Thyroxine 5-deiodinase

Thyroxine 5-deiodinase also known as type III iodothyronine deiodinase (EC number 1.21.99.3) is an enzyme that in humans is encoded by the DIO3 gene.[5][6] This enzyme catalyses the following chemical reaction

3,3',5'-triiodo-L-thyronine + iodide + A + H⁺ ${\displaystyle \rightleftharpoons }$ L-thyroxine + AH₂

DIO3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4TR3, 4TR4
Identifiers
Aliases	DIO3, 5DIII, D3, DIOIII, TXDI3, deiodinase, iodothyronine, type III, iodothyronine deiodinase 3, Dio3 Gene
External IDs	OMIM: 601038 MGI: 1306782 HomoloGene: 1044 GeneCards: DIO3
Gene location (Human) Chr. Chromosome 14 (human)[1] Band 14q32.31 Start 101,561,351 bp[1] End 101,563,452 bp[1]
Gene location (Mouse) Chr. Chromosome 12 (mouse)[2] Band 12|12 F1 Start 110,279,068 bp[2] End 110,281,097 bp[2]
Gene ontology Molecular function • oxidoreductase activity • thyroxine 5-deiodinase activity • thyroxine 5'-deiodinase activity Cellular component • integral component of membrane • endosome • cell membrane • endosome membrane • membrane Biological process • thyroid hormone generation • oxidation-reduction process • thyroid hormone catabolic process • hormone biosynthetic process • positive regulation of multicellular organism growth • apoptotic process • retinal cone cell development • biological process • negative regulation of eye photoreceptor cell development • retinal cone cell apoptotic process • thyroid hormone metabolic process • macromolecule metabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1735	107585
Ensembl	ENSG00000197406	ENSMUSG00000075707
UniProt	P55073	Q91ZI8
RefSeq (mRNA)	NM_001362	NM_172119
RefSeq (protein)	NP_001353	NP_742117
Location (UCSC)	Chr 14: 101.56 – 101.56 Mb	Chr 12: 110.28 – 110.28 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

The protein encoded by this intronless gene belongs to the iodothyronine deiodinase family. It catalyzes the inactivation of thyroid hormone by inner ring deiodination of the prohormone thyroxine (T₄) and the bioactive hormone 3,3',5-triiodothyronine (T₃) to inactive metabolites, 3,3',5'-triiodothyronine (RT₃) and 3,3'-diiodothyronine (T₂), respectively. This enzyme is highly expressed in the pregnant uterus, placenta, fetal and neonatal tissues, suggesting that it plays an essential role in the regulation of thyroid hormone inactivation during embryological development.[7]

Discovery

The gene was mapped to chromosome 14q32 using fluorescence in situ hybridization (FISH) in 1998.[8]

Structure

This protein contains a selenocysteine (Sec) residue, which is essential for efficient enzyme activity. The selenocysteine is encoded by the UGA codon, which normally signals translation termination. The 3' UTR of Sec-containing genes have a common stem-loop structure, the sec insertion sequence (SECIS), which is necessary for the recognition of UGA as a Sec codon rather than as a stop signal.[7]

Function

Thyroxine 5-deiodinase
Identifiers
EC number	1.21.99.3
CAS number	74506-30-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

The DIO3 gene codes for type 3 iodothyronine deiodinase (D3), an enzyme that inactivates thyroid hormones and is highly expressed throughout fetal development, peaking early and decreasing towards the end of gestation. Part of the DLK1-Dio3 imprinting control region, this gene is one involved in the epigenetic process that causes a subset of genes to be regulated based on their parental origin .[9] Such imprinted genes are required for the formation of the placenta as well as the development of cellular lineages such as those derived from the mesoderm and ectoderm.[10] D3 is found in the pregnant uterus, placenta, and mammalian fetal tissues where it is thought to be involved in the transfer of thyroid hormone between the mother and fetus.[11] Expression of D3 contributes to the development of the brain, skin, liver, bone, ovary, testis, intestine, and brown adipose tissue. Introductory observations of D3-deficient mice indicate growth retardation and even some neonatal death. Due to its ability to activate or inactivate thyroid hormone, Dio3 coding of D3 could be a target for therapeutic intervention in insulin-related illness such as diabetes. In addition, an abnormal amount of Dio3 related to insufficient thyroid hormone levels could be responsible for the disruption of brain development in conjunction with alcohol exposure.[12] Many factors modify genetic imprinting of Dio3, making it a potential aid in understanding prenatal insults and their production of spectrum disorders.

References

1. GRCh38: Ensembl release 89: ENSG00000197406 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000075707 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Chopra IJ, Chua Teco GN (Jan 1982). "Characteristics of inner ring (3 or 5) monodeiodination of 3,5-diiodothyronine in rat liver: evidence suggesting marked similarities of inner and outer ring deiodinases for iodothyronines". Endocrinology. 110 (1): 89–97. doi:10.1210/endo-110-1-89. PMID 7053997.
6. Köhrle J (2002). Iodothyronine deiodinases. Methods in Enzymology. 347. pp. 125–167. doi:10.1016/s0076-6879(02)47014-0. ISBN 9780121822484. PMID 11898402.
7. "Entrez Gene: Deiodinase, iodothyronine, type III".
8. Hernandez A, Park JP, Lyon GJ, Mohandas TK, St Germain DL (Oct 1998). "Localization of the type 3 iodothyronine deiodinase (DIO3) gene to human chromosome 14q32 and mouse chromosome 12F1". Genomics. 53 (1): 119–121. doi:10.1006/geno.1998.5505. PMID 9787088.
9. Lin SP, Coan P, da Rocha ST, Seitz H, Cavaille J, Teng PW, Takada S, Ferguson-Smith AC (Jan 2007). "Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region". Development. 134 (2): 417–426. doi:10.1242/dev.02726. PMID 17166925.
10. Hernandez A, Fiering S, Martinez E, Galton VA, St Germain D (Nov 2002). "The gene locus encoding iodothyronine deiodinase type 3 (Dio3) is imprinted in the fetus and expresses antisense transcripts". Endocrinology. 143 (11): 4483–4486. doi:10.1210/en.2002-220800. PMID 12399446.
11. Medina MC, Molina J, Gadea Y, Fachado A, Murillo M, Simovic G, Pileggi A, Hernández A, Edlund H, Bianco AC (Oct 2011). "The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion". Endocrinology. 152 (10): 3717–3727. doi:10.1210/en.2011-1210. PMC 3176649. PMID 21828183.
12. Sittig LJ, Shukla PK, Herzing LB, Redei EE (Jul 2011). "Strain-specific vulnerability to alcohol exposure in utero via hippocampal parent-of-origin expression of deiodinase-III". FASEB Journal. 25 (7): 2313–2324. doi:10.1096/fj.10-179234. PMC 3114527. PMID 21429942.

Further reading

• Kuiper GG, Klootwijk W, Visser TJ (Jun 2003). "Substitution of cysteine for selenocysteine in the catalytic center of type III iodothyronine deiodinase reduces catalytic efficiency and alters substrate preference". Endocrinology. 144 (6): 2505–13. doi:10.1210/en.2003-0084. PMID 12746313.
• Bessho K, Etani Y, Ichimori H, Miyoshi Y, Namba N, Yoneda A, Ooue T, Chihara T, Morii E, Aoki T, Murakami M, Mushiake S, Ozono K (Feb 2010). "Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with consumptive hypothyroidism". European Journal of Pediatrics. 169 (2): 215–21. doi:10.1007/s00431-009-1009-x. PMID 19548001.
• Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeöld A, Curcio-Morelli C, Harney JW, Luongo C, Mulcahey MA, Larsen PR, Huang SA, Bianco AC (Jun 2008). "The thyroid hormone-inactivating deiodinase functions as a homodimer". Molecular Endocrinology. 22 (6): 1382–1393. doi:10.1210/me.2007-0490. PMC 2422829. PMID 18356288.
• Dentice M, Salvatore D (Jun 2011). "Deiodinases: the balance of thyroid hormone: local impact of thyroid hormone inactivation". The Journal of Endocrinology. 209 (3): 273–82. doi:10.1530/JOE-11-0002. PMID 21398344.
• Medina MC, Molina J, Gadea Y, Fachado A, Murillo M, Simovic G, Pileggi A, Hernández A, Edlund H, Bianco AC (Oct 2011). "The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion". Endocrinology. 152 (10): 3717–3727. doi:10.1210/en.2011-1210. PMC 3176649. PMID 21828183.
• Luk JM, Burchard J, Zhang C, Liu AM, Wong KF, Shek FH, Lee NP, Fan ST, Poon RT, Ivanovska I, Philippar U, Cleary MA, Buser CA, Shaw PM, Lee CN, Tenen DG, Dai H, Mao M (Sep 2011). "DLK1-DIO3 genomic imprinted microRNA cluster at 14q32.2 defines a stemlike subtype of hepatocellular carcinoma associated with poor survival". The Journal of Biological Chemistry. 286 (35): 30706–30713. doi:10.1074/jbc.M111.229831. PMC 3162431. PMID 21737452.
• Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I, Briasoulis E (Mar 2013). "The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis". Cellular and Molecular Life Sciences. 70 (5): 795–814. doi:10.1007/s00018-012-1080-8. PMID 22825660.
• Romitti M, Wajner SM, Zennig N, Goemann IM, Bueno AL, Meyer EL, Maia AL (Sep 2012). "Increased type 3 deiodinase expression in papillary thyroid carcinoma". Thyroid. 22 (9): 897–904. doi:10.1089/thy.2012.0031. PMID 22823995.
• Hernandez A, Park JP, Lyon GJ, Mohandas TK, St Germain DL (Oct 1998). "Localization of the type 3 iodothyronine deiodinase (DIO3) gene to human chromosome 14q32 and mouse chromosome 12F1". Genomics. 53 (1): 119–21. doi:10.1006/geno.1998.5505. PMID 9787088.

External links

• Thyroxine+5-deiodinase at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.