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生物正交化学反应正日益成为在活体内对生物大分子进行特异标记的一种有效方法. 最近涌现出的一个突出的例子是将金属钯催化的碳碳偶联反应这一在有机合成领域具有里程碑意义的反应拓展到生物大分子的标记上. 在活细胞上进行生物正交反应的一个先决条件是需要将参与这类反应的正交官能团特异地引入到目标生物大分子当中. 遗传密码子拓展技术是将多种生物正交活性基团引入到蛋白质当中的一种先进的手段; 最近发展出的基于吡咯赖氨酸氨酰合成酶和tRNA的体系能够将携带有生物正交官能团的非天然氨基酸有效地引入到原核生物、真核生物, 甚至是动物体内的蛋白质上. 在这一展望中, 我们首先介绍在生物正交反应和遗传密码子拓展这两个领域内的研究前沿与进展. 接着我们将讨论将这些新发展的研究工具, 尤其是基于钯催化的生物正交反应和基于吡咯赖氨酸氨酰合成酶的遗传密码子拓展技术, 应用于标记和修饰哺乳动物细胞蛋白质上的优势和诱人前景. 生物相兼容性更好的正交反应和更为灵活的非天然氨基酸引入技术必将有力地增强和拓宽人们在活细胞环境下特异操纵蛋白质的能力. 相似文献
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基于天然氨基酸的蛋白质修饰种类繁多,由于在不同的氨基酸上所进行的修饰会对蛋白质的结构和功能产生不同的影响,所以科学家们一直在探索基于天然氨基酸特异的蛋白质修饰策略。本文主要以半胱氨酸、酪氨酸和蛋白质氮端特异修饰为例,简要回顾目前基于天然氨基酸的蛋白质化学的相关工作。 相似文献
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多肽与蛋白质作为生物体内的活性物质和生命活动的物质基础,在信号传递、能量利用、免疫应答等基础生理过程发挥着至关重要的作用,并与多种疾病的发生密切相关。获得一定数量高纯度的多肽和蛋白质是研究其结构、生物学功能以及开发相关药物的重要前提。天然多肽与蛋白质的来源主要有动植物的组织器官、微生物的次级代谢产物等。目前,自然提取、重组技术和化学合成是多肽与蛋白质的主要获得途径。相较于从天然产物中提取分离和基因重组表达,化学合成能够方便地在多肽与蛋白质的任意位点引入非天然氨基酸或特定类型的翻译后修饰基团,如糖基化、磷酸化、荧光团及光交联反应基团等,极大地促进了多肽与蛋白质在基础医学及生物医药研究领域的应用发展。本综述全面介绍了多肽与蛋白质的各种化学合成研究策略,并讨论了这些策略的基本原理、优缺点及应用价值,旨在为多肽及蛋白质的合成研究提供参考。 相似文献
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蛋白质的位点特异性修饰近年来取得了重要进展. 本文对该领域新近发展的利用高张力烯烃或炔烃与四嗪类化合物的Diels-Alder生物正交反应, 通过基因编码的方式在蛋白质中位点特异性地插入其中一个组分, 从而实现蛋白质的快速荧光标记进行了介绍. 相似文献
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From amino acids to heteroaromatics--thiopeptide antibiotics, nature's heterocyclic peptides 总被引:1,自引:0,他引:1
Amino acids, the building blocks of proteins, also serve as precursors to a wide range of other naturally occurring substances including alkaloids, antibiotics, and, the subject of this Review, heterocyclic peptides. Simple alpha-amino acids are converted into complex arrays of heteroaromatic rings that display interesting and potent biological activity. The thiopeptide antibiotics, with their complex molecular architectures, are wonderful examples. In this Review we show how organic chemists have developed innovative methods for the synthesis of the heterocyclic ring systems, including routes inspired by the likely biosynthetic processes, and successfully assembled such building blocks into the final target molecule by application of orthogonal protecting groups and coupling methodologies. 相似文献
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Tushar Kanti Chakraborty Pothukanuri Srinivasu Subhasish Tapadar Bajjuri Krishna Mohan 《Journal of Chemical Sciences》2004,116(4):187-207
To meet the growing demands for the development of new molecular entities for discovering new drugs and materials, organic
chemists have started working on many new concepts that can help to assimilate knowledge-based structural diversities more
efficiently than ever before. Emulating the basic principles followed by Nature to build its vast repertoire of biomolecules,
organic chemists are developing many novel multifunctional building blocks and using them to create ‘nature-like’ and yet
unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl,
amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature’s
molecular arsenal. In recent years, sugar amino acids have been used extensively in the area of peptidomimetic studies. Advances
made in the area of combinatorial chemistry can provide the necessary technological support for rapid compilations of sugar
amino acidbased libraries exploiting the diversities of their carbohydrate frameworks and well-developed solid-phase peptide
synthesis methods. This perspective article chronicles some of the recent applications of various sugar amino acids, furan
amino acids, pyrrole amino acids etc. and many other related building blocks in wide-ranging peptidomimetic studies 相似文献
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Although chemists can synthesize virtually any small organic molecule, our ability to rationally manipulate the structures of proteins is quite limited, despite their involvement in virtually every life process. For most proteins, modifications are largely restricted to substitutions among the common 20 amino acids. Herein we describe recent advances that make it possible to add new building blocks to the genetic codes of both prokaryotic and eukaryotic organisms. Over 30 novel amino acids have been genetically encoded in response to unique triplet and quadruplet codons including fluorescent, photoreactive, and redox‐active amino acids, glycosylated amino acids, and amino acids with keto, azido, acetylenic, and heavy‐atom‐containing side chains. By removing the limitations imposed by the existing 20 amino acid code, it should be possible to generate proteins and perhaps entire organisms with new or enhanced properties. 相似文献
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Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides 总被引:1,自引:0,他引:1
Córdova A Zou W Dziedzic P Ibrahem I Reyes E Xu Y 《Chemistry (Weinheim an der Bergstrasse, Germany)》2006,12(20):5383-5397
In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed. 相似文献
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Dr. Ivana Drienovská Matúš Gajdoš Alexia Kindler Mahsa Takhtehchian Barbara Darnhofer Prof. Dr. Ruth Birner-Gruenberger Dr. Mark Dörr Prof. Uwe T. Bornscheuer Prof. Dr. Robert Kourist 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(54):12338-12342
Protein design is limited by the diversity of functional groups provided by the canonical protein „building blocks“. Incorporating noncanonical amino acids (ncAAs) into enzymes enables a dramatic expansion of their catalytic features. For this, quick identification of fully translated and correctly folded variants is decisive. Herein, we report the engineering of the enantioselectivity of an esterase utilizing several ncAAs. Key for the identification of active and soluble protein variants was the use of the split-GFP method, which is crucial as it allows simple determination of the expression levels of enzyme variants with ncAA incorporations by fluorescence. Several identified variants led to improved enantioselectivity or even inverted enantiopreference in the kinetic resolution of ethyl 3-phenylbutyrate. 相似文献
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The genetic code of cells is near-universally triplet, and since many ribosomal mutations are lethal, changing the cellular ribosome to read nontriplet codes is challenging. Herein we review work on the incorporation of unnatural amino acids into proteins in response to quadruplet codons, and the creation of an orthogonal translation system in the cell that uses an evolved orthogonal ribosome to efficiently direct the incorporation of unnatural amino acids in response to quadruplet codons. Using this system multiple distinct unnatural amino acids have been incorporated and used to genetically program emergent properties into recombinant proteins. Extension of approaches to incorporate multiple unnatural amino acids may allow the combinatorial biosynthesis of materials and therapeutics, and drive investigations into whether life with additional genetically encoded polymers can evolve to perform functions that natural biological systems cannot. 相似文献
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Nonproteinogenic Amino Acid Building Blocks for Nonribosomal Peptide and Hybrid Polyketide Scaffolds
Prof. Christopher T. Walsh Dr. Robert V. O'Brien Prof. Chaitan Khosla 《Angewandte Chemie (International ed. in English)》2013,52(28):7098-7124
Freestanding nonproteinogenic amino acids have long been recognized for their antimetabolite properties and tendency to be uncovered to reactive functionalities by the catalytic action of target enzymes. By installing them regiospecifically into biogenic peptides and proteins, it may be possible to usher a new era at the interface between small molecule and large molecule medicinal chemistry. Site‐selective protein functionalization offers uniquely attractive strategies for posttranslational modification of proteins. Last, but not least, many of the amino acids not selected by nature for protein incorporation offer rich architectural possibilities in the context of ribosomally derived polypeptides. This Review summarizes the biosynthetic routes to and metabolic logic for the major classes of the noncanonical amino acid building blocks that end up in both nonribosomal peptide frameworks and in hybrid nonribosomal peptide‐polyketide scaffolds. 相似文献
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Natural supramolecular assemblies exhibit unique structural and functional properties that have been optimized over the course of evolution. Inspired by these natural systems, various bio‐nanomaterials have been developed using peptides, proteins, and nucleic acids as components. Peptides are attractive building blocks because they enable the important domains of natural protein assemblies to be isolated and optimized while retaining the original structures and functions. Furthermore, the peptide subunits can be conjugated with exogenous molecules such as peptides, proteins, nucleic acids, and metal nanoparticles to generate advanced functions. In this personal account, we summarize recent progress in the construction of peptide‐based nanomaterial designed from natural supramolecular systems, including (1) artificial viral capsids, (2) self‐assembled nanofibers, and (3) protein‐binding motifs. The peptides inspired by nature should provide new design principles for bio‐nanomaterials. 相似文献
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Guang-Zong Tian Xiao-Li Wang Jing Hu Xue-Bin Wang Xiao-Qiang Guo Jian Yin 《中国化学快报》2015,26(8):922-930
In order to meet the increasing demands for the development of large varieties of new molecules for discovering new drugs and materials, organic chemists are developing many novel multifunctional building blocks, which are assembled rationally to create ‘nature-like' and yet unnatural organic molecules with well-defined structures and useful properties. Sugar amino acids(SAAs), the carbohydrate derivatives bearing both amino and carboxylic acid functional groups, are important ones of these multifunctional building blocks, which can be used to create novel materials with potential applications as glycomimetics and peptidomimetics. This review will focus on recent synthetic strategies of SAAs and their applications in creating large number of structurally diverse glycomimetics and peptidomimetics. 相似文献
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《Angewandte Chemie (International ed. in English)》2017,56(33):9680-9703
The goal of xenobiology is to design biological systems endowed with unusual biochemical functions, whereas enzymology concerns the study of enzymes, the workhorses of biocatalysis. Biocatalysis employs enzymes and organisms to perform useful biotransformations in synthetic chemistry and biotechnology. During the past few years, the effects of incorporating noncanonical amino acids (ncAAs) into enzymes with potential applications in biocatalysis have been increasingly investigated. In this Review, we provide an overview of the effects of new chemical functionalities that have been introduced into proteins to improve various facets of enzymatic catalysis. We also discuss future research avenues that will complement unnatural mutagenesis with standard protein engineering to produce novel and versatile biocatalysts with applications in synthetic organic chemistry and biotechnology. 相似文献