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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
-
-
?
3,5-diiodo-L-tyrosine + dithionite
3-iodo-L-tyrosine + ? + I-
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
3-bromo-L-tyrosine + NADP+ + bromide
3,5-dibromo-L-tyrosine + NADPH + H+
3-bromo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + Br-
-
-
-
-
?
3-chloro-L-tyrosine + NADP+ + chloride
3,5-dichloro-L-tyrosine + NADPH + H+
3-chloro-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + Cl-
-
-
-
-
?
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + iodide
-
-
-
r
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
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
additional information
?
-
3,5-diiodo-L-tyrosine + dithionite
3-iodo-L-tyrosine + ? + I-
-
solubilized enzyme preparations are active with dithionite, but not with NADPH. Particle-bound enzyme uses both dithionite and NADPH. At concentrations of substrate below 1 microM, 3,5-diiodo-L-tyrosine is more rapidly deiodinated than 3-iodo-L-tyrosine, which is reversed at concentrations greater than 5 microM
-
-
?
3,5-diiodo-L-tyrosine + dithionite
3-iodo-L-tyrosine + ? + I-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
solubilized enzyme preparations are active with dithionite, but not with NADPH. Particle-bound enzyme uses both dithionite and NADPH. At concentrations of substrate below 1 microM, 3,5-diiodo-L-tyrosine is more rapidly deiodinated than 3-iodo-L-tyrosine, which is reversed at concentrations greater than 5 microM
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
?
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
substrate 3-iodo-L-tyrosine is preferred over 3,5-diiodotyrosine
-
-
?
3-bromo-L-tyrosine + NADP+ + bromide
3,5-dibromo-L-tyrosine + NADPH + H+
-
-
-
?
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+
-
-
-
?
3-chloro-L-tyrosine + NADP+ + chloride
3,5-dichloro-L-tyrosine + NADPH + H+
low activity
-
-
?
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+
-
-
-
?
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
-
?
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
?
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 + 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 + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
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
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
r
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
additional information
?
-
no activity with 3-fluoro-L-tyrosine
-
-
?
additional information
?
-
-
no activity with 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
?
-
-
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
-
-
?
additional information
?
-
-
while L-iodotyrosines are almost completely dehalogenated, D-iodotyrosines, alpha-methyl-DL-iodotyrosines and 3,5-diiodo-4-hydroxyphenyl-DL-lactic acid are poor substrates for the deiodinase. No substrates are 3,5-diiodo-4-hydroxyphenyl-alpha-guanidyl propionic acid, 3,5-diiodo-4-hydroxyphenyl propionic acid, 3,5-diiodotyramine, 3-iodo-5-nitro-L-tyrosine and 3-iodo-L-phenylalanine
-
-
?
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3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADP+ + I-
-
-
-
?
3-iodo-L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
3-iodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + I-
-
-
-
?
L-tyrosine + 2 NADP+ + 2 iodide
3,5-diiodo-L-tyrosine + 2 NADPH + 2 H+
L-tyrosine + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
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+
-
-
-
?
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 + 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 + NADP+ + iodide
3,5-diiodo-L-tyrosine + NADPH + H+
overall reaction
-
-
?
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
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
L-tyrosine + NADP+ + iodide
3-iodo-L-tyrosine + NADPH + H+
-
-
-
?
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2',3,4',5,6'-pentachlorobiphenyl-4-ol
-
2',3,4',6'-tetrachlorobiphenyl-4-ol
-
2,2',5,5'-tetrachlorobiphenyl-4-ol
-
2,3,6-tribromo-4-(2,4-dibromophenoxy)phenol
-
2,3-dibromo-4-(2,4-dibromophenoxy)phenol
-
2,5-dibromo-4-(2,4-dibromophenoxy)phenol
-
3,5-diiodo-L-tyrosine
-
pronounced substrate inhibition above 5 microM
3-bromo-4-(2,4-dibromophenoxy)phenol
-
3-hydroxy-2,2',5,5'-tetrachlorobiphenyl
-
4'-hydroxy-2,2',4,5'-tetrabromodiphenyl ether
-
-
4'-hydroxy-2,2',4-tribromodiphenyl ether
-
-
4,4'-dihydroxy-3,3',5,5'-tetrachlorobiphenyl
-
4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl
-
-
4-hydroxy-2,2',3,4',5-pentabromodiphenyl ether
-
-
4-hydroxy-2,3,3',4'-tetrabromodiphenyl ether
-
-
5-bromo-2-(2,4-dibromophenoxy)phenol
-
5-bromo-2-(4-bromophenoxy)phenol
-
benzbromarone
-
-
erythrosine B
-
-
phloxine B
-
-
Rose bengal
-
most potent inhibitor tested
triclosan
-
-
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
-
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Congenital Hypothyroidism
Mutations in the iodotyrosine deiodinase gene and hypothyroidism.
Goiter
Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations.
Goiter
Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.
Goiter
Towards the timely diagnosis of hypothyroidism caused by DEHAL1 gene defects.
Goiter
[Quantitative aspects of iodine metabolism in one case of congenital iodotyrosine deiodinase defect (author's transl)]
Graves Disease
Characterisation of DEHAL1 expression in thyroid pathologies.
Hyperthyroidism
A Nonradioactive DEHAL Assay for Testing Substrates, Inhibitors, and Monitoring Endogenous Activity.
Hypothyroidism
Genetic Evaluation of Congenital Hypothyroidism with Gland in situ Using Targeted Exome Sequencing.
Hypothyroidism
Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations.
Hypothyroidism
Molecular characterization of iodotyrosine dehalogenase deficiency in patients with hypothyroidism.
Hypothyroidism
Mutations in the iodotyrosine deiodinase gene and hypothyroidism.
Hypothyroidism
Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.
Hypothyroidism
Towards the timely diagnosis of hypothyroidism caused by DEHAL1 gene defects.
Hypothyroidism
[Quantitative aspects of iodine metabolism in one case of congenital iodotyrosine deiodinase defect (author's transl)]
Intellectual Disability
Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.
Intellectual Disability
Towards the timely diagnosis of hypothyroidism caused by DEHAL1 gene defects.
iodotyrosine deiodinase deficiency
Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations.
iodotyrosine deiodinase deficiency
Towards the pre-clinical diagnosis of hypothyroidism caused by iodotyrosine deiodinase (DEHAL1) defects.
iodotyrosine deiodinase deficiency
Towards the timely diagnosis of hypothyroidism caused by DEHAL1 gene defects.
Thyroid Cancer, Papillary
Characterisation of DEHAL1 expression in thyroid pathologies.
Thyroid Carcinoma, Anaplastic
Characterisation of DEHAL1 expression in thyroid pathologies.
Thyroid Diseases
Iodotyrosine deiodinase isozymes in the normal and in thyroid diseases.
Thyroid Neoplasms
Characterisation of DEHAL1 expression in thyroid pathologies.
Thyroid Nodule
Characterisation of DEHAL1 expression in thyroid pathologies.
Thyrotoxicosis
Characterisation of DEHAL1 expression in thyroid pathologies.
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4.1
2-iodophenol
pH and temperature not specified in the publication
0.0011 - 0.44
3,5-diiodo-L-tyrosine
0.008
3-bromo-L-tyrosine
at pH 7.4, temperature not specified in the publication
0.021
3-chloro-L-tyrosine
at pH 7.4, temperature not specified in the publication
0.001 - 0.05
3-iodo-L-tyrosine
0.027
NADPH
-
method 125I release, pH 7.4, 37°C
additional information
additional information
-
0.0011
3,5-diiodo-L-tyrosine
-
method NADPH oxidation, pH 7.4, 37°C
0.0015
3,5-diiodo-L-tyrosine
-
method 125I release, pH 7.4, 37°C
0.00202
3,5-diiodo-L-tyrosine
cosubstrate NADPH, pH 7.4, 25°C
0.0025
3,5-diiodo-L-tyrosine
-
pH 7.4, 38°C
0.0044
3,5-diiodo-L-tyrosine
cosubstrate dithionite, pH 7.4, 25°C
0.019
3,5-diiodo-L-tyrosine
enzyme expressed in Pichia pastoris, pH not specified in the publication, temperature not specified in the publication
0.04
3,5-diiodo-L-tyrosine
enzyme expressed in Escherichia coli and lacking the transmembrane domain, pH not specified in the publication, temperature not specified in the publication
0.44
3,5-diiodo-L-tyrosine
mutant Y157F, expressed in Escherichia coli and lacking the transmembrane domain, pH not specified in the publication, temperature not specified in the publication
0.001
3-iodo-L-tyrosine
-
method NADPH oxidation, pH 7.4, 37°C
0.0011
3-iodo-L-tyrosine
-
method 125I release, pH 7.4, 37°C
0.004
3-iodo-L-tyrosine
-
pH not specified in the publication, temperature not specified in the publication
0.0066
3-iodo-L-tyrosine
-
pH not specified in the publication, temperature not specified in the publication
0.007
3-iodo-L-tyrosine
-
pH not specified in the publication, temperature not specified in the publication
0.0073
3-iodo-L-tyrosine
pH and temperature not specified in the publication
0.008
3-iodo-L-tyrosine
-
pH not specified in the publication, temperature not specified in the publication
0.014
3-iodo-L-tyrosine
at pH 7.4, temperature not specified in the publication
0.019
3-iodo-L-tyrosine
pH not specified in the publication, temperature not specified in the publication
0.031
3-iodo-L-tyrosine
pH 7.6, temperature not specified in the publication, recombinant enzyme
0.05
3-iodo-L-tyrosine
-
pH 7.4, 38°C
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
-
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evolution
domain swaps at each N and C terminus consistent with the nitro-FMN reductase superfamily
malfunction
increased sup-18(+) expression in body-wall muscles specifically enhances the behavioral defects of sup-10(n983gf) mutants
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
metabolism
genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. The SUP-9 two-pore domain K+ channel is most closely related to human TASK-3. unc-93 encodes a conserved multi-pass transmembrane protein. An evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 is required for its specific activation by SUP-10 and SUP-18 but not by UNC-93
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
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 enzyme, catalyzing the reductive dehalogenation, is a critical enzyme in maintaining iodine homeostasis
physiological function
the NADH oxidase/flavin reductase, an orthologue of mammalian iodotyrosine deiodinase (IYD), functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The enzyme SUP-18 is a type-I transmembrane protein with an NADH oxidase/flavin reductase domain that resides intracellularly and can function without plasma membrane localization. The enzyme regulates the activity of the muscle two-pore domain potassium SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability
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
physiological function
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the enzyme, catalyzing the reductive dehalogenation, is a critical enzyme in maintaining iodine homeostasis
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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
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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
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the human enzyme harbors a conserved nitroreductase domain
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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
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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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
E154Q
the mutation diminishes the affinity of the enzyme for 3,5-diiodo-L-tyrosine by 30fold
K179Q
the mutation diminishes the affinity of the enzyme for 3,5-diiodo-L-tyrosine by 46fold
Y158F
the mutation results in a 7fold decrease in the enzyme's affinity for 3,5-diiodo-L-tyrosine
A220T
naturally occuring mutation involved in iodotyrosine deiodinase
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
K178Q
upon expression in Escherichia coli, inactive and insoluble
E153Q
the mutant exhibits no measurable binding affinity for 3-chloro-L-tyrosine
E153Q
mutation reduces the deiodinase activity to an undetectable level. Mutant exhibits no measurable binding affinity for the substrate
Y157F
the mutation weakens the binding of 3-chloro-L-tyrosine by 20fold
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%
additional information
naturally occuring sup-18 loss-of-function mutations, e.g. splice-junction mutants and spontaneaous mutations, overview
additional information
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naturally occuring sup-18 loss-of-function mutations, e.g. splice-junction mutants and spontaneaous mutations, overview
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
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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
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