蛋白质的化学修饰与生化药物

综述了为解除异体蛋白质的免疫原性、延长循环半衰期而进行的蛋白质化学修饰的进展，同时展望了蛋白质化学修饰的生化药物开发的进展，并强调蛋白质的化学修饰是生化药物研究开发的重要手段之一。     

聚乙二醇——酶轭合物研究进展

<正> 用水溶性多聚物对酶蛋白进行化学修饰,改变酶分子的性质、探索解决药用酶中存在问题的途径是酶工程的研究方向之一。近年来得以广泛研究和利用的便是聚乙二醇(PEG)与酶的轭合物。PEG是无毒的线性分子,易于广泛收集从二聚体到分子量达10~6多聚体的不同组分,具有良好的生物相容性。美国FDA已批准 PEG用于药物(肠外、局部、栓剂、鼻喷雾剂)、食物和化妆品。酶经PEG化学修饰后改变了酶的理化性质,使之在有机溶剂中也呈现活性,增加了稳定性和体内半衰期,降低或消除了免疫原性;因PEG轭合而增加了酶的分子量,导致药代动力学性质的改变。酶经PEG化学修饰称为PEG-酶轭合物,作为药物和生物反应器的催化剂有巨大的实用意义。     

蛋白质和多肽类药物分子化学修饰的研究进展

目的蛋白质、多肽等药物分子免疫原性和毒副反应的存在及体内作用时间短等问题限制了其应用 ,这可以通过化学修饰部分或全部加以克服。随着生物大分子构效关系逐步得到揭示 ,生物大分子化学修饰的研究迅速发展。此文对蛋白质、多肽等药物分子化学修饰的国内外研究现状和发展动态加以评述 ,包括化学修饰原理、化学修饰方法、修饰后药物分子的应用等     

右旋糖苷及PEG—2对大肠杆菌L—天冬酰胺酶的化学修饰

本文综述了活化右旋糖苷和含有两条聚乙二醇链的ＰＥＧ－２对大肠杆菌Ｌ－天冬酰胺酶的化学修饰。修饰酶可保持５０％酶活，并且明显提高了抗胰蛋白酶及胰凝乳蛋白酶水解的能力，降低对特异的天冬酰胺酶抗体的敏感性，体内实验还表明修饰酶在动物体内循环持久性延长，使之更适于作为治疗药物。     

酶疗法的疑难问题和解决办法

酶是很好的治疗药物。只要极少量就能在生理 pH 及体温下迅速产生巨大的、非常专一的效应。至今已有许多应用。起初是蛋白水解酶和其他水解酶的局部应用或粗制品口服。后来用高纯度的酶治疗癌、凝血紊乱、遗传病、炎症、消化障碍、药物中毒和肾功不良。近十年来,已发展了许多技术来改进酶的治疗性质,如:1.可溶性化学修饰;2.不溶性化学修饰或固定在表面上;3.将酶包埋入生物可降解的或惰性物质的胶囊中。辅因     

酶工程与抗生素工业

酶工程是现代生物技术的重要组成部分,它作为一项高新技术将为各工业的发展起重要推动作用。介绍了酶固定化、基因工程菌（细胞）的固定化、植物细胞培养产酶、酶的化学修饰、核酸酶、抗体酶、酶标药物的理论和技术研究的最新进展以及酶工程在医药工业中的应用,对酶工程的发展前景进行了探讨。     

超氧化物歧化酶的化学修饰进展

超氧化物歧化酶是生物体内能清除超氧阴离子自由基的一类重要酶,具有重要的生理功能和广泛的应用前景。化学修饰的方法可以提高其稳定性,改善酶的药学性质。本文简要综述了超氧化物歧化酶活性部位酪氨酸,组氨酸的化学修饰;重点综述了生物活性物质,药用辅料,二酶缀合物对非活性部位的化学修饰,以及相关病理研究。评价了这些修饰反应的特点和结果 ,并对其研究前景进行了展望。     

肝靶向前体药物的研究进展

目前，乙型肝炎、肝癌等疾病之所以缺乏有效的治疗药物，除治疗药物本身的药理作用尚不够理想外，其主要原因就是不能将药物有效的运输至肝脏的病变部位，即肝靶向性差。为提高肝脏的药物浓度以及药物对某些肝脏疾病的疗效和降低毒副作用，国内、外学针对以肝脏为靶器官的给药系统进行了广泛研究，其中之一即运用前体药物原理提高药物的肝靶向性。前体药物（Prodrugs）简称前药，是活性药物经过化学修饰后得到的化合物，在体内通过酶的作用又转化为原来的药物而发挥药效，以利于药物的吸收、分布、代谢和排泄。     

蚯蚓纤溶酶的研究进展及趋势

综述了蚯蚓纤溶酶的理化性质、酶学性质、药效学特性、化学修饰及分子生物学等方面的研究进展 ,提出了蚯蚓纤溶酶研究领域的发展方向。     

酶工程专家——王树岐研究员

王树岐研究员是我国著名的酶工程专家，在我国最先从事酶化学修饰的研究，一直致力于生化技术的科研与教学工作，在生化制药等方面成就突出，为酶工程技术发展贡献了重要力量。     

Methodologies and strategies for the bioengineering of lantibiotics

Lantibiotics are ribosomally synthesized, post-translationally modified, peptide antibiotics containing unusual amino acids such as dehydrated amino acids and lanthionine. These unusual amino acids impose conformational constraints on the peptide and contribute to the biological activity and high physicochemical stability of lantibiotics. Recent researches on the modification enzymes responsible for dehydration and cyclization have considerably increased our understanding of their molecular characteristics and relaxed specificity. These insights enabled us to exploit these modification enzymes for developing new lantibiotic variants with improved therapeutic potential. Several methodologies have been explored to engineer novel lantibiotics. Here, we outline the current knowledge of modification enzymes. We also describe the methodologies and strategies used to engineer lantibiotics and provide some examples of successful generation of lantibiotics with enhanced activity.     

Chemical modification monitored by electrospray mass spectrometry: a rapid and simple method for identifying and studying functional residues in enzymes

A simple method to identify functional amino acids in enzymes is described. This method is based on the mass spectrometric detection of molecular weight changes as the consequence of chemical modification of enzymes with group-specific reagents. Here we report the use of phenylglyoxal, trinitrobenzene sulfonic acid, tetranitromethane and diethylpyrocarbonate to identify functional amino acid residues. Precise information is obtained about the stoichiometry of reaction, and a relationship between the loss of enzyme activity and the amount of chemical modification is easily established. Modification sites are located by proteolytic digestion of the modified enzyme, followed by peptide mapping based on high-pressure liquid chromatography using an electrospray mass spectrometer as an on-line detector. In comparison with more conventional methods, protein modification is monitored directly without the need to use radioactively or spectrally labelled reagents. The methodology is limited only by the stability of the chemically modified species produced. The method has been used to characterise the active sites of several shikimate pathway enzymes, and the results obtained have been confirmed by site-directed mutagenesis and X-ray crystallography.     

Aminoglycoside modifying enzymes

Aminoglycosides have been an essential component of the armamentarium in the treatment of life-threatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymatic modification is the most prevalent in the clinical setting. Aminoglycoside modifying enzymes catalyze the modification at different –OH or –NH₂ groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltranferases, phosphotransferases, or acetyltransferases. The number of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymatic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymatic action or of the expression of the modifying enzymes.     

Impacts of climate change on hypersaline conditions of estuaries and xenobiotic toxicity

Climate change has had significant impacts on the hydrologic cycle of the planet. Of particular concern are estuarine environments, such as San Francisco Bay (USA) which is fed by diminishing snow pack runoff leading to gradual increases in salinity. Salinity enhances the acute toxicity of several agricultural chemicals in anadromous fish through augmented biochemical activation catalyzed by enzymes that are induced during hypersaline acclimation. This review discusses the mechanisms of the enhanced toxicity, the enzymes involved and the regulation of the enzymes by hypersaline conditions. Given the rapid changes taking place in the world's waterways, environmental modification of toxicological pathways should be a significant focus of the research community as the toxicity of multiple xenobiotics may be enhanced.     

海地瓜蛋白酶解物类蛋白反应修饰及其对ACE活性的影响

目的研究海地瓜酶解物类蛋白反应修饰及其对ACE活性的影响。方法采用复合酶酶解海地瓜体壁蛋白,得到具有降血压活性的酶解物,利用类蛋白反应进行修饰,考察酶的种类、底物浓度、温度、酶添加量对类蛋白反应的影响,得到不同修饰程度的产物,测定其ACE抑制活性。结果与结论经过类蛋白反应修饰后,显著提高了酶解液的ACE抑制活性。体系中游离氨基的减少量呈不规则变化,修饰产物的IC50值也呈不规则下降,其中反应1h和4h的修饰产物IC50值最低,分别是0.62mg.mL-1和0.75mg.mL-1。分析体系中游离氨基酸的组成,发现脯氨酸的结合能显著提高海地瓜体壁蛋白酶解物的ACE抑制活性。     

Aminoglycoside-modifying enzymes: mechanisms of catalytic processes and inhibition.

The most prevalent mechanism for resistance to aminoglycoside antibiotics is mediated through their enzymatic modification in resistant organisms. Dozens of aminoglycoside-modifying enzymes are known at the gene sequence level, but few have been characterized in the details of their mechanism. This review summarizes the state of knowledge of the best studied of these enzymes, focusing on their catalytic mechanisms and inhibition.     

表观遗传修饰应用于真菌次级代谢调控研究的最新进展

真菌次级代谢产物的生物合成与其基因簇所在染色体的表观遗传状态密切相关,通过表观遗传修饰能够调控真菌的次级代谢过程.分子表观遗传修饰方法主要通过敲除或过表达表观遗传相关酶类的编码基因,而化学表观遗传修饰方法则是外源加入化学表观遗传修饰酶抑制剂.二者都能促进基因的转录,进而激活沉默的生物合成基因簇,提高真菌次级代谢产物的化...