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
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]
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]
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
↑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. PMID7053997.
↑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. PMID9787088.
↑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. PMID17166925.
↑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. PMID12399446.
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. PMID12746313.
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. PMID19548001.
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. PMID21398344.
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. PMID22825660.
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. PMID22823995.
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. PMID9787088.