MECHANISM OF SELENOPROTEIN SYNTHESIS IN EUKARYOTES

硒是一种必需的微量元素，它已经引发了相当大的 由于鉴定出越来越多的酶 含有氨基酸，硒半胱氨酸。许多这样的酶 催化对健康或生命至关重要的反应。第一 确定了哺乳动物的硒酶，谷胱甘肽过氧化物酶， 催化过氧化物解毒，从而保护免受氧化 压力。另一类氧化还原硒酶--硫氧还蛋白 还原酶，在适当的转录因子折叠和 生成用于脱氧核苷酸合成的还原等价物。这个 碘甲腺原氨酸脱碘酶，也是硒酶，催化甲状腺激素 激活和失活，因此对调节 甲状腺激素的多种功能。其他类型的硒蛋白 正在被发现，有证据表明入侵和重要 在许多生物过程中发挥作用。除了蜂窝 函数，越来越多的数据正在积累与硒有关的信息 在一些病毒的病理中。硒的状态似乎是 影响艾滋病毒复制和艾滋病进展的宿主选择 柯萨奇病毒强毒株及其对细胞凋亡的敏感性 传染性软体肿痘病毒感染。研究还表明， 硒对肺癌、结肠癌和前列腺癌的保护作用。 将硒半胱氨酸掺入蛋白质需要一种新的 翻译步骤，其中UGA指定硒半胱氨酸插入。 硒蛋白存在于真核生物、真细菌和古生物中，但 公司成立的机制是不同的。虽然很多人都知道 在细菌中掺入硒半胱氨酸，我们对 真核过程中，一些更耐人寻味的机制 问题是谎言，已经落后了。这项提议的重点是 加深对硒半胱氨酸掺入过程的理解 在真核生物中，通过对RNA和蛋白质因子的研究 调解这一过程，以及他们之间的互动。这包括 对RNA序列的持续结构研究 硒半胱氨酸的掺入，有趣的是，最近发现了一些 这些结构中的多态似乎会对 人类疾病。我们还将重点放在识别和 与这些RNA相互作用的蛋白质因子的特性 以调节核糖体的整合。最后，提出了研究建议。 包括对调节的功能和机制的研究 新鉴定的硒蛋白。

Selenium is an essential trace element which has provoked considerable interest due to identification of a growing number of enzymes that contain the amino acid, selenocysteine. A number of these enzymes catalyze reactions that are critical to health or life. The first identified mammalian selenoenzymes, the glutathione peroxidases, catalyze detoxification of peroxides and thus, protection from oxidative stress. Another class of redox selenoenzymes, the thioredoxin reductases, play roles in proper transcription factor folding and generating reducing equivalents for deoxribonucleotide synthesis. The iodothyronine deiodinases, also selenoenzymes, catalyze thyroid hormone activation and inactivation and are thus essential to regulation of the many functions of thyroid hormone. Additional classes of selenoproteins are being discovered, with evidence for intruiging and important functions in many biological processes. In addition to cellular functions, a growing body of data is accumulating implicating selenium in the pathology of a number of viruses. Selenium status appears to affect HIV replication and the progression of AIDS, host selection for virulent strains of Coxsackie virus, and sensitivity to apoptosis in Molluscum contagiosum poxvirus infection. Studies have also implicated selenium in protection from lung, colon, and prostate cancer. Incorporation of selenocysteine into proteins requires a novel translation step in which UGA specifies selenocysteine insertion. Selenoproteins are found in eukaryotes, eubacteria, and archae, but the mechanisms of incorporation are distinct. While much is known about selenocysteine incorporation in bacteria, our knowledge about the eukaryotic process, where some of the more intriguing mechanistic questions lie, has lagged behind. The focus of this proposal is to further our understanding of the process of selenocysteine incorporation in eukaryotes, through investigation of the RNA and protein factors mediating this process, and their interactions. This includes continuing structural studies of the RNA sequences that direct selenocysteine incorporation, and intriguingly, some recently identified polymorphisms in these structures that appear to have consequences for human disease. We are also focusing on identification and characterization of the protein factors that interact with these RNAs to mediate incorporation at the ribosome. Finally, proposed studies include investigation of the functions and mechanisms of regulation of newly identified selenoproteins.