminal is observed in Sf9 cells, whereas expression in Pichia pastoris remains low despite codon optimization. The desired expression in Escherichia coli can be achieved after replacing the two conserved Cys residues of the deiodinase with Ala and fusing the resulting protein to thioredoxin. This construct provides abundant enzyme for crystallography and mutagenesis
additional information
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target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals