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Thyroxine 5-deiodinase

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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.[1][2] This enzyme catalyses the following chemical reaction

3,3',5'-triiodo-L-thyronine + iodide + A + H+ L-thyroxine + AH2

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.[3]

Discovery

The gene was mapped to chromosome 14q32 using fluorescence in situ hybridization (FISH) in 1998.[4]

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.[3]

Function

Thyroxine 5-deiodinase
Identifiers
EC no.1.21.99.3
CAS no.74506-30-2
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
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NCBIproteins

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 (see Genomic Imprinting).[5] 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.[6] 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.[7] 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.[8] Many factors modify genetic imprinting of Dio3, making it a potential aid in understanding prenatal insults and their production of spectrum disorders.

References

  1. ^ 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.
  2. ^ Köhrle J (2002). "Iodothyronine deiodinases". Methods in Enzymology. 347: 125–167. doi:10.1016/s0076-6879(02)47014-0. PMID 11898402.
  3. ^ a b "Entrez Gene: Deiodinase, iodothyronine, type III".
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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. PMID 21828183.
  8. ^ 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. PMID 21429942.{{cite journal}}: CS1 maint: unflagged free DOI (link)

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). 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). 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). doi:10.1210/me.2007-0490. 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). 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). doi:10.1210/en.2011-1210. 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). doi:10.1074/jbc.M111.229831. PMID 21737452.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • 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). 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). 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). doi:10.1006/geno.1998.5505. PMID 9787088.

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

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