Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.
Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action.
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甲状腺激素脱碘酶——一种硒酶家族，充当甲状腺激素作用的看门人。
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发表时间：
1996
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通讯作者：
Josef Köhrle
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作者：
Josef Köhrle
甲状腺激素的发育和组织特异性脱碘导致激素原甲状腺素活化为促甲状腺激素活性T3以及T3及其结合物失活或T4失活以产生潜在的调节活性rT3。到目前为止，至少有三种脱碘酶同工酶已被鉴定和克隆，脱碘酶同工酶代表了一个新的真核硒蛋白家族，可以为其分配酶功能。硒状态对这些脱碘酶同工酶的表达有不同程度的调节作用，表明这些酶的硒掺入存在层次性。目前，似乎硒缺乏在体内不影响II型5 '-脱碘酶或5-脱碘酶的表达到显著的程度，而I型5'-脱碘酶至少在肝脏和肾脏中在严重硒缺乏中减少。然而，在正常的midurology每日硒摄入量已经饱和的脱碘酶同工酶的表达的要求。到目前为止，仅在特定饮食中观察到5 '-D I表达减少和T3产生减少，例如PKU或囊性纤维化，其中离子（碘化物，亚硒酸盐？）可能会受到影响。在低T3综合征的条件下观察到通过5 ′-DI活性的T3产生的进一步改变，所述低T3综合征包括从碳水化合物戒断到重症监护患者的广谱临床病症。目前尚不清楚补充硒或T3治疗是否对这些患者有益。脱碘酶表达的显著组织特异性需要对这些酶与甲状腺激素作用的表达之间的关系进行更详细的检查，甲状腺激素作用由核T3受体家族或线粒体、质膜或细胞骨架中的受体和信号转导分子介导。脱碘酶位于质膜内侧或内质网的胞质侧，将这些酶定位于战略性重要位置，使其能够充当核受体的守门人。与参与具有激素或信号传导功能的化合物的活化或失活的其他酶类似，脱碘酶是靶组织中激素活化或非靶组织中失活的内分泌调节中的关键元件。因此，在开发组织或酶特异性药理学干预之前，需要对这些酶的功能、调节和基因结构进行详细的分子、细胞生物学和生理学分析。然而，第一批数据表明，至少在滤泡性甲状腺癌中，用类维生素A治疗可以重新诱导肿瘤组织中5'-脱碘酶I型表达的降低。需要进一步的研究来证明类维生素A可能是一个有用的治疗工具，用于甲状腺癌的再分化治疗，这些甲状腺癌无法手术干预或缺乏放射性碘的摄取和储存。脱碘酶同工酶在中枢神经系统中的重要功能以及区域和细胞特异性表达远未被理解。目前的第一个证据表明，甲状腺激素脱碘，甲状腺激素浓度和甲状腺激素反应基因在成人大脑中的表达之间存在密切的相互作用，以及甲状腺激素代谢和神经递质合成释放和作用之间的紧密调节和相互作用。
Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5'-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5'-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5'-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5'-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if selenium supplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, or cytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membrane or the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before a development of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5'-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove that retinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action.