Clean Enzymatic Oxidation of 12α‐Hydroxysteroids to 12‐Oxo‐Derivatives Catalyzed by Hydroxysteroid Dehydrogenase

Tonin Fabio; Alvarenga Natália; Ye Jia Zheng; Arends Isabel W. C. E.; Hanefeld Ulf

摘要

Abstract > The C12 specific oxidation of hydroxysteroids is an essential reaction required for the preparation of pharmaceutical ingredients like ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA), which can be synthesized by Wolff‐Kishner reduction of the obtained 12‐oxo‐hydroxysteroids. 12α‐hydroxysteroid dehydrogenases (12α‐HSDHs) have been shown to perform this reaction with high yields, under mild conditions and without the need of protection and deprotection steps, required in chemical synthesis. Here, the recombinant expression and biochemical characterization of the nicotinamide adenine dinucleotide (NAD + )‐dependent HSDH from Eggerthella lenta ( El 12α‐HSDH) are reported. This enzyme shows comparable properties with the well‐known nicotinamide adenine dinucleotide phosphate (NADP + )‐dependent enzyme from Clostridium sp . 48–50. In order to perform a viable and atom efficient enzymatic hydroxysteroid oxidation, NAD(P)H oxidase (NOX) was employed as cofactor regeneration system: NOX uses oxygen (O <sub>2</sub> ) as sacrificial substrate and produces only water as side product. 10?mM of cholic acid was fully and selectively converted to 12‐oxo‐CDCA in 24?h. The possibility to employ this system on UCA and 7‐oxo‐deoxycholic acid (7‐oxo‐DCA) as substrates was additionally investigated. The performance of the El 12α‐HSDH was evaluated also in combination with a “classical” regeneration system (oxaloacetate/malate dehydrogenase) showing full conversion in 4?h. Finally, the feasibility of a catalytic aerobic‐NAD + ‐dependent enzymatic oxidation was shown on a preparative scale (oxidation of CA to 12‐oxo‐CDCA) employing the El 12α‐HSDH‐NOX system in a segmented‐flow‐reactor. > <blockFixed type="graphic"> <mediaResourceGroup> <mediaResource alt="image" href="urn:x-wiley:16154150:media:adsc201900144:adsc201900144-toc-0001"/> </mediaResourceGroup> </blockFixed> </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> > 羟类羟类氧化的C12特异性氧化是制备核发氧胆酸（UDCA）和ChenodeOxycholic酸（CDCA）等药物成分所需的基本反应，其可以通过所获得的12-氧代 - 羟类甾醇的Wolff-Kishner减少合成。已经显示12α-羟类脱氢酶（12α-HSDHS），以在温和条件下，在化学合成中不需要保护和脱保护步骤，在温和条件下进行该反应。这里，烟酰胺腺嘌呤二核苷酸的重组表达和生物化学表征（NAD + </ sup> ） - 依赖HSDH来自 eggerthella lenta </ i> （ el </ i> 报道了12α-HSDH）。该酶显示出与众所周知的烟酰胺腺嘌呤二核苷酸磷酸酯（NADP + </ sup> ） - 依赖酶来自 Clostridium sp </ i> 。 48-50。为了进行可行和原子的酶促酶促氧化氧化，使用NAD（P）H氧化酶（NOx）作为辅因子再生系统：NOx使用氧气（O. <sub> 2 </ sub> ）作为牺牲基材，仅生产作为副产品的水。完全且选择性地将10毫米胆酸在24μm中选择性地转化为12-氧代-CDCA。另外研究在UCA和7-氧代 - 脱氧胆酸（7-氧代DCA）上使用该系统作为基质的可能性。表现的 el </ i> 评估12α-HSDH，也与“经典”再生系统（草酰乙酸盐/苹果酸盐脱氢酶）组合，显示出4μl的全转化。最后，催化有氧-NAD的可行性 + </ sup> - 在制备尺度（Ca氧化至12-氧代-CDCA）上显示依赖性酶促氧化 el </ i> 12α-HSDH-NOx系统在分段 - 流量反应器中。 </ p> > <blockfixed type =“图形”> <mediaresourcegroup> <MediareSource Alt =“图像”Href =“URN：X-Wiley：16154150：媒体：ADSC201900144：ADSC201900144-TOC-0001”/> </ mediaresourcegroup> </ blockfixed> </ 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-19407/'>《Advanced synthesis & catalysis》</a> <b style="margin: 0 2px;">|</b><span>2019年第11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=Tonin Fabio&option=202" target="_blank" rel="nofollow">Tonin Fabio;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Alvarenga Natália&option=202" target="_blank" rel="nofollow">Alvarenga Natália;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Ye Jia Zheng&option=202" target="_blank" rel="nofollow">Ye Jia Zheng;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Arends Isabel W. C. E.&option=202" target="_blank" rel="nofollow">Arends Isabel W. C. E.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Hanefeld Ulf&option=202" target="_blank" rel="nofollow">Hanefeld Ulf;</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 BiotechnologyDelft University of TechnologyVan der Maasweg 9 2629 HZ Delft The Netherlands;</p> <p>Department of BiotechnologyDelft University of TechnologyVan der Maasweg 9 2629 HZ Delft The Netherlands;</p> <p>Department of BiotechnologyDelft University of TechnologyVan der Maasweg 9 2629 HZ Delft The Netherlands;</p> <p>Department of BiotechnologyDelft University of TechnologyVan der Maasweg 9 2629 HZ Delft The Netherlands;</p> <p>Department of BiotechnologyDelft University of TechnologyVan der Maasweg 9 2629 HZ Delft The Netherlands;</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/238.html" title="化学工业">化学工业;</a><a href="https://www.zhangqiaokeyan.com/clc/1186.html" title="物理化学（理论化学）、化学物理学">物理化学（理论化学）、化学物理学;</a><a href="https://www.zhangqiaokeyan.com/clc/7777.html" title="化学反应过程">化学反应过程;</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=Bile acids&option=203" rel="nofollow">Bile acids;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=NAD+-dependent&option=203" rel="nofollow">NAD+-dependent;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=12α-hydroxysteroid dehydrogenases&option=203" rel="nofollow">12α-hydroxysteroid dehydrogenases;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=NAD(P)H oxidase&option=203" rel="nofollow">NAD(P)H oxidase;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Flow-reactor&option=203" rel="nofollow">Flow-reactor;</a> </p> <div class="translation"> 机译：胆汁酸;NAD + - 依存;12α-羟类脱氢酶;NAD（P）H氧化酶;流量反应器; </div> </li> </ul> </div> </div> <div class="literature cardcommon" id="literaturereference" style="display:none"> <div class="similarity "> <h3 class="all_title" id="enpatent111">引文网络</h3> <div class="referencetab clearfix"> <ul id="referencedaohang"> <li dataid="referenceul">参考文献</li> <li dataid="citationul">引证文献</li> <li dataid="commonreferenceul">共引文献</li> <li dataid="commoncitationul">同被引文献</li> <li dataid="tworeferenceul">二级参考文献</li> <li dataid="twocitationul">二级引证文献</li> </ul> </div> <div class="reference_details" id="referenceList"> <ul id="referenceul"></ul> <ul id="citationul"></ul> <ul id="commonreferenceul"></ul> <ul id="commoncitationul"></ul> <ul id="tworeferenceul"></ul> <ul id="twocitationul"></ul> </div> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/journal-foreign-detail/0704022693671.html">Clean Enzymatic Oxidation of 12α‐Hydroxysteroids to 12‐Oxo‐Derivatives Catalyzed by Hydroxysteroid Dehydrogenase</a> <b>[J]</b> . <span> <a 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. 2013-01-09</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：通过还原羟基类固醇化合物或使用羟基类固醇脱氢酶氧化羟基类固醇化合物制备类固醇衍生物的方法 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130420261741.html">PROCESS FOR THE PREPARATION OF STEROID DERIVATIVES BY REDUCTION OF OXOSTEROID COMPOUNDS OR BY OXIDATION OF HYDROXYSTEROID COMPOUNDS USING A HYDROXYSTEROID DEHYDROGENASE</a> <b>[P]</b> . <span> 外国专利：  PL2004838T3 </span> <span> . 2012-11-30</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：通过还原氧甾类化合物或使用羟基甾体脱氢酶氧化羟基甾体化合物制备甾体衍生物的方法 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130422839617.html">PROCESS FOR THE PREPARATION OF STEROID DERIVATIVES BY REDUCTION OF OXOSTEROID 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