Köhrle J
Abteilung für Molekulare Innere Medizin und Klinische Forschergruppe der Medizinischen Poliklinik der Universität Würzburg, Germany.
Mol Cell Endocrinol. 1999 May 25;151(1-2):103-19. doi: 10.1016/s0303-7207(99)00040-4.
Tissue-specific activation and inactivation of ligands of nuclear receptors which belong to the steroid retinoid-thyroid hormone superfamily of transcription factors represents an important principle of development- and tissue-specific local modulation of hormone action. Recently, several enzyme families have been identified which act as 'guardians of the gate' of ligand-activated transcription modulation. Three monodeiodinase isoenzymes which are involved in activation the 'prohormone' L-thyroxine (T4), the main secretory product of the thyroid gland, have been identified, characterized, and cloned. Both, type I and type II 5'-deiodinase generate the thyromimetically active hormone 3,3',5-triiodothyronine (T3) by reductive deiodination of the phenolic ring of T4. Inactivation of T4 and its product T3 occurs by deiodination of iodothyronines at the tyrosyl ring. This reaction is catalyzed both the type III 5-deiodinase and also by the type I enzyme, which has a broader substrate specificity. The three deiodinases appear to constitute a newly discovered family of selenocysteine-containing proteins and the presence of selenocysteine in the protein is critical for enzyme activity. Whereas the selenoenzyme characteristics of the type I and type III deiodinases are definitively established some controversy still exists for the type II 5'-deiodinase in mammals. The mRNA probably encoding the type II 5'-deiodinase subunit is markedly longer than those of the two other deiodinases and its selenocysteine-insertion element is located more than 5 kB downstream of the UGA-codon in the 3'-untranslated region. The three deiodinase isoenzymes show a distinct development- and tissue-specific pattern of expression, operate at individual optimal substrate levels, are differently regulated and modulated by hormones, cytokines, signaling pathways, natural factors, and pharmaceuticals. Whereas circulating T3 mainly originates from hepatic production via the type I 5'-deiodinase, the local cellular thyroid hormone concentration in various tissues including the central nervous system is controlled by complex para-, auto-, and intracrine interactions of all three deiodinases. Local thyroid hormone availability is further modulated by conjugation reactions of the phenolic 4'-OH-group of iodothyronines, which also inactivate the thyroid hormones.
属于类固醇类视黄酸 - 甲状腺激素转录因子超家族的核受体配体的组织特异性激活和失活，代表了激素作用的发育和组织特异性局部调节的一个重要原则。最近，已鉴定出几个酶家族，它们充当配体激活转录调节的“门户守护者”。已鉴定、表征并克隆了三种参与激活“前激素”L - 甲状腺素（T4）（甲状腺的主要分泌产物）的单脱碘酶同工酶。I型和II型5'-脱碘酶均通过T4酚环的还原性脱碘生成具有甲状腺激素活性的激素3,3',5 - 三碘甲状腺原氨酸（T3）。T4及其产物T3的失活是通过甲状腺原氨酸在酪氨酸环处的脱碘作用发生的。该反应由III型5 - 脱碘酶以及具有更广泛底物特异性的I型酶催化。这三种脱碘酶似乎构成了一个新发现的含硒代半胱氨酸的蛋白质家族，并且蛋白质中硒代半胱氨酸的存在对酶活性至关重要。虽然I型和III型脱碘酶的硒酶特性已明确确定，但哺乳动物中II型5'-脱碘酶仍存在一些争议。可能编码II型5'-脱碘酶亚基的mRNA明显长于其他两种脱碘酶的mRNA，其硒代半胱氨酸插入元件位于3'-非翻译区UGA密码子下游超过5 kB处。这三种脱碘酶同工酶表现出独特的发育和组织特异性表达模式，在各自最佳底物水平下起作用，受激素、细胞因子、信号通路、天然因子和药物的调节方式不同。虽然循环中的T3主要通过I型5'-脱碘酶由肝脏产生，但包括中枢神经系统在内的各种组织中的局部细胞甲状腺激素浓度由所有三种脱碘酶的复杂旁分泌、自分泌和内分泌相互作用控制。甲状腺激素的局部可用性还通过甲状腺原氨酸酚4'-OH基团的结合反应进一步调节，该反应也使甲状腺激素失活。
