Any feedback?
Information on EC 1.21.1.1 - iodotyrosine deiodinase and Organism(s) Homo sapiens
for references in articles please use BRENDA:EC1.21.1.1Please wait a moment until all data is loaded. This message will disappear when all data is loaded.
EC Tree
1.21.1.1 iodotyrosine deiodinaseIUBMB Comments
The enzyme activity has only been demonstrated in the direction of 3-deiodination. Present in a transmembrane flavoprotein. Requires FMN.
Specify your search results
Word Map
- 1.21.1.1
- thyroid
- iodide
-
deiodination
- hypothyroidism
- diiodotyrosine
- thyroglobulin
-
dehalogenation
-
halotyrosines
-
iodothyronine
- nitroreductase
- goiter
-
bromo
-
chlorotyrosine
-
organification
- diagnostics
- synthesis
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Synonyms
iodotyrosine deiodinase, dehal1, sup-18, dehal1 protein, dehal1b, iodotyrosine dehalogenase 1, nadh oxidase/flavin reductase, sup-18 iyd, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
IYD
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.
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-iodophenol + NADP+ + iodide
?
2-iodophenol binds very weakly to the enzyme and is dehalogenated with a catalytic efficiency that is more than 4 orders of magnitude lower than that for 3-iodo-L-tyrosine
-
-
?
3-bromo-L-tyrosine + NADP+ + bromide
3,5-dibromo-L-tyrosine + NADPH + H+
-
-
-
?
3-chloro-L-tyrosine + NADP+ + chloride
3,5-dichloro-L-tyrosine + NADPH + H+
low activity
-
-
?
L-tyrosine + 2 NADP+ + 2 bromide
3,5-dibromo-L-tyrosine + 2 NADPH + 2 H+
-
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
-
-
r
L-tyrosine + 2 NADP+ + 2 chloride
3,5-dichloro-L-tyrosine + 2 NADPH + 2 H+
-
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
-
-
r
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
-
-
-
?
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
stepwise single electron transfer involving FMN, ferredoxin, and NADPH, overview. Ability of the substrate to provide multiple interactions with the isoalloxazine system ofFMN that are usually provided by protein side chains. Ligand binding acts to template the active site geometry and significantly stabilize the one-electron-reduced semiquinone form of FMN
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
via mono-iodotyrosine
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
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
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
via mono-iodotyrosine, the reaction might involve an additional ferredoxin reductase
-
-
r
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
additional information
?
-
a synergy between substrate selectivity and catalytic activity is created by the enzyme. No activity with the substrate analog 3-fluoro-L-tyrosine
-
-
?
additional information
?
-
-
a synergy between substrate selectivity and catalytic activity is created by the enzyme. No activity with the substrate analog 3-fluoro-L-tyrosine
-
-
?
additional information
?
-
analytical detection method for iodotyrosine, overview
-
-
?
additional information
?
-
-
analytical detection method for iodotyrosine, overview
-
-
?
additional information
?
-
-
fluorotyrosine is an inert substrate analogue
-
-
?
additional information
?
-
the enzyme can act as a general dehalogenase, promoting reductive dehalogenation of 3-bromo- and 3-chloro-L-tyrosine, though not 3-fluoro-L-tyrosine
-
-
?
additional information
?
-
-
the enzyme can act as a general dehalogenase, promoting reductive dehalogenation of 3-bromo- and 3-chloro-L-tyrosine, though not 3-fluoro-L-tyrosine
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
-
-
-
?
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
-
-
-
-
r
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
via mono-iodotyrosine
-
-
r
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
flavin
-
presence of a neutral flavin radical during the reaction. Radical is stable and persists at 4°C under aerobic conditions for many days
FMN
FMN binds non-covalently at the dimer interface established by a helix from each of the two identical subunits involving residues Ser102 and Ser128. Iodotyrosine deiodinase utilizes FMN to maintain iodide homeostasis by reductive deiodination of iodotyrosine. In the absence of an active site ligand, only the oxidized and two-electron-reduced forms of FMN are detected
additional information
the cofactors form a redox electron transport chain, overview
-
additional information
-
the cofactors form a redox electron transport chain, overview
-
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
among polychlorinated biphenyls and polybrominated diphenyl ethers without a hydroxyl group tested, including their methoxylated metabolites, none is inhibitory
-
additional information
target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals, e.g. food colorants, pharmaceuticals, agrochemicals, and antiparasitics, effects of environmental halogenated chemicals on iodotyrosine deiodinase activity, overview. Non-hydroxylated PCBs (e.g., 2,2',4,4'-tetrachlorobiphenyl) and PBDEs (e.g., 2,2',4,4'-tetrabromodiphenyl ether), nitrofen, trichlabendazole, miconazole and amiodarone lack IYD-inhibitory activity
-
additional information
-
target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals, e.g. food colorants, pharmaceuticals, agrochemicals, and antiparasitics, effects of environmental halogenated chemicals on iodotyrosine deiodinase activity, overview. Non-hydroxylated PCBs (e.g., 2,2',4,4'-tetrachlorobiphenyl) and PBDEs (e.g., 2,2',4,4'-tetrabromodiphenyl ether), nitrofen, trichlabendazole, miconazole and amiodarone lack IYD-inhibitory activity
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0073
3-iodo-L-tyrosine
pH and temperature not specified in the publication
0.031
3-iodo-L-tyrosine
pH 7.6, temperature not specified in the publication, recombinant enzyme
additional information
additional information
Michaelis-Menten steady-state kinetics. Dissociation constants for different substrate analogues, overview
-
additional information
additional information
-
Michaelis-Menten steady-state kinetics. Dissociation constants for different substrate analogues, overview
-
additional information
additional information
-
rapid kinetics of dehalogenation promoted by iodotyrosine deiodinase from human thyroid, substrates chloro-, bromo-, and iodotyrosine bind with similar rate constants, overview. Standard two-state model, no intermediate complex accumulates during closure of the active site lid induced by substrate
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0102
3-iodo-L-tyrosine
pH and temperature not specified in the publication
0.208
3-iodo-L-tyrosine
pH 7.6, temperature not specified in the publication, recombinant enzyme
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
6.72
3-iodo-L-tyrosine
pH 7.6, temperature not specified in the publication, recombinant enzyme
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
6 - 9
pH dependence of IYD binding and turnover, tightest binding was measured near a neutral pH of 7.67.7
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
domain swaps at each N and C terminus consistent with the nitro-FMN reductase superfamily
malfunction
metabolism
-
reductive dehalogenation such as that catalyzed by iodotyrosine deiodinase is highly unusual in aerobic organisms but necessary for iodide salvage from iodotyrosine generated during thyroxine biosynthesis
physiological function
additional information
malfunction
loss-of-function mutations of the enzyme lead to the iodotyrosine deiodinase deficiency (ITDD), characterized by accumulation of mono- and diiodotyrosines in thyroid gland, plasma, and urine, hypothyroidism, compressive goiter and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. Patients harboring DEHAL1 defects so far described all belong to consanguineous families, phenotype, overview. Lack of biochemical expression of the disease at the beginning of life
malfunction
thyroid dysfunction can have very serious consequences, including mental retardation
physiological function
a FMN moiety that is involved in reduced NADPH-dependent reductive deiodination of 3-iodo-Ltyrosine (MIT) and 3,5-diiodo-L-tyrosine (DIT), which are released along with the thyroid hormones T4 and T3 during thyroglobulin proteolysis. Iodotyrosine deiodinase is involved in iodide salvage by catalyzing deiodination of iodinated by-products of thyroid hormone production. Thyroid hormones play important roles in growth, development, differentiation, and basal metabolic homeostasis, as well as in brain development in human fetus and children
physiological function
iodotyrosine deiodinase utilizes FMN to maintain iodide homeostasis by reductive deiodination of iodotyrosine
physiological function
-
reductive dehalogenation such as that catalyzed by iodotyrosine deiodinase is highly unusual in aerobic organisms but necessary for iodide salvage from iodotyrosine generated during thyroxine biosynthesis
physiological function
the thyroidal enzyme deiodinates mono- and diiodotyrosines (MIT, DIT) and recycles iodine, a scarce element in the environment, for the efficient synthesis of thyroid hormone, function and proposed components of the iodotyrosine deiodinase system, overview
additional information
a synergy between substrate selectivity and catalytic activity is created by the enzyme, active site and cofactor and substrate binding structures, overview
additional information
-
a synergy between substrate selectivity and catalytic activity is created by the enzyme, active site and cofactor and substrate binding structures, overview
additional information
the human enzyme harbors a conserved nitroreductase domain
additional information
-
the human enzyme harbors a conserved nitroreductase domain
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). IYD1_HUMAN
289
1
33360
Swiss-Prot
Secretory Pathway (Reliability: 1)
F6VN83_HUMAN
284
1
32589
TrEMBL
Secretory Pathway (Reliability: 1)
F5H543_HUMAN
192
1
22432
TrEMBL
other Location (Reliability: 1)
Q2VPV9_HUMAN
165
1
18917
TrEMBL
Mitochondrion (Reliability: 3)
C9JXJ9_HUMAN
270
1
31314
TrEMBL
Secretory Pathway (Reliability: 1)
IYD1_HUMAN
289
1
33360
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
30000
two identical subunits of human IYD form an alphabeta fold, 2 * 30000, recombinant enzyme, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterodimer
two identical subunits of human IYD form an alphabeta fold, 2 * 30000, recombinant enzyme, SDS-PAGE
additional information
additional information
the enzyme contains three domains: an N-terminal transmembrane region, an intermediate domain, and a catalytic domain
additional information
-
the enzyme contains three domains: an N-terminal transmembrane region, an intermediate domain, and a catalytic domain
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
putative signal peptide with a possible cleavage site between Ala23 and Asp24
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
hanging drop vapor diffusion method, using 80 mM Tris-HCl pH 8.5, 100 mM MgCl2, 24% (w/v) PEG 4000 and 20% glycerol
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, 20°C. 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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
I116T
naturally occuring mutation involved in iodotyrosine deiodinase deficiency, the mutant shows highly reduced activity compared to te wild-type enzyme
R101W
naturally occuring mutation involved in iodotyrosine deiodinase deficiency, the mutant shows highly reduced activity compared to te wild-type enzyme
additional information
additional information
mutations occuring in enzyme deficiency include homozygous one inframe-deletion of three base pairs (F105-I106L) and two missense (R101W, I116T). The mutations are located in close vicinity of each other within exon 2 of the gene encoding a putative FMN-binding site at the nitroreductase catalytic domain of the protein. All three mutations dramatically reduce the in vitro activity of the enzyme, one is also prematurely degraded
additional information
-
mutations occuring in enzyme deficiency include homozygous one inframe-deletion of three base pairs (F105-I106L) and two missense (R101W, I116T). The mutations are located in close vicinity of each other within exon 2 of the gene encoding a putative FMN-binding site at the nitroreductase catalytic domain of the protein. All three mutations dramatically reduce the in vitro activity of the enzyme, one is also prematurely degraded
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant SUMO-tagged enzyme from Escherichia coli strain Rosetta 2(DE3) by nickel affinity chromatography, tag removal, and gel filtration
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene DEHAL1, DNA and amino acid sequence determination and analysis, genotyping of healthy and iodotyrosine deiodinase deficiency samples
gene DEHAL1, recombinant expression of N-terminally SUMO-tagged enzyme in Escherichia coli strain Rosetta 2(DE3)
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
diagnostics
improvement of pre-clinical detection of iodotyrosine deiodinase deficiency during the neonatal time
medicine
-
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
additional information
additional information
target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals
additional information
-
target for disruption of thyroid hormone homeostasis by environmental halogenated chemicals
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Krause, K.; Karger, S.; Gimm, O.; Sheu, S.; Dralle, H.; Tannapfel, A.; Schmid, K.; Dupuy, C.; Fuhrer, D.
Characterisation of DEHAL1 expression in thyroid pathologies
Eur. J. Endocrinol.
156
295-301
2007
Homo sapiens
Gnidehou, S.; Caillou, B.; Talbot, M.; Ohayon, R.; Kaniewski, J.; Noel-Hudson, M.S.; Morand, S.; Agnangji, D.; Sezan, A.; Courtin, F.; Virion, A.; Dupuy, C.
Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide close to the thyroglobulin iodination site
FASEB J.
18
1574-1576
2004
Homo sapiens (Q6PHW0), Sus scrofa (Q6TA49)
McTamney, P.M.; Rokita, S.E.
A mammalian reductive deiodinase has broad power to dehalogenate chlorinated and brominated substrates
J. Am. Chem. Soc.
131
14212-14213
2009
Homo sapiens
Shimizu, R.; Yamaguchi, M.; Uramaru, N.; Kuroki, H.; Ohta, S.; Kitamura, S.; Sugihara, K.
Structure-activity relationships of 44 halogenated compounds for iodotyrosine deiodinase-inhibitory activity
Toxicology
314
22-29
2013
Homo sapiens
Iglesias, A.; Garcia-Nimo, L.; Cocho de Juan, J.A.; Moreno, J.C.
Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects
Best Pract. Res. Clin. Endocrinol. Metab.
28
151-159
2014
Homo sapiens (Q6PHW0), Homo sapiens
Bobyk, K.D.; Ballou, D.P.; Rokita, S.E.
Rapid kinetics of dehalogenation promoted by iodotyrosine deiodinase from human thyroid
Biochemistry
54
4487-4494
2015
Homo sapiens
Shimizu, R.
Iodotyrosine deiodinase, a novel target of environmental halogenated chemicals for disruption of the thyroid hormone system in mammals
Biol. Pharm. Bull.
37
1430-1434
2014
Homo sapiens (Q6PHW0), Homo sapiens
Hu, J.; Chuenchor, W.; Rokita, S.E.
A switch between one- and two-electron chemistry of the human flavoprotein iodotyrosine deiodinase is controlled by substrate
J. Biol. Chem.
290
590-600
2015
Homo sapiens (Q6PHW0), Homo sapiens
Sun, Z.; Su, Q.; Rokita, S.E.
The distribution and mechanism of iodotyrosine deiodinase defied expectations
Arch. Biochem. Biophys.
632
77-87
2017
Homo sapiens (Q6PHW0), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 1.21.1.1)
Use of this online version of BRENDA is free under the CC BY 4.0 license. See terms of use for full details.
Release 2023.1 (January 2023)
Legal
Curated at
Member of
