Directed Evolution of a Tryptophan 2,3‐Dioxygenase for the Diastereoselective Monooxygenation of Tryptophans

Wei Yanxin; Lu Chen; Jiang Shengsheng; Zhang Yanyan; Li Qiuchun; Bai Wen‐Ju; Wang Xiqing

摘要

Abstract > Herein, we report an engineered enzyme that can monooxygenate unprotected tryptophan into the corresponding 3a‐hydroxyhexahydropyrrolo[2,3‐b]indole‐2‐carboxylic acid (HPIC) in a single, scalable step with excellent turnover number and diastereoselectivity. Taking advantage of directed evolution, we analyzed the stepwise oxygen‐insertion mechanism of tryptophan 2,3‐dioxygenases, and transformed tryptophan 2,3‐dioxygenase from Xanthomonas campestris into a monooxygenase for oxidative cyclization of tryptophans. It was revealed that residue F51 is vital in determining the product ratio of HPIC to N ′‐formylkynurenine. Our reactions and purification procedures use no organic solvents, resulting in an eco‐friendly method to prepare HPICs for further applications. </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”>抽象</ title> > 在此，我们报告了一种工程化酶，其在单个可扩展的步骤中，可以将不受保护的色氨酸单氧化成相应的3A-羟基吡咯醇[2,3-B]吲哚-2-羧酸（HPIC），其具有优异的周转数和非对映选择性。利用定向的进化，我们分析了色氨酸2,3-二氧基酶的逐步氧气插入机制，并将色氨酸2,3-二氧化根酶从Xanthomonas Chamrestris转化为单氧基酶，用于氧化色氨酸的环化。据透露，残留物F51对于确定HPIC的产品比至至关重要 n </ i> '-formylkynurenine。我们的反应和纯化程序使用没有有机溶剂，导致一种生态友好型方法，用于制备进一步应用的HPIC。 </ p> </摘要> </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-19011/'>《Angewandte Chemie》</a> <b style="margin: 0 2px;">|</b><span>2020年第8期</span><b style="margin: 0 2px;">|</b><span>共5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=Wei Yanxin&option=202" target="_blank" rel="nofollow">Wei Yanxin;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Lu Chen&option=202" target="_blank" rel="nofollow">Lu Chen;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Jiang Shengsheng&option=202" target="_blank" rel="nofollow">Jiang Shengsheng;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Zhang Yanyan&option=202" target="_blank" rel="nofollow">Zhang Yanyan;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Li Qiuchun&option=202" target="_blank" rel="nofollow">Li Qiuchun;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Bai Wen‐Ju&option=202" target="_blank" rel="nofollow">Bai Wen‐Ju;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Wang Xiqing&option=202" target="_blank" rel="nofollow">Wang Xiqing;</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>College of Bioscience and BiotechnologyYangzhou UniversityYangzhou Jiangsu 225009 China;</p> <p>College of Bioscience and BiotechnologyYangzhou UniversityYangzhou Jiangsu 225009 China;</p> <p>College of Bioscience and BiotechnologyYangzhou UniversityYangzhou Jiangsu 225009 China;</p> <p>Testing CenterYangzhou UniversityYangzhou Jiangsu 225009 China;</p> <p>College of Bioscience and BiotechnologyYangzhou UniversityYangzhou Jiangsu 225009 China;</p> <p>Department of ChemistryStanford UniversityStanford California 94305 USA;</p> <p>College of Bioscience and BiotechnologyYangzhou UniversityYangzhou Jiangsu 225009 China;</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/1188.html" title="应用化学">应用化学;</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=monooxygenation&option=203" rel="nofollow">monooxygenation;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=natural products&option=203" rel="nofollow">natural products;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=protein engineering&option=203" rel="nofollow">protein engineering;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=tryptophan 2&option=203" rel="nofollow">tryptophan 2;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=3-dioxygenase&option=203" rel="nofollow">3-dioxygenase;</a> </p> <div class="translation"> 机译：定向演化;单氧化;天然产品;蛋白质工程;色氨酸2;3-二氧化根酶; 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<a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=孔泳&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,孔泳</a> <span> <a href="/journal-cn-7555/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 常州大学学报（自然科学版） </a> </span> <span> . 2019</span><span>,第006期</span> </span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/academic-journal-cn_journal-changzhou-university-natural-science-edition_thesis/0201281483732.html">功能性二氧化硅微球的制备及对色氨酸对映体的高效拆分研究</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=吴大同&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 吴大同</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=孔泳&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,孔泳</a> <span> <a href="/journal-cn-21774/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 常州大学学报：自然科学版 </a> </span> <span> . 2019</span><span>,第006期</span> </span> </div> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/academic-journal-cn_china-medical-herald_thesis/0201252767640.html">酪氨酸3-加单氧酶/色氨酸5-加单氧酶激活蛋白的新研究进展</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=曾媛媛&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 曾媛媛</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=魏丽&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,魏丽</a> <span> <a href="/journal-cn-6686/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 中国医药导报 </a> </span> <span> . 2016</span><span>,第009期</span> </span> </div> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/academic-journal-cn_progress-physiological-sciences_thesis/0201288779174.html">色氨酸2,3-双加氧酶调控炎症免疫反应在疾病中的作用</a> <b>[J]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=李素素&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 李素素</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=常艳&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,常艳</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=魏伟&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,魏伟</a> <span> <a href="/journal-cn-5773/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 生理科学进展 </a> </span> <span> . 2021</span><span>,第001期</span> </span> </div> </li> <li> <div> <b>6. </b><a class="enjiyixqcontent" href="/academic-conference-cn_meeting-6796_thesis/020221757110.html">色氨酸-2,3-加双氧酶(TD02)的异源表达及酶活测定</a> <b>[C]</b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=周峰&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 周峰</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=王磊&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,王磊</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=胡昌华&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor">,胡昌华</a> <span> <a href="/conference-cn-6796/" target="_blank" rel="nofollow" class="tuijian_authcolor"> . 2012年第五届全国微生物遗传学学术研讨会 </a> <span> <span> . 2012</span> </span> </div> </li> <li> <div> <b>7. </b><a class="enjiyixqcontent" href="/academic-degree-domestic_mphd_thesis/020315812811.html">色氨酸2,3--双加氧酶对色氨酸及类似物单加氧反应的定向进化</a> <b>[A] </b> <span> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=魏研欣&option=202" target="_blank" rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 魏研欣</a> <span> . 2020</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120100977176.html">作为吲哚胺2,3-二加氧酶和/或色氨酸2,3-二加氧酶选择性抑制剂的新颖的5或8-取代的咪唑并1,5-a吡啶</a> <b>[P]</b> . <span> 中国专利： CN109952300A </span> <span> . 2019-06-28</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/061203351324.html">树杈状分子印迹二氧化硅修饰氧化铟锡电极应用于电化学识别色氨酸对映体</a> <b>[P]</b> . <span> 中国专利： CN107238644B </span> <span> . 2019.06.04</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130403312183.html">Inhibitors of Tryptophan 2,3-dioxygenase (Tryptophan 2,3-dioxygenase)</a> <b>[P]</b> . <span> 外国专利：  KR20190027877A </span> <span> . 2019-03-15</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：色氨酸2，3-二加氧酶的抑制剂（色氨酸2，3-二加氧酶） </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130412214978.html">Heterocyclic compounds Regulators of indoleamine 2,3-dioxygenase 1 and / or indoleamine 2,3-dioxygenase - 2 and / or tryptophan 2,3-dioxygenase, Intermediate Compound, Pharmaceutical composition, useful in the treatment of cancer, viral and bacterial infections, autoimmune disorders, Diseases Des inflammatory.</a> <b>[P]</b> . <span> 外国专利：  CL2015002556A1 </span> <span> . 2016-04-08</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：杂环化合物吲哚胺2，3-二加氧酶1和/或吲哚胺2，3-二加氧酶2和/或色氨酸2，3-二加氧酶的调节剂，中间体化合物，药物组合物，可用于治疗癌症，病毒和细菌感染，自身免疫性疾病，炎性疾病。 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130500184999.html">NOVEL SUBSTITUTED 1,3,8-TRIAZASPIRO4,5DECANE-2,4-DIONE COMPOUNDS AS INDOLEAMINE 2,3-DIOXYGENASE (IDO) AND/OR TRYPTOPHAN 2,3-DIOXYGENASE (TDO) INHIBITORS</a> <b>[P]</b> . <span> 外国专利：  WO2021126725A1 </span> <span> . 2021-06-24</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：新型取代的1,3,8-三氮杂物[4,5]癸烷-2,4-二酮化合物作为吲哚胺2,3-二氧合酶（IDO）和/或色氨酸2,3-二氧化根酶（TDO）抑制剂 </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 class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704028160989','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> <h2>期刊订阅</h2> <img src="https://cdn.zhangqiaokeyan.com/img/loginclose.png" alt="关闭" onclick="$('.journalsub-pop-up').hide()"> <p class="pardon">抱歉，该期刊暂不可订阅，敬请期待！</p> <p class="current">目前支持订阅全部北京大学中文核心（2020）期刊目录。</p> <div style="display: flex;margin-top: 69px;justify-content: 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