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Information on EC 1.21.99.3 - thyroxine 5-deiodinase and Organism(s) Mus musculus and UniProt Accession Q91ZI8
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1.21.99.3 thyroxine 5-deiodinaseIUBMB Comments
The enzyme activity has only been demonstrated in the direction of 5-deiodination. This removal of the 5-iodine, i.e. from the inner ring, largely inactivates the hormone thyroxine.
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Word Map
- 1.21.99.3
- thyroid
- triiodothyronine
- hypothyroidism
- tsh
-
deiodination
- pituitary
-
euthyroidism
- 3,5,3'-triiodothyronine
- adipose
-
5'-deiodination
- propylthiouracil
- l-thyroxine
-
prohormone
- 3,3',5'-triiodothyronine
- thyrotropin
- selenocysteine
-
selenoproteins
-
selenoenzyme
-
iopanoic
- methimazole
-
dlk1-dio3
-
pituitary-thyroid
- 3,3'-diiodothyronine
- medicine
-
monodeiodination
-
extrathyroidal
-
se-deficient
-
t3-dependent
-
selenium-deficient
-
hypothalamic-pituitary-thyroid
- amiodarone
-
thyroidectomized
-
harderian
-
nonthyroidal
-
thyroxine-binding
-
thyrotropin-releasing
-
thermogenic
-
thyromimetically
-
inner-ring
- 6-n-propyl-2-thiouracil
-
thyroid-stimulating
-
thyrotoxicosis
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
5'-deiodinase, type iii deiodinase, type 3 iodothyronine deiodinase, deiodinase 3, t4-5'-deiodinase, type iii iodothyronine deiodinase, dio3b, iodothyronine monodeiodinase, deiodinase-3, dio3a, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
deiodinase, thyroxine 5-
-
-
-
-
diiodothyronine 5'-deiodinase
-
-
-
-
iodothyronine 5-deiodinase
-
-
-
-
iodothyronine inner ring monodeiodinase
-
-
-
-
type 3 deiodinase
type III iodothyronine deiodinase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-
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. This removal of the 5-iodine, i.e. from the inner ring, largely inactivates the hormone thyroxine.
CAS REGISTRY NUMBER
COMMENTARY
74506-30-2
-
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
3,3',5'-triiodo-L-thyronine + iodide + acceptor + H+
L-thyroxine + reduced acceptor
-
-
-
?
3,3',5-triiodo-L-thyronine + AH2
3,3'-diiodothyronine + iodide + A + H+
-
-
-
?
3,3',5'-triido-L-thyronine + iodide + A + H+
L-thyroxine + AH2
-
assay at pH 7.2
-
-
?
3,3',5'-triiodo-L-thyronine + AH2
3,3'-diiodo-L-thyronine + iodide + A + H+
-
type 3 deiodinase terminates thyroid hormone action by inactivating T3
-
-
?
3,3',5'-triiodo-L-thyronine + reduced acceptor
3,3'-diiodo-L-thyronine + iodide + acceptor + H+
-
-
-
-
?
3,3',5-triiodo-L-thyronine + AH2
3,3'-diiodo-L-thyronine + iodide + A + H+
-
-
hormonally inactive
-
?
3,5,3'-triiodo-L-thyronine + AH2
3,3'-diiodothyronine + iodide + A + H+
-
-
-
-
?
L-3',5'-diiodothyronine + AH2
L-5'-iodothyronine + iodide + A + H+
-
phenolic ring deiodination of 3',5'-T2 by Dio2
-
-
?
L-3,5,3'-triiodothyronine + AH2
L-3,3'-diiodothyronine + iodide + A + H+
-
5-deionination by isozyme Dio1
-
-
?
L-3-iodothyronine + AH2
L-thyronine + iodide + A + H+
-
tyrosyl ring deiodination of 3-iodothyronamine by isozyme Dio3
-
-
?
L-thyroxine + AH2
3,3',5'-triiodo-L-thyronine + iodide + A + H+
-
enzyme III performs the inactivation of 3,3',5,5'-tetraiodo-L-thyronine
hormonally inactive
-
?
L-thyroxine + AH2
3,3',5'-triiodo-L-thyronine + iodide + A + H+
-
enzyme performs the inactivation of 3,3',5,5'-tetraiodo-L-thyronine and plays a critical role in regulating and maintaining the local 3,3',5-triiodo-L-thyronine content
-
-
?
additional information
?
-
-
isozyme type III performs the inactivation of 3,3',5,5'-tetraiodo-L-thyronine and enzyme plays a critical role in regulating and maintaining the local 3,3',5-triiodo-L-thyronine content
-
-
?
additional information
?
-
-
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
-
-
?
additional information
?
-
-
isozyme Dio1 from mouse liver membrane fractions catalyzes a weak 3'-deiodination of 3,3'-T2 as well as faint 5-deiodinations of both T3 and 3,5-T2
-
-
?
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
3,3',5'-triiodo-L-thyronine + iodide + acceptor + H+
L-thyroxine + reduced acceptor
-
-
-
?
3,3',5'-triiodo-L-thyronine + reduced acceptor
3,3'-diiodo-L-thyronine + iodide + acceptor + H+
-
-
-
-
?
3,3',5-triiodo-L-thyronine + AH2
3,3'-diiodo-L-thyronine + iodide + A + H+
-
-
hormonally inactive
-
?
L-thyroxine + AH2
3,3',5'-triiodo-L-thyronine + iodide + A + H+
-
enzyme III performs the inactivation of 3,3',5,5'-tetraiodo-L-thyronine
hormonally inactive
-
?
additional information
?
-
-
isozyme type III performs the inactivation of 3,3',5,5'-tetraiodo-L-thyronine and enzyme plays a critical role in regulating and maintaining the local 3,3',5-triiodo-L-thyronine content
-
-
?
additional information
?
-
-
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
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
by activation of type 3 deiodinase during illness reduction of thyroid hormone levels
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
wild type, G2N2C and Tb3A transgenic BCC cell lines expressing Gli2 under the control of the keratin 5 promoter
additional information
additional information
type 3 deiodinase activity, although normally expressed at very low levels in adult peripheral tissues, is increased to significant levels in the skin, kidney, and muscle of both fasted wild-type and type 1 and 2 deiodinase KO mice
additional information
-
not: kidney, healthy adult liver, pituitary gland, thyroid gland
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological role of thyroid hormones in the regulation of insulin secretion, overview. type 3 iodothyronine deiodinase-mediated thyroid hormone inactivation is thought to participate in glucose-stimulated insulin secretion from beta cellsA cAMP pathway mediates the pretranslational regulation of D3 expression in MIN6 cells
physiological function
malfunction
physiological function
physiological function
protective role in hearing by influence of thyroid hormone, influence on cochlear development and auditory function, thyroid hormone-inactivating enzyme
physiological function
type 3 deiodinase plays a role in the fasting-induced alterations in thyroid hormone homeostasis. The enzyme activity is increased in kidney, muscle, and liver up to 4fold during fasting. The observed fasting-induced reductions in the circulating T3 and T4 levels are mediated in part by increased the enzyme activity and by the sequestration of thyroid hormone and their metabolites in tissues, overview
physiological function
type 3 iodothyronine deiodinase (D3) converts thyroxine (T4) and 3,5,3'-triiodothyronine (T3) to3,3',5-triiodothyronine (rT3) and 3,3'-diiodothyronine (T2), respectively, inactivating thyroid hormones in a cell-specific fashion
malfunction
-
in Dio3-deficient mice, about 80% of both M opsin+ and S opsin+ cones are lost through neonatal cell death
malfunction
-
enzyme-deficient mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine treatment. They also exhibit increased thyroid hormone action in the hypothalamus, with abnormal expression and triiodothyronine sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. Enzyme-deficient mice also display elevated locomotor activity and increased energy expenditure
physiological function
-
role in innate immune response, reduction of thyroid hormone levels during illness, protective role in defense against acute bacterial infection, probably by reinforcement of microbial killing capacity of neutrophils
physiological function
-
the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase
physiological function
-
enzyme-mediated regulation of thyroid hormone action in the central nervous system influences multiple critical determinants of energy balance
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). IOD3_MOUSE
304
0
34111
Swiss-Prot
Mitochondrion (Reliability: 5)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
structure of the catalytic domain of mouse deiodinase Dio3, to 1.9 A resolution. The catalytic Sec170 is positioned in the loop connecting beta1 to alpha1. It points toward an elongated cleft that likely represents the iodothyronine binding site. The deiodination step follows a selenolate inline attack on the iodine delta-hole weakening the carbon-iodine bond. The abstracted iodonium is replaced by a proton approaching from the opposite side of the ring. The proton is conveyed to the 5-position of the iodothyronine along a triad His219, Glu200, and Ser167, with residues Tyr197 and Thr169 participating in the organization of an intricate H-bond network
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
E200T
R275A
the mutant shows sharply reduced activity compared to the wild type enzyme
S167A
T169A
T169S
Y197F
S167A
the mutant shows about 90% reduced activity compared to the wild type enzyme
T169S
the mutant shows about 60% reduced activity compared to the wild type enzyme
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of RNAi to knock down type 3 deiodinase in transient transfection experiments using G2N2C, Tb3A, and wild type keratinocytes
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
glucagon-like peptide-1 stimulates type 3 iodothyronine deiodinase expression in Min6 cells in a dose-dependent manner through a GLP-1 receptor-cAMP-PKA-medicated mechanism, and this effect is inhibited by the protein kinase A inhibitor H-89. Exendin-4, a GLP-1 receptor agonist, and forskolin also stimulates type 3 deiodinase expression in MIN6 cells. A cAMP pathway mediates the pretranslational regulation of D3 expression in MIN6 cells
the enzyme activity is increased in kidney, muscle, and liver up to 4fold during fasting
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
sonic hedgehog pathway plays a critical role in hair follicle physiology and is constitutively active in basal cell carcinomas, induces TYPE 3 DEIODINASE in proliferating keratinocytes and in BCCs through Gli2, reversing this T3 deficiency may be a therapeutic approach for BCCs and perhaps other TYPE 3 DEIODINASE-expressing tumors
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Koehrle, J.
Iodothyronine deiodinases
Methods Enzymol.
347
125-167
2002
Bos taurus, Homo sapiens, Mus musculus, Rattus norvegicus, vertebrata
Dentice, M.; Luongo, C.; Huang, S.; Ambrosio, R.; Elefante, A.; Mirebeau-Prunier, D.; Zavacki, A.M.; Fenzi, G.; Grachtchouk, M.; Hutchin, M.; Dlugosz, A.A.; Bianco, A.C.; Missero, C.; Larsen, P.R.; Salvatore, D.
Sonic hedgehog-induced type 3 deiodinase blocks thyroid hormone action enhancing proliferation of normal and malignant keratinocytes
Proc. Natl. Acad. Sci. USA
104
14466-14471
2007
Homo sapiens, Mus musculus
Ng, L.; Hernandez, A.; He, W.; Ren, T.; Srinivas, M.; Ma, M.; Galton, V.A.; St Germain, D.L.; Forrest, D.
A protective role for type 3 deiodinase, a thyroid hormone-inactivating enzyme, in cochlear development and auditory function
Endocrinology
150
1952-1960
2009
Mus musculus (Q91ZI8)
Boelen, A.; Kwakkel, J.; Wieland, C.W.; St Germain, D.L.; Fliers, E.; Hernandez, A.
Impaired bacterial clearance in type 3 deiodinase-deficient mice infected with Streptococcus pneumoniae
Endocrinology
150
1984-1990
2009
Mus musculus
Ng, L.; Lyubarsky, A.; Nikonov, S.S.; Ma, M.; Srinivas, M.; Kefas, B.; St Germain, D.L.; Hernandez, A.; Pugh, E.N.; Forrest, D.
Type 3 deiodinase, a thyroid-hormone-inactivating enzyme, controls survival and maturation of cone photoreceptors
J. Neurosci.
30
3347-3357
2010
Mus musculus
Piehl, S.; Heberer, T.; Balizs, G.; Scanlan, T.S.; Kohrle, J.
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
3286-3296
2008
Homo sapiens, Mus musculus
Galton, V.A.; Hernandez, A.; St Germain, D.L.
The 5-deiodinases are not essential for the fasting-induced decrease in circulating thyroid hormone levels in male mice: possible roles for the type 3 deiodinase and tissue sequestration of hormone
Endocrinology
155
3172-3181
2014
Mus musculus (Q91ZI8)
Akiyama, S.; Ogiwara, T.; Aoki, T.; Tsunekawa, K.; Araki, O.; Murakami, M.
Glucagon-like peptide-1 stimulates type 3 iodothyronine deiodinase expression in a mouse insulinoma cell line
Life Sci.
115
22-28
2014
Mus musculus (Q91ZI8), Mus musculus
Schweizer, U.; Schlicker, C.; Braun, D.; Khrle, J.; Steegborn, C.
Crystal structure of mammalian selenocysteine-dependent iodothyronine deiodinase suggests a peroxiredoxin-like catalytic mechanism
Proc. Natl. Acad. Sci. USA
111
10526-10531
2014
Mus musculus (Q91ZI8), Mus musculus
Wu, Z.; Martinez, M.E.; St Germain, D.L.; Hernandez, A.
Type 3 deiodinase role on central thyroid hormone action affects the leptin-melanocortin system and circadian activity
Endocrinology
158
419-430
2017
Mus musculus
Schweizerulrich U, S.U.; Steegborn C, S.C.
New insights into the structure and mechanism of iodothyronine deiodinases
J. Mol. Endocrinol.
55
T37-T52
2015
Mus musculus
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