基因组中硒蛋白的信息学

人类已经步入"后基因组"时代,基因组研究的重心将由测定基因的DNA序列转移到解释生命的所有遗传信息,从分子整体水平对生物学功能的研究,在分子层面上探索人类健康和疾病的奥秘.硒蛋白基因是各种基因组中一类重要的蛋白质基因,从基因组中寻找新的硒蛋白基因,对于硒蛋白生物功能的探索具有十分重要的意义.本文就硒代半胱氨酸插入元件(SECIS)结构特征、从基因组中寻找硒蛋白的生物信息学方法及其研究进展作了简要介绍,并对未来的发展趋势进行了展望.     

血管硒蛋白与动脉粥样硬化*

动脉粥样硬化是一种严重危害人类健康的慢性炎症血管疾病,随着我国人民生活水平的不断提高和人口的老龄化,其发病率逐年增高。本文结合本课题组的工作,对血管硒蛋白与动脉粥样硬化的关系进行了介绍。主要的研究进展表明：动脉粥样硬化的发生与血管氧化性损伤有密切关系,硒作为一种重要的必需微量元素主要以硒蛋白的形式存在于血管之中,对氧化型固醇导致的血管损伤有明显的抑制作用;其机理可能与硒蛋白的抗氧化作用、调节血液前列环素和血栓素的比例改善血液流通、以及抑制氧化型固醇诱导的血管细胞凋亡等有关。     

硒蛋白S的结构、功能及与疾病的关系

硒是一种人体必需的微量营养元素,其主要生物功能是通过硒蛋白实现。硒蛋白S （SELENOS）是一种主要存在于内质网膜的硒蛋白,参与了内质网相关蛋白降解过程。SELENOS主要是通过胞质中的卷曲螺旋结构域和C-端含硒代半胱氨酸残基的无规结构区发挥生物功能的。大量体外研究结果显示,SELENOS有调节氧化应激、内质网应激、炎症等功能,进而可能影响心血管疾病、2型糖尿病、阿尔茨海默症等疾病的发生发展。此外,流行病学观察研究发现SELENOS基因的多种单核苷酸多态性与心血管疾病、癌症等疾病密切相关。本文综述了SELENOS结构、功能及与疾病的关系,总结了SELENOS研究中尚待解决的问题,并对其未来的发展方向进行了展望。     

硒蛋白的抗氧化性研究与第21个氨基酸的发现

硒是人体必需的微量元素,以硒代半胱氨酸(Sec)的形式存在于蛋白质中作为硒酶的活性中心发挥作用,其生物功能主要是抗氧化。由于硒与人体健康具有十分密切的关系,所以硒蛋白的研究有着重要的理论和实际意义。本文以第一个硒蛋白细胞谷胱甘肽过氧化物酶为例,结合作者自己的工作,重点对该硒酶的结构、催化机制和模拟进行了综述,并就TGA编码Sec致第21个氨基酸的发现以及基于硒代半胱氨酸插入元件(SECIS)的特征寻找新硒蛋白的研究进展进行了介绍。     

硒蛋白M及其与重大疾病的关系

硒蛋白M(SelM)是2002年应用生物信息学方法发现的一种内质网硒蛋白,其二级结构中含有一个氧化还原调节基序CXXU,且该蛋白在脑中大量表达。SelM因具有维持机体氧化还原水平、保护神经细胞和调节钙稳态平衡等重要作用,近年成为研究热点。本文结合本课题组的研究结果,对硒蛋白M的最新研究进展、生物功能、与重大疾病的关系及今后研究方向等方面进行了综述和展望。     

内质网硒蛋白的研究进展

硒是哺乳动物必需的一种微量营养元素,主要以硒代半胱氨酸的形式存在于各种硒蛋白中,硒的主要生物功能通过硒蛋白实现.在25种哺乳动物硒蛋白中,有7种硒蛋白位于内质网,分别为2型脱碘酶、15-kDa硒蛋白、硒蛋白M、硒蛋白T、硒蛋白K、硒蛋白S和硒蛋白N.除了2型脱碘酶外,对其余内质网硒蛋白知之甚少.最近一些研究显示,一些内质网硒蛋白在氧化还原平衡调节、蛋白质折叠质量控制、错误折叠蛋白从内质网逆向转运至胞质、Ca2+稳态调节、内质网应激调节及炎症调节等过程中发挥作用.本文介绍了每种内质网硒蛋白的结构、功能及其生理和病理作用的一些最新研究进展,并对未来需要研究的内容进行了展望.     

生命的微量元素硒

硒是动物体必需的微量元素,对于硒的研究,古今中外积累了大量系统的资料,本文针对硒的营养、硒的代谢、硒的分子生物学与硒的补给方面作了综述,并对当前补硒现状谈了看法,仅供参考。     

蛋氨酸亚砜还原酶的结构特征及与神经退行性疾病的关系

蛋氨酸易被氧化为蛋氨酸亚砜,使生物体中氧化还原平衡失调,诱发各种疾病.蛋氨酸亚砜还原酶(Msrs)能将蛋氨酸亚砜还原成蛋氨酸,恢复蛋白的结构与功能,对调控多种氧化应激相关疾病具有重要作用.本文结合本课题组的研究结果,介绍了Msrs的分类进化、结构特征、催化机理和基因工程表达;综述了Msrs与衰老、帕金森病和阿尔茨海默病的关系,以探讨有关Msrs研究的发展方向和应用前景.     

硒蛋白与糖尿病——硒的两面性

糖尿病是危害人类健康的全球性重大疾病,胰岛素抵抗是诱发2型糖尿病的重要因素。微量必需元素硒与人体健康密切相关,通过硒蛋白发挥多种重要生物学功能。近年来硒与糖尿病的关系引人关注,早期研究表明硒具有类胰岛素作用,可望用于防治糖尿病,但近来的人群试验和动物研究却表明硒在糖尿病发生发展中的作用具有两面性,长期补充一定剂量的硒反而增加了胰岛素抵抗和2型糖尿病的发病率。而且,硒在糖尿病发生发展中的两面性被证实与几种硒蛋白密切相关,包括谷胱甘肽过氧化物酶1(GPx1)、硒蛋白S(SelS)和硒蛋白P(SelP)等。本文结合本课题组的工作介绍了硒在糖尿病中的两面性以及硒蛋白在糖尿病发生发展中的作用,并对未来的研究方向进行了展望。     

蛹虫草中硒的赋存形态及蛋白硒分析

为研究蛹虫草中硒的赋存形态,并进一步探究蛹虫草硒蛋白组分中硒含量的分布,以蛹虫草子实体为研究对象,用DAN荧光法测定了硒含量,用连续提取法进行了蛋白硒分析。结果表明,蛹虫草最高硒含量为89.486mg·kg-1,有机硒占85.96%;蛹虫草中蛋白硒、多糖硒和核酸硒分别占有机硒的71.4%~77.1%、19.7%~32.3%和0.138%~2.727%;在硒蛋白组分中虫草盐溶性蛋白、水溶性蛋白、醇溶性蛋白和碱溶性蛋白结合硒分别占总蛋白硒的55.13%~56.80%、20.47%~24.60%、15.30%~16.49%和2.99%~3.35%。蛹虫草具有很强的富硒能力;在蛹虫草子实体中,有机硒主要与蛋白质、多糖、核酸等生物大分子结合,其中蛋白质结合硒是硒的主要赋存形态;在蛋白质组分中,又以盐溶性蛋白质结合硒量最多。     

The Effects of Selenium on Bone Health: From Element to Therapeutics

Osteoporosis, characterized by low bone mass and a disruption of bone microarchitecture, is traditionally treated using drugs or lifestyle modifications. Recently, several preclinical and clinical studies have investigated the effects of selenium on bone health, although the results are controversial. Selenium, an important trace element, is required for selenoprotein synthesis and acts crucially for proper growth and skeletal development. However, the intake of an optimum amount of selenium is critical, as both selenium deficiency and toxicity are hazardous for health. In this review, we have systematically analyzed the existing literature in this field to determine whether dietary or serum selenium concentrations are associated with bone health. In addition, the mode of administration of selenium as a supplement for treating bone disease is important. We have also highlighted the importance of using green-synthesized selenium nanoparticles as therapeutics for bone disease. Novel nanobiotechnology will be a bridgehead for clinical applications of trace elements and natural products.     

Mechanisms Affecting the Biosynthesis and Incorporation Rate of Selenocysteine

Selenocysteine (Sec) is the 21st non-standard proteinogenic amino acid. Due to the particularity of the codon encoding Sec, the selenoprotein synthesis needs to be completed by unique mechanisms in specific biological systems. In this paper, the underlying mechanisms for the biosynthesis and incorporation of Sec into selenoprotein were comprehensively reviewed on five aspects: (i) the specific biosynthesis mechanism of Sec and the role of its internal influencing factors (SelA, SelB, SelC, SelD, SPS2 and PSTK); (ii) the elements (SECIS, PSL, SPUR and RF) on mRNA and their functional mechanisms; (iii) the specificity (either translation termination or translation into Sec) of UGA; (iv) the structure–activity relationship and action mechanism of SelA, SelB, SelC and SelD; and (v) the operating mechanism of two key enzyme systems for inorganic selenium source flow before Sec synthesis. Lastly, the size of the translation initiation interval, other action modes of SECIS and effects of REPS (Repetitive Extragenic Palindromic Sequences) that affect the incorporation efficiency of Sec was also discussed to provide scientific basis for the large-scale industrial fermentation for the production of selenoprotein.     

Studies on the reaction between reduced riboflavin and selenocystine

Selenocysteine (Sec) is a crucial component of mammalian thioredoxin reductase (TrxR) where it serves as a nucleophile for disulfide bond rupture in thioredoxin (Trx). Generation of the reduced state of Sec in TrxR requires consecutive two electron transfer steps, namely: (i) from NADPH to flavin adenine dinucleotide, (ii) from reduced flavin to the disulfide bond Cys⁵⁹‐S‐S‐Cys⁶⁴, and finally (iii) from Cys⁵⁹ and Cys⁶⁴ to the selenosulfide bond Cys⁴⁹⁷‐S‐Se‐Sec⁴⁹⁸. In this work, we studied the reaction between reduced riboflavin (RibH2) and selenocystine (Sec‐Sec), an oxidized form of Sec. The interaction between RibH2 and Sec‐Sec proceeded relatively slowly in comparison with its reverse reaction, that is, reduction of riboflavin (Rib) by Sec. The rate constant for the reaction between RibH2 and Sec‐Sec was (7.9 ± 0.1) × 10^?2 M^?1 s^?1 (pH 7.0, 25.0°C). The reaction between Rib and Sec proceeded via two steps, namely, a rapid reversible binding of Rib to Sec having a protonated selenol group to form a Sec‐Rib complex, followed by nucleophilic attack of Sec‐Rib by a second Sec molecule harboring a deprotonated selenol group. The equilibrium constant for the overall reduction process of Rib by Sec is (1.2 ± 0.1) × 10⁶ M^?1 (25.0°C). The finding that the interaction of RibH2 with oxidized selenol is reversible with its equilibrium favored toward the reverse reaction provides an additional explanation for the exceptional mechanism of the mammalian Trx/TrxR system involving transient reduction of a disulfide bond.     

Reassessment of an Innovative Insulin Analogue Excludes Protracted Action yet Highlights the Distinction between External and Internal Diselenide Bridges

Long-acting insulin analogues represent the most prescribed class of therapeutic proteins. An innovative design strategy was recently proposed: diselenide substitution of an external disulfide bridge. This approach exploited the distinctive physicochemical properties of selenocysteine (U). Relative to wild type (WT), Se-insulin[C7U^A, C7U^B] was reported to be protected from proteolysis by insulin-degrading enzyme (IDE), predicting prolonged activity. Because of this strategy's novelty and potential clinical importance, we sought to validate these findings and test their therapeutic utility in an animal model of diabetes mellitus. Surprisingly, the analogue did not exhibit enhanced stability, and its susceptibility to cleavage by either IDE or a canonical serine protease (glutamyl endopeptidase Glu-C) was similar to WT. Moreover, the analogue's pharmacodynamic profile in rats was not prolonged relative to a rapid-acting clinical analogue (insulin lispro). Although [C7U^A, C7U^B] does not confer protracted action, nonetheless its comparison to internal diselenide bridges promises to provide broad biophysical insight.     

硒与HIV感染的关系研究进展

HIV感染及AIDS至今依然严重威胁着人类的生命,因而成为医学界研究的热点。本文着重从硒与细胞因子角度揭示硒与HIV和AIDS在发生、发展中的关系,证明其扮演的重要角色,提示了一种研究HIV和AIDS的新方向。     

Modelling the Inhibition of Selenoproteins by Small Molecules Using Cysteine and Selenocysteine Derivatives

Small molecule-based electrophilic compounds such as 1-chloro-2,4-dinitrobenzene (CDNB) and 1-chloro-4-nitrobenzene (CNB) are currently being used as inhibitors of cysteine- and selenocysteine-containing proteins. CDNB has been used extensively to determine the activity of glutathione S-transferase and to deplete glutathione (GSH) in mammalian cells. Also, CDNB has been shown to irreversibly inhibit thioredoxin reductase (TrxR), a selenoenzyme that catalyses the reduction of thioredoxin (Trx). Mammalian TrxR has a C-terminal active site motif, Gly-Cys-Sec-Gly, and both the cysteine and selenocysteine residues could be the targets of the electrophilic reagents. In this paper we report on the stability of a series of cysteine and selenocysteine derivatives that can be considered as models for the selenoenzyme–inhibitor complexes. We show that these derivatives react with H₂O₂ to generate the corresponding selenoxides, which undergo spontaneous elimination to produce dehydroalanine. In contrast, the cysteine derivatives are stable towards such elimination reactions. We also demonstrate, for the first time, that the arylselenium species eliminated from the selenocysteine derivatives exhibit significant redox activity by catalysing the reduction of H₂O₂ in the presence of GSH (GPx (glutathione peroxidase)-like activity), which suggests that such redox modulatory activity of selenium compounds may have a significant effect on the cellular redox state during the inhibition of selenoproteins.     

红豆型营养保健(平衡)米硒的营养评分及防癌作用研究

用２,３－二氨基萘荧光法测得每１００ｇ红豆型营养平衡米和稻米中硒为０．０６０和０．００６９ｍｇ,并对平衡米,稻米及６种食物的硒作了营养评分（ＮＳＦ）,评得平衡米,稻米,黄豆,瘦肉、鲜牛奶、鸡蛋、草鱼、大白菜的晒营养评分值（ＮＳＦＶ）分别为６２０、４０、０．６、６、０．０２、４、０．４、０．２。发现平衡米ＮＳＦＶ比稻米等食品高,有显著差异（Ｐ〈０．０５）。又用平衡米和稻米分别与六种食物为儿童配膳并作     

Bioactivity-Directed Fractionation of Alkaloids from Some Amaryllidaceae Plants and Their Anticholinesterase Activity

Chloroform:methanol extracts of the bulbs of five Amaryllidaceae plants, namely Galanthus elwesii Hooker fil., G. Ikariae L., Narcissus tazetta subsp. tazetta L., Leucojum aestivum L., and Pancratium maritimum L. growing in Turkey, were evaluated for their anticholinesterase activity by the Ellman method in comparison with galanthamine as the standard drug. Bioactivity-directed fractionation and isolation studies carried out on G. ikariae and N. tazetta subsp. tazetta extracts afforded eight Amaryllidaceae-type alkaloids in total. We found that the activity of both plant extracts was due to the synergistic interaction of the alkaloids isolated.