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首页> 外文期刊>Chembiochem: A European journal of chemical biology >Beating Bias in the Directed Evolution of Proteins: Combining High‐Fidelity on‐Chip Solid‐Phase Gene Synthesis with Efficient Gene Assembly for Combinatorial Library Construction
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Beating Bias in the Directed Evolution of Proteins: Combining High‐Fidelity on‐Chip Solid‐Phase Gene Synthesis with Efficient Gene Assembly for Combinatorial Library Construction

机译：在蛋白质的定向演变中击败偏见：将高保真片上固相基因合成与有效基因组合组合，用于组合图书馆建设

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Abstract > Saturation mutagenesis (SM) constitutes a widely used technique in the directed evolution of selective enzymes as catalysts in organic chemistry and in the manipulation of metabolic paths and genomes, but the quality of the libraries is far from optimal due to the inherent amino acid bias. Herein, it is shown how this fundamental problem can be solved by applying high‐fidelity solid‐phase chemical gene synthesis on silicon chips followed by efficient gene assembly. Limonene epoxide hydrolase was chosen as the catalyst in the model desymmetrization of cyclohexene oxide with the stereoselective formation of ( R , R )‐ and ( S , S )‐cyclohexane‐1,2‐diol. A traditional combinatorial PCR‐based SM library, produced by simultaneous randomization at several residues by using a reduced amino acid alphabet, and the respective synthetic library were constructed and compared. Statistical analysis at the DNA level with massive sequencing demonstrates that, in the synthetic approach, 97?% of the theoretically possible DNA mutants are formed, whereas the traditional SM library contained only about 50?%. Screening at the protein level also showed the superiority of the synthetic library; many highly ( R , R )‐ and ( S , S )‐selective variants being discovered are not found in the traditional SM library. With the prices of synthetic genes decreasing, this approach may point the way to future directed evolution. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>摘要</标题> >饱和诱变（SM）构成了在催化剂的选择性酶的定向演变中的广泛使用的技术在有机化学和制服代谢路径和基因组中，但图书馆的质量远非由于固有的氨基酸偏压而最佳。在此，示出了如何通过在硅芯片上施加高保真固相化学基因合成，然后有效基因组装来解决这种根本问题。选择柠檬烯环氧化物水解酶作为催化剂，作为催化剂，在环己烯氧化物的模型脱水中，具有（ R r，<I> R r C） - 和（ S </ i> ， s </ i>）-cyclohexane-1,2-二醇。通过使用还原氨基酸字母表在几个残基同时随机化产生传统的组合PCR基SM库，并构建并进行比较各自的合成文库。具有大规模测序的DNA水平的统计分析表明，在合成方法中，形成了理论上可能的DNA突变体的97％，而传统的SM文库仅包含约50μm。筛选蛋白质水平也显示出合成文库的优越性;许多高度（ R </ i>， R </ i>） - 并且未发现所发现的 - 被发现的 - 选择性变体在传统的SM库中。随着合成基因的价格下降，这种方法可能指出未来定向演化的方式。 </ p> </ abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-16039/'>《Chembiochem: A European journal of chemical biology》</a> <b style="margin: 0 2px;">|</b><span>2018年第3期</span><b style="margin: 0 2px;">|</b><span>共8页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Li Aitao&option=202" target="_blank" rel="nofollow">Li Aitao;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Acevedo‐Rocha Carlos G.&option=202" target="_blank" rel="nofollow">Acevedo‐Rocha Carlos G.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Sun Zhoutong&option=202" target="_blank" rel="nofollow">Sun Zhoutong;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cox Tony&option=202" target="_blank" rel="nofollow">Cox Tony;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Xu Jia Lucy&option=202" target="_blank" rel="nofollow">Xu Jia Lucy;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Reetz Manfred T.&option=202" target="_blank" rel="nofollow">Reetz Manfred T.;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>Department of Synthetic Organic ChemistryMax-Planck-Institut für KohlenforschungKaiser-Wilhelm-Platz 1 45470 Muelheim Germany;</p> <p>Biosyntia ApS2100 Copenhagen Denmark;</p> <p>Tianjin Institute of Industrial BiotechnologyChinese Academy of Sciences32 West 7th Avenue Tianjin Airport Economic Area Tianjin 300308 P.R. China;</p> <p>Twist Bioscience455 Mission Bay Boulevard South San Francisco CA 94158 USA;</p> <p>Twist Bioscience455 Mission Bay Boulevard South San Francisco CA 94158 USA;</p> <p>Department of Synthetic Organic ChemistryMax-Planck-Institut für KohlenforschungKaiser-Wilhelm-Platz 1 45470 Muelheim Germany;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/179.html" title="分子生物学">分子生物学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=directed evolution&option=203" rel="nofollow">directed evolution;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=enzymes&option=203" rel="nofollow">enzymes;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=polymerase chain reaction&option=203" rel="nofollow">polymerase chain reaction;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=saturation mutagenesis&option=203" rel="nofollow">saturation mutagenesis;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=solid-phase synthesis&option=203" rel="nofollow">solid-phase synthesis;</a> </p> <div class="translation"> 机译：定向演化;酶;聚合酶链反应;饱和诱变;固相合成; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab 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</span> <span> . 2019-08-23</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130453453129.html">Novel substrate for solid phase combinatorial library generation, apparatus for preparing addressable portions thereof, and a method of preparing a library</a> <b>[P]</b> . <span> 外国专利： <!-- 英国专利： --> GB9726983D0 </span> <span> . 1998-02-18</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：用于固相组合文库生成的新型基质，用于制备其可寻址部分的设备以及制备文库的方法 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130454413991.html">Fusion protein Fusion protein The soluble composition of the host cell material Process to generate a neutralizing anti-toxin directed against Clostridium botulinum toxin type A antibody to purify a recombinant fusion protein derived from a Clostridium botulinum toxin type A process to generate an antitoxin neutralizing directed against clostridium difficile toxin type b antibody treatment process process to generate a neutralizing antitoxin directed against clostridium difficile type a toxin composition process to vaccinate an individual to produce neutralizing antitoxin directed against clostridium difficile toxin processing the detection of clostridium antigens difficile in an ample process of purification of toxins from clostridium difficile from a culture and process of generation of a solid dosage form of a bird antitoxin directed against a protein of clostridial toxin</a> <b>[P]</b> . <span> 外国专利： <!-- --> BR9509903A </span> <span> . 1997-11-25</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：融合蛋白融合蛋白宿主细胞材料的可溶性组成物产生针对A型肉毒梭菌毒素的中和抗毒素的过程纯化源自A型肉毒杆菌毒素的重组融合蛋白的抗体产生针对人肉毒杆菌的抗毒素的过程B型艰难梭菌毒素抗体处理工艺过程，产生针对A艰难梭菌毒素的中和抗毒素组合物，对个体进行疫苗接种，以生产针对艰难梭菌毒素的中和抗毒素，在充足的纯化纯化过程中检测艰难梭菌抗原来源于梭状芽胞杆菌毒素蛋白的鸟抗毒素固体剂型的培养物和固体剂型产生过程中的艰难梭菌毒素 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130419757151.html">METHODS OF GENERATING MODIFIED POLYNUCLEOTIDE LIBRARIES AND METHODS OF USING THE SAME FOR DIRECTED PROTEIN EVOLUTION</a> <b>[P]</b> . <span> 外国专利： <!-- 欧洲知识产权局专利： --> EP2526192A2 </span> <span> . 2012-11-28</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：生成修饰的多核苷酸肽库的方法和用于蛋白质直接进化的方法 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div 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