CN112752841B - 经修饰的甾醇酰基转移酶 - Google Patents
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Abstract
本发明涉及经修饰的甾醇酰基转移酶,所述经修饰的甾醇酰基转移酶具有朝向要在维生素D3的生物技术生产中使用的维生素D3前体7‑脱氢胆固醇(7‑DHC)的酰化的改善的活性和/或特异性。本发明还涉及一种表达所述经修饰的酶的酵母菌株,以及所述酵母菌株在用于产生维生素D3或其衍生物和/或代谢产物的方法中的用途。
Description
本发明涉及经修饰的甾醇酰基转移酶,所述经修饰的甾醇酰基转移酶具有朝向要在维生素D3的生物技术生产中使用的维生素D3前体7-脱氢胆固醇(7-DHC)的酰化的改善的活性和/或特异性。本发明还涉及一种表达所述经修饰的酶的酵母菌株,以及所述酵母菌株在用于产生维生素D3或其衍生物和/或代谢产物的方法中的用途。
维生素D3(也称为胆钙化醇或胆骨化醇)可以在哺乳动物皮肤中由前维生素D3(也称为7-脱氢胆固醇或7-DHC)合成,前维生素D3是在暴露于紫外光时胆固醇生物合成的产物,由此7-DHC被光化学转化为前维生素D3,前维生素D3在体温下异构化为生物活性形式维生素D3。在肝脏中,维生素D3转化为无生物活性的25-羟基维生素D3(也称为骨化二醇(calcidiol/calcifediol)、25-羟基胆钙化醇、25-OH-D3或HyD),这是维生素D3的主要循环形式。进一步的羟基化发生在肾脏中。
对于维生素D3的工业生产,(原则上)化学和生物技术合成两者都是可行的。化学合成开始于从例如羊毛脂中分离出胆固醇,然后将所述胆固醇脱氢成7-DHC,7-DHC是化学和生物技术合成两者中的重要中间体。通过暴露于紫外光和进一步的纯化/萃取步骤,将7-DHC转化为维生素D3。经修饰的酵母菌株可用于7-DHC的生物合成,其中乙酰辅酶A在多步酶促过程中转换为7-DHC。所述酶促转换发生在酵母的内质网中。细胞膜中不需要的过量的甾醇,包括7-DHC及其前体,过量的甾醇对酵母有毒并且因此作为甾醇酯存储在细胞内的细胞器(所谓的脂质体)中,它们可以从所述细胞器中进一步分离出。游离甾醇与脂质体中存储的甾醇(主要以甾醇酯形式)之间的平衡是通过几种蛋白质(酶)的作用,包括甾醇酰基转移酶的作用触发的。在酵母,特别是酿酒酵母(Saccharomyces cerevisiae)中,甾醇的酯形成主要由两种甾醇酰基转移酶Are1p和Are2p进行。
由于所述甾醇酰基转移酶的非特异性作用,存储在脂质体内的甾醇酯库是相对多样的,包括但不限于例如麦角甾醇、酵母甾醇、羊毛甾醇、烯胆甾烷醇、胆甾-5,7,24(25)-三烯醇、或7-DHC的酯。由于只有7-DHC的前体胆甾-5,7,24(25)-三烯醇,而不是酵母甾醇可用于维生素D3合成,因此需要将特定的酯(例如7-DHC的酯)选择性存储到脂质体中和/或需要增加由此类酵母菌株产生的7-DHC的中间体的周转,所述7-DHC的中间体被进一步转换为维生素D3和/或其衍生物或代谢物。同样也是本发明的焦点的特定代谢物是25-羟基维生素D3。
因此,持续性的任务是产生能够产生甾醇的宿主细胞(例如酵母),所述宿主细胞具有高7-DHC生产率/对7-DHC的特异性和/或减少的副产物/中间体(包括酵母甾醇、羊毛甾醇或烯胆甾烷醇),特别是存储在脂质体中的此类中间体的酯的积累。
令人惊讶地,我们现在发现,可经由在ARE2和/或ARE1的序列中引入某些氨基酸取代来使宿主细胞中甾醇酰基转移酶活性的特异性朝向7-DHC偏移,这将导致宿主细胞朝向作为维生素D3生产中的重要中间体的7-DHC的更高生产率和/或产物比率。
因此,本发明涉及具有甾醇酰基转移酶活性的经修饰的酶,即经修饰的甾醇酰基转移酶,特别是甾醇酰基转移酶同种型Are1p和/或Are2p的活性,所述经修饰的酶包含在与根据SEQ ID NO:1的多肽中的选自592和/或595位的残基对应的一个或多个位置处的一个或多个氨基酸取代,所述经修饰的酶具有相对于包括酵母甾醇在内的副产物/中间体增加的朝向7-DHC的特异性。
已经从酿酒酵母中分离出了显示ARE1活性的根据SEQ ID NO:1的多肽,包括编码此类根据SEQ ID NO:1的多肽的多核苷酸。已经从酿酒酵母中分离出了显示ARE2活性的根据SEQ ID NO:3的多肽,包括编码此类根据SEQ ID NO:3的多肽的多核苷酸。
术语“甾醇酰基转移酶”、“酰基转移酶”、“ARE”、“具有酰基转移酶活性的酶”或仅“酶”在本文中可互换使用,并且是指酶[EC2.3.1.26],即将脂肪酰基基团从一个分子转移至另一个分子的酰基转移酶。此类转移或酶促活性可以通过技术人员已知的手段来测量。已从不同来源,包括哺乳动物、酵母或植物分离出了甾醇酰基转移酶。ARE1和ARE2都能够将甾醇(例如酵母甾醇和/或7-DHC)酰化成相应的酯。在本文中,“经修饰的”酶,即经修饰的酰基转移酶,与例如酵母甾醇的酯化和/或包含例如7-DHC或酵母甾醇的总甾醇酯的改进形成相比,具有优选的朝向7-DHC的酯化的活性和/或特异性。优选的酰基转移酶同种型(isoform)是Are1p或Are2p。在本文中,“未修饰的”甾醇酰基转移酶,特别是ARE1和ARE2,是指不携带如本文所定义的一个或多个氨基酸取代的相应内源酶。
在本文中,携带如本文所定义的经修饰的甾醇酰基转移酶活性,特别是包含如本文所定义的一个或多个氨基酸取代的ARE2和/或ARE1的宿主细胞被称为“经修饰的”宿主细胞。携带未修饰的甾醇酰基转移酶活性,即编码野生型ARE1和/或ARE2基因的相应宿主细胞被称为“未修饰的”宿主细胞。
在本文中,指定维生素D3中间体的术语“酵母甾醇”、“羊毛甾醇”、“烯胆甾烷醇”、“胆甾-5,8,24(25)-三烯醇”、“胆甾-5,7,24(25)-三烯醇”或“7-DHC”包括所述化合物的游离形式和酯形式两者。在本文中,甾醇混合物包含7-DHC和“副产物”或中间体,包括但不限于酵母甾醇、羊毛甾醇、烯胆甾烷醇、胆甾-5,8,24(25)-三烯醇或胆甾-5,7,24(25)-三烯醇。
在本文中,“产生胆固醇的酵母”不再能够产生麦角甾醇,而是产生包括但不限于以下的胆固醇产物:胆甾-5,7,24(25)-三烯醇、胆甾-5,8,24(25)-三烯醇、胆甾-7,24(25)-二烯醇、7-DHC或酵母甾醇。具体地,这可以通过引入erg5erg6双敲除来实现。
在一个实施方式中,如本文所定义的经修饰的酶,特别是经修饰的ARE1活性,包含在与根据SEQ ID NO:1的多肽中的残基592对应的位置处的氨基酸取代,优选地由亮氨酸取代苯丙氨酸(F592L)。优选地,具有经修饰的ARE1活性的酶源自酵母属(Saccharomyces),例如酿酒酵母(S.cerevisiae)。与表达未修饰的内源ARE1的菌株相比,使用所述经修饰的ARE1酶时,甾醇混合物中7-DHC与酵母甾醇的比率可增加至少约15%。
在一个实施方式中,如本文所定义的经修饰的酶,特别是经修饰的ARE1活性,包含在与根据SEQ ID NO:1的多肽中的残基595对应的位置处的氨基酸取代,优选地由亮氨酸取代苯丙氨酸(G595D)。优选地,具有经修饰的ARE1活性的酶源自酵母属(Saccharomyces),例如酿酒酵母(S.cerevisiae)。与表达未修饰的内源ARE1的菌株相比,使用所述经修饰的ARE1酶时,甾醇混合物中7-DHC与酵母甾醇的比率可以增加多于一倍,即增加至少约55%。
在另一实施方式中,如本文所定义的经修饰的酶,特别是经修饰的ARE2活性,包含在与根据SEQ ID NO:3的多肽中的残基624对应的位置处的氨基酸取代,优选地由亮氨酸取代苯丙氨酸(F624L)。优选地,具有经修饰的ARE2活性的酶源自酵母属,例如酿酒酵母。与表达未修饰的内源ARE2的菌株相比,使用所述经修饰的ARE2酶时,甾醇混合物中7-DHC与酵母甾醇的比率可增加至少约15%。
在另一实施方式中,如本文所定义的经修饰的酶,特别是经修饰的ARE2活性,包含在与根据SEQ ID NO:3的多肽中的残基627对应的位置处的氨基酸取代,优选地由天冬氨酸取代甘氨酸(G627D)。优选地,具有经修饰的ARE2活性的酶源自酵母属,例如酿酒酵母。与表达未修饰的内源ARE2的菌株相比,使用所述经修饰的ARE2酶时,甾醇混合物中7-DHC与酵母甾醇的比率可增加至少约15%。
可以将与SEQ ID NO:1中的残基F592L和/或G595D对应的位置处的所述一个或多个氨基酸取代与如本文所定义的其他取代(即,如本文所述的与根据SEQ ID NO:3的多肽中的氨基酸残基624和/或627对应的一个或多个位置上的取代)进行组合。优选地,可以将与SEQ ID NO:1中的残基F592L对应的位置处的氨基酸取代与其他取代(例如在与SEQ ID NO:1中的G595D和/或SEQ ID NO:3中的F624L和/或SEQ ID NO:3中的G627D对应的一个或多个位置处的氨基酸取代)进行组合。优选的经修饰的酶是这样的酶,所述酶具有ARE1活性并且包含在与SEQ ID NO:1中的G595D对应的位置处的至少一个氨基酸取代,显示出在所述甾醇混合物中至少约30%、35%、40%、45%更高的7-DHC滴度,至少约15%、20%、25%、30%更少的酵母甾醇,其中所述甾醇混合物中的7-DHC的百分比为约70-76%。
在本文中,ARE1和/或ARE2的活性被修饰。这可以通过以下方式来实现:例如将一个或多个突变引入编码ARE1和/或ARE2的内源基因中,即,如本文所述的一个或多个位置上的氨基酸取代。技术人员知道如何遗传操纵酵母细胞,从而导致ARE1和/或ARE2活性的改变。这些遗传操纵包括但不限于例如使用质粒、病毒或其他载体进行基因置换、基因扩增、基因破坏、转染、转化。
可以以不同的方式来执行核酸或氨基酸中的突变产生,即诱变,诸如通过随机化或定点诱变,由诸如辐射等试剂引起物理损伤、化学处理,或插入遗传元件。技术人员知道如何引入突变。
本发明特别地涉及如本文所定义的此类经修饰的ARE1和/或ARE2酶在用于产生维生素D3的中间体7-DHC的方法中的用途。优选地,本发明的经修饰的酶被引入合适的宿主细胞和/或在合适的宿主细胞中表达,所述合适的宿主细胞为例如酵母,优选地产生甾醇的酵母,特别是产生胆固醇的酵母细胞,例如选自酿酒酵母、裂殖酵母属(Schizosaccharomycesspp.)、毕赤酵母属(Pichia spp.)、克鲁维酵母属(Klyuveromyces spp.)、汉逊酵母属(Hansenula spp.)或解脂耶氏酵母(Yarrowia lipolytica),优选地酿酒酵母。将经修饰的宿主用于生产7-DHC,所述7-DHC可以进一步转化为维生素D3和/或25-羟基维生素D3。
可以进一步修饰合适的宿主细胞,以进一步增加7-DHC的产量和/或减少副产物的积累,7-DHC是朝向维生素D3生物合成的重要中间体。
因此,在一个实施方式中,本发明涉及一种酵母菌株,所述酵母菌株具有改变的ARE1和/或ARE2活性,并且此外其中ERG5和ERG6被灭活。可以通过以下方式来进一步修饰酵母细胞:表达具有C24还原酶活性的异源酶,所述异源酶特别地选自EC 1.3.1.72,例如作用于胆甾-7,24-二烯醇、酵母甾醇或三烯醇(例如胆甾-5,7,25-三烯醇)的异源C24还原酶,优选地植物或脊椎动物甾醇Δ24还原酶,更优选地来自脊椎动物来源,甚至更优选地来自人、猪、狗、小鼠、大鼠、马、斑马鱼(Danio rerio)或任何已知来源,只要所述酶可以在所述酵母细胞内表达即可。最优选地,甾醇Δ24还原酶选自斑马鱼、大鼠或人。表达所述甾醇Δ24还原酶的序列是可公开可得的,包括但不限于UniProtKB/Swiss-Prot参考Q15392、Q60HC5、Q8VCH6、Q5BQE6、Q39085或P93472(参见例如WO2003064650)。使用此类酵母菌株时,存在于甾醇混合物中的7-DHC的百分比为基于甾醇的总量在约70%或更高的范围内,优选地例如75%、80%、88%、90%、95%、98%。
在另一个实施方式中,可以通过以下方式来进一步修饰根据本发明的宿主细胞:引入参与7-DHC的生物合成的内源酶的同源物,例如C5-甾醇去饱和酶(ERG3)和/或C8-甾醇异构酶(ERG2),导致对7-DHC的特异性和/或7-DHC生产率提高并且副产物或维生素D3中间体(包括但不限于酵母甾醇、羊毛甾醇和/或烯胆甾烷醇)的积累减少。优选地,如本文所定义的经修饰的宿主细胞包含异源ERG2和/或ERG3,其中ERG2优选地选自玉米黑粉菌(Ustilago maydis)(源自UniProtKB P32360的序列),和/或其中所述ERG3优选地选自巴斯德毕赤酵母(Pichia pastoris)(来源于UniProtKB C4QY87的序列)或粟酒裂殖酵母(Schizosaccharomyces pombe)(来源于UniProtKB O94457的序列)。包含ERG2和ERG3同源物两者以及如本文所定义的经修饰的ARE1和/或ARE2的菌株产生的甾醇混合物具有超过约80%的7-DHC百分比和增加了至少约15%至20%的7-DHC与胆甾-8-烯醇和/或烯胆甾烷醇的比率。甚至更优选的是如本文所定义的经修饰的菌株,所述经修饰的菌株还包含如上所述的ERG2和/或ERG3同源物的两个或更多个拷贝。
在一个特定的实施方式中,本发明涉及一种用于将宿主细胞改善为朝向7-DHC生产的方法,其中所述经修饰的宿主细胞如本文所定义,即经由在如本文所定义的甾醇酰基转移酶ARE1和/或ARE2中引入一个或多个氨基酸取代而被修饰,特别是产生胆固醇的酵母细胞,优选地其中ERG5和ERG6被灭活并且其中任选地表达具有如本文所定义的C-24还原酶活性的异源酶,和/或其中任选地表达内源性ERG2和/或ERG3的同源物的酵母细胞,其中所述宿主细胞被改进为使得由所述宿主细胞产生的甾醇总量中7-DHC的百分比从增加到约至少70%、75%、80%,优选地88%、90%、95%、98%,特别地其中与表达所述未修饰的,即野生型ARE1和/或ARE2活性的酵母菌株相比,7-DHC与包括酵母甾醇和胆甾-8-烯醇在内的副产物的比率增加了至少约5%、10%、15%、18%、20%、25%。
在本发明的一个方面中,将包含如本文所定义的经修饰的ARE1和/或ARE2活性的宿主细胞用于生产维生素D3前体7-DHC的方法中。经修饰的宿主细胞可以如技术人员关于相应产生胆固醇的宿主细胞所已知的那样在需氧或厌氧条件下在补充有适当营养物的水性培养基中培养。任选地,如本领域已知的,所述培养是在参与电子转移的蛋白质和/或辅因子存在下进行的。宿主细胞的培养/生长可以以分批、补料分批、半连续或连续模式进行。如本领域技术人员所已知的,取决于宿主细胞,优选地,维生素D3及其前体(例如7-DHC)的生产可以变化。维生素D3生产中7-DHC和其他中间体的培养和分离描述于例如WO2011067144或WO2017108799中。7-DHC可以从甾醇混合物中分离和/或任选地进一步纯化,并且可以使用本领域已知的方法进一步转换成维生素D3和/或25-羟基维生素D3。
使用如本文所述的宿主细胞,甾醇酰基转移酶活性的底物特异性可朝向7-DHC偏移,从而导致由所述宿主细胞所产生的总甾醇中7-DHC的百分比为至少约70%,其中在合适的培养条件下发酵约100小时后产生的7-DHC的滴度高达约10g/l或更大。
术语“ARE1”和“Are1p”、“ARE2”和“Are2p”、“ERG5”和“Erg5p”、“ERG6”和“Erg6p”在本文中可互换使用,并且是指由相应基因are1、are2、erg5和erg6编码的多肽。出于本发明的目的,产生胆固醇的酵母细胞被修饰为使得其确实显示出ARE1和/或ARE2的经修饰的活性,例如在内源性ARE1、ARE2或两者中携带修饰,从而导致ARE1和/或ARE2的经修饰的特异性,其中所述修饰是经由引入如本文所定义的一个或多个氨基酸取代而实现的。
编码ERG5、ERG6、ARE1、ARE2、ERG2、ERG3或甾醇Δ24还原酶(ERG4)的基因,如本文所用的酵母细胞的培养和遗传工程改造是已知的并且描述于例如US 7608421中。
在本文中,术语“C-24-还原酶”或“Δ24-还原酶”在本文中可互换地使用。在酵母中,该酶由erg4编码,并且对24位上的碳原子的甲基有活性。因此,在所述位置上不显示此类甲基的三烯醇不是酵母ERG4的可接受底物。
术语“C-8甾醇异构酶”、“Δ8,7-异构酶”或“具有C-8甾醇异构酶活性的酶”在本文中可互换地使用,并且是指能够催化胆甾-8-烯醇转换为胆甾-7-烯醇和/或酵母甾醇转换为胆甾-7,24-二烯醇的酶。在酵母中,该酶由erg2编码。要在根据本发明的经修饰的宿主细胞中使用的优选的ERG2同源物是与SEQ ID NO:5具有至少约41%,例如至少44%、45%、48%、49%、53%、56%、60%、70%、80%、90%、92%、95%、98%或至多100%同一性的多肽,所述多肽显示出C-8甾醇异构酶活性并且包含编码此类多肽的多核苷酸,可从玉米黑粉菌获得。特别地,在如本文所定义的经修饰的宿主细胞中表达所述ERG2同源物的1个或更多个拷贝,例如至少约1个、2个、3个、5个拷贝。
术语“C-5甾醇去饱和酶”、“具有C-5甾醇去饱和酶活性的酶”在本文中可互换使用,并且是指能够催化胆甾-8-烯醇转换为胆甾-7,24-二烯醇和/或胆甾-7-烯醇转换为胆甾-5,7,24-三烯醇和/或7-DHC的酶。在酵母中,该酶由erg3编码。要在根据本发明的经修饰的宿主细胞中使用的优选的ERG3同源物是与SEQ ID NO:7具有至少约45%,例如至少50%、52%、60%、70%、80%、90%、92%、95%、98%或至多100%的同一性的多肽,所述多肽显示出C-5甾醇去饱和酶活性并且包含编码此类多肽的多核苷酸,可从巴斯德毕赤酵母(Pichiapastoris)或粟酒裂殖酵母(Schizosaccharomyces pombe)获得。特别地,在如本文所定义的经修饰的宿主细胞中表达所述ERG3同源物的1个或更多个拷贝,例如至少1个、2个、3个、5个拷贝。
术语“序列同一性”、“%同一性”在本文中可互换使用。出于本发明的目的,在此限定,为了确定两个氨基酸序列或两个核酸序列的序列同一性百分比,对序列进行比对以实现最佳比较目的。为了优化两个序列之间的比对,可以在进行比较的两个序列中的任一序列中引入空位。此类比对可以在被比较的序列的全长上进行。或者,可以在较短的长度上进行比对,例如在约20个、约50个、约100个或更多个核苷酸/碱基或氨基酸上进行比对。序列同一性是两个序列之间在所报告的比对区域上相同匹配的百分比。可以使用用于两个序列的比对的Needleman和Wunsch算法来确定两个氨基酸序列之间或两个核苷酸序列之间的序列同一性百分比(Needleman,S.B.和Wunsch,C.D.(1970)J.Mol.Biol.48,443-453)。氨基酸序列和核苷酸序列都可以通过该算法来进行比对。已在计算机程序NEEDLE中实现了Needleman-Wunsch算法。出于本发明的目的,使用来自EMBOSS程序包的NEEDLE程序(2.8.0版或更高版本,EMBOSS:The European Molecular Biology Open Software Suite(2000)Rice,Longden和Bleasby,Trends in Genetics 16,(6),第276-277页,http://emboss.bioinformatics.nl/)。对于蛋白质序列,使用EBLOSUM62来用于取代矩阵。对于核苷酸序列,使用EDNAFULL。所使用的任选参数是为10的空位开放罚分和为0.5的空位延伸罚分。技术人员将理解,当使用不同的算法时,所有这些不同的参数将产生略微不同的结果,但是两个序列的总体同一性百分比不会显著改变。
如上所述通过程序NEEDLE进行比对后,查询序列与本发明序列之间的序列同一性百分比计算如下:比对中在两个序列中显示相同氨基酸或相同核苷酸的对应位置的数目除以减去比对中的空位总数后的比对总长度。如本文所限定的同一性可以通过使用NOBRIEF选项从NEEDLE获得,并在程序的输出中标记为“最长同一性”。如果所比较的两个氨基酸序列在它们的任何氨基酸上都没有差异,则它们是相同的或具有100%的同一性。关于本文所限定的源自植物的酶,技术人员知道事实上植物来源的酶可包含叶绿体靶向信号,所述叶绿体靶向信号将经由特定的酶(例如叶绿体加工酶(chloroplast processing enzyme,CPE))被切割。
如本文所定义的ARE2和ARE1酶/同源物还包括带有不改变酶活性的一个或多个氨基酸取代的酶,即所述酶相对于野生型酶显示出相同的性质并催化如本文所定义的甾醇的酰化。此类突变也称为“沉默突变”,其不改变如本文所述的酶的(酶促)活性。
在本文中,关于酶的术语“比活性”或“活性”是指其催化活性,即其催化从给定底物形成产物的能力。比活性定义了在给定时间段内和在限定温度下每限定量的蛋白质消耗的底物和/或产生的产物的量。通常,比活性表示为每mg蛋白质每分钟消耗的底物或形成的产物的μmol数。通常,μmol/min缩写为U(=Unit)。因此,在本文件全文中可互换地使用μmol/min/(mg蛋白质)或U/(mg蛋白质)的比活性单位定义。如果酶在体内(即在如本文所限定的宿主细胞内)或在合适的底物存在下的合适的(无细胞)系统内执行其催化活性,则所述酶是有活性的。技术人员知道如何测量酶活性,例如通过HPLC。
关于本发明,应当理解的是,生物(诸如微生物、真菌、藻类或植物)也包括具有相同生理性质的此类物种的同义词或基名(basonyms),如由国际原核生物命名法(International Code of Nomenclature of Prokaryotes)或关于藻类、真菌和植物的国际命名法(International Code of Nomenclature)(Melbourne法)所限定的。
特别地,本发明的特征在于以下实施方式:
(1)一种具有甾醇酰基转移酶活性的经修饰的酶,所述经修饰的酶包含在与根据SEQ ID NO:1的多肽中的选自592和/或595位的残基对应的一个或多个位置处的一个或多个氨基酸取代,优选地与F592L和/或G595D对应的取代。
(2)如本文所定义并且根据实施方式(1)所述的经修饰的酶,所述经修饰的酶催化包括7-脱氢胆固醇(7-DHC)和酵母甾醇在内的甾醇的酯化,其中与使用相应的未修饰酶的催化中的7-DHC与酵母甾醇的比率相比,所述甾醇酯中7-DHC与酵母甾醇的比率增加了至少约15%。
(3)如本文所定义并且根据实施方式(1)或(2)所述的经修饰的酶,其中所述氨基酸取代选自G595D。
(4)一种宿主细胞,优选地酵母,更优选地产生甾醇的酵母,甚至更优选地产生胆固醇的酵母,所述宿主细胞包含如本文所定义并且根据实施方式(1)、(2)、(3)所述的经修饰的酶。
(5)如本文所定义并且根据实施方式(4)所述的宿主细胞,所述宿主细胞用于产生包含7-DHC和酵母甾醇的甾醇混合物,其中与表达未修饰的酶的宿主细胞相比,7-DHC与酵母甾醇的比率增加了至少约15%。
(6)如本文所定义并且根据实施方式(4)或(5)所述的宿主细胞,其中ERG5和ERG6被灭活。
(7)如本文所定义并且根据实施方式(4)、(5)、(6)所述的宿主细胞,其中所述细胞表达选自具有甾醇Δ24还原酶活性的EC 1.3.1.72的异源酶,优选地其中所述异源酶源自植物或脊椎动物,更优选地源自人、猪、狗、小鼠、大鼠、马或斑马鱼。
(8)如本文所定义并且根据实施方式(4)、(5)、(6)、(7)所述的宿主细胞,其中所述宿主细胞选自由以下项组成的组:酵母属、裂殖酵母属、毕赤酵母属、克鲁维酵母属、汉逊酵母属和耶氏酵母属,优选地选自酿酒酵母、裂殖酵母属、毕赤酵母属、克鲁维酵母属、汉逊酵母属或解脂耶氏酵母。
(9)一种用于降低包含酵母甾醇和7-DHC的甾醇混合物中的酵母甾醇的百分比的方法,所述方法包括在合适的条件下培养如本文所定义并且根据实施方式(4)、(5)、(6)、(7)、(8)所述的所述的宿主细胞,以及任选地从所述甾醇混合物中分离和/或纯化所述7-DHC。
(10)一种用于提高包含7-DHC和酵母甾醇的甾醇混合物中7-DHC的百分比的方法,所述方法包括在合适的条件下培养如本文所定义并且根据实施方式(4)、(5)、(6)、(7)、(8)所述的宿主细胞,以及任选地从所述甾醇混合物中分离和/或纯化所述7-DHC。
(11)一种用于产生7-DHC的方法,所述方法包括使用如本文所定义并且根据实施方式(4)、(5)、(6)、(7)、(8)、(9)、(10)所述的宿主细胞将乙酰辅酶A酶促转换成包含酵母甾醇和7-DHC的甾醇混合物,其中所述甾醇混合物中7-DHC的百分比为至少约70%。
(12)如本文所定义并且根据实施方式(11)所述的方法,其中还将所述7-DHC转换成维生素D3。
(13)如本文所定义并且根据实施方式(11)或(12)所述的方法,其中将所述7-DHC进一步转换成25-羟基维生素D3。
(14)如本文所定义并且根据实施方式(1)、(2)、(3)所述的经修饰的酶或如本文所定义并且根据实施方式(4)、(5)、(6)、(7)、(8)、(9)、(10)所述的宿主细胞在用于产生7-DHC的方法中的用途,其中所述7-DHC是从包含酵母甾醇和7-DHC的甾醇混合物中分离出的,并且其中与分别使用相应的未修饰的酶和宿主细胞的方法相比,7-DHC与酵母甾醇的比率增加了至少约15%。
以下实施例仅是说明性的,并不意图以任何方式限制本发明的范围。
实施例
实施例1:通用方法、菌株和质粒
本文所述的所有基本分子生物学和DNA操纵程序通常是根据Sambrook等人(1989.Molecular Cloning:A Laboratory Manual.Cold Spring Harbor LaboratoryPress:New York)或Ausubel等人(1998.Current Protocols in MolecularBiology.Wiley:New York)执行的。表1和表2中列出了所用酿酒酵母菌株和质粒的基因型。从野生型CEN.PK背景菌株开始构建酿酒酵母7-DHC生产菌株Y2140。将erg5破坏盒转化到该野生型菌株中,所述erg5破坏盒含有经密码子优化的来自斑马鱼的甾醇24-还原酶的基因,所述基因侧接有PGK1启动子和CYC1终止子与TRP1的组合。随后,转化了erg6破坏盒,所述erg6破坏盒含有来自大鼠的甾醇24-还原酶的基因,所述基因侧接有TDH3启动子和PGK1终止子与LEU2的组合。所有提及的菌株均为MATα,并带有截短的组成型活性HMG-CoA还原酶基因(tHMG1)的过表达拷贝。
表1:酿酒酵母菌株。
表2:用于构建ARE突变的质粒。“Scer”是指酿酒酵母。
实施例2:ARE1-WT质粒pHyD459的构建
通过DNA2.0合成野生型酿酒酵母ARE1,在5'末端掺入XbaI位点(TCTAGAACAAAatg......)并在3'末端掺入PstI位点。将其使用独特的XbaI和PstI位点克隆到erg4Δ::HygR缺失质粒中。随后通过KpnI-AgeI克隆使用LEU2替换HygR部分。
实施例3:ARE1突变基因的克隆
通过以下方式生成酿酒酵母ARE1突变变体pMB7584(F592L):将由ARE1产生的经BsrGI-BsaI切割的PCR产物(根据SEQ ID NO:16和SEQ ID NO:17的寡核苷酸)与通过使SEQID NO:19和SEQ ID NO:20退火到经BsrGI-PstI切割的pHyD459中而得到的双链寡核苷酸连接。类似地,通过以下方式生成酿酒酵母ARE1突变变体pMB7585(G595D):将由ARE1产生的经BsrGI-BsaI切割的PCR产物(根据SEQ ID NO:16和SEQ ID NO:18的寡核苷酸)与通过使SEQID NO:21和SEQ ID NO:22退火到经BsrGI-PstI切割的pHyD459中而得到的双链寡核苷酸连接。序列表中列出了本文所用的寡核苷酸以及其他序列。
实施例3:将ARE1 WT基因和突变基因引入酿酒酵母中
为了测试突变ARE1基因与WT基因相比对7-DHC产生的影响,使用以下三种不同的构建体转化菌株Y2140:
(1)质粒pHyD459的SalI片段,其为在PGK1启动子和LEU2控制下的具有WT ARE1基因的erg4破坏构建体;
(2)质粒pMB7584的SalI片段,其为在PGK1启动子和LEU2控制下的具有are1 F592L基因的erg4破坏构建体;
(3)质粒pMB7585的SalI片段,其为在PGK1启动子和LEU2控制下的具有are1 G595D基因的erg4破坏构建体。
在(基本培养基)30℃下选择转化体,并筛选潮霉素敏感性。从这些转化得到的菌株在上表1中列出。随后如以下在实施例4中所述测定这些菌株的7-DHC生产率和总7-DHC甾醇纯度。
实施例4:ARE突变菌株中的甾醇的HPLC分析
首先将待测试的菌株接种到YPD琼脂上,并在30℃下孵育48小时。从这些板上接种两毫升YPD预培养物,并在30℃下在滚轮(roller wheel)上生长24小时。在24孔微量滴定板中,从预培养物中接种0.8mL的YPD+10g/L的乙醇,至最终OD600为0.5。使微量滴定板在潮湿环境中在30℃下生长,并在具有3mm轨道的摇床上以800rpm振荡。在接种后24小时和48小时,将16μl乙醇作为进料添加到每个孔中。在接种后72小时,对细胞取样以获得甾醇含量。
为了从培养物中提取甾醇,将80微升全发酵液吸移到带有玻璃珠粒的2mLPrecellys管中。加入八百微升的皂化溶液(5%KOH的乙醇溶液),并将样品放入Precellys24均化器中,并以6500rpm搅动3个循环,每个循环15秒。然后加入六十微升冰醋酸,并将试管以最高速度离心1分钟。通过HPLC测定上清液的甾醇含量(参见表3)。
表3:对照和ARE1和/或ARE2突变菌株中7-DHC与选定的甾醇中间体的比率。“Lano-/latho”是指羊毛甾醇和烯胆甾烷醇的混合物,“zym”是指酵母甾醇。数值以mg/ml甾醇计。
作为筛选各种酿酒酵母Are1突变体的结果,发明人发现了许多Are1变体,所述Are1变体当表达时以较高的总生产率、较少的甾醇副产物(酵母甾醇、烯胆甾烷醇、羊毛甾醇、胆甾-8-烯醇等)积聚或以这两种效果来产生7-DHC。
序列表
<110> 帝斯曼知识产权资产管理有限公司
<120> 经修饰的甾醇酰基转移酶
<130> 32957-WO-PCT
<160> 15
<170> PatentIn version 3.5
<210> 1
<211> 610
<212> PRT
<213> 酿酒酵母(Saccharomyces cerevisiae)
<400> 1
Met Thr Glu Thr Lys Asp Leu Leu Gln Asp Glu Glu Phe Leu Lys Ile
1 5 10 15
Arg Arg Leu Asn Ser Ala Glu Ala Asn Lys Arg His Ser Val Thr Tyr
20 25 30
Asp Asn Val Ile Leu Pro Gln Glu Ser Met Glu Val Ser Pro Arg Ser
35 40 45
Ser Thr Thr Ser Leu Val Glu Pro Val Glu Ser Thr Glu Gly Val Glu
50 55 60
Ser Thr Glu Ala Glu Arg Val Ala Gly Lys Gln Glu Gln Glu Glu Glu
65 70 75 80
Tyr Pro Val Asp Ala His Met Gln Lys Tyr Leu Ser His Leu Lys Ser
85 90 95
Lys Ser Arg Ser Arg Phe His Arg Lys Asp Ala Ser Lys Tyr Val Ser
100 105 110
Phe Phe Gly Asp Val Ser Phe Asp Pro Arg Pro Thr Leu Leu Asp Ser
115 120 125
Ala Ile Asn Val Pro Phe Gln Thr Thr Phe Lys Gly Pro Val Leu Glu
130 135 140
Lys Gln Leu Lys Asn Leu Gln Leu Thr Lys Thr Lys Thr Lys Ala Thr
145 150 155 160
Val Lys Thr Thr Val Lys Thr Thr Glu Lys Thr Asp Lys Ala Asp Ala
165 170 175
Pro Pro Gly Glu Lys Leu Glu Ser Asn Phe Ser Gly Ile Tyr Val Phe
180 185 190
Ala Trp Met Phe Leu Gly Trp Ile Ala Ile Arg Cys Cys Thr Asp Tyr
195 200 205
Tyr Ala Ser Tyr Gly Ser Ala Trp Asn Lys Leu Glu Ile Val Gln Tyr
210 215 220
Met Thr Thr Asp Leu Phe Thr Ile Ala Met Leu Asp Leu Ala Met Phe
225 230 235 240
Leu Cys Thr Phe Phe Val Val Phe Val His Trp Leu Val Lys Lys Arg
245 250 255
Ile Ile Asn Trp Lys Trp Thr Gly Phe Val Ala Val Ser Ile Phe Glu
260 265 270
Leu Ala Phe Ile Pro Val Thr Phe Pro Ile Tyr Val Tyr Tyr Phe Asp
275 280 285
Phe Asn Trp Val Thr Arg Ile Phe Leu Phe Leu His Ser Val Val Phe
290 295 300
Val Met Lys Ser His Ser Phe Ala Phe Tyr Asn Gly Tyr Leu Trp Asp
305 310 315 320
Ile Lys Gln Glu Leu Glu Tyr Ser Ser Lys Gln Leu Gln Lys Tyr Lys
325 330 335
Glu Ser Leu Ser Pro Glu Thr Arg Glu Ile Leu Gln Lys Ser Cys Asp
340 345 350
Phe Cys Leu Phe Glu Leu Asn Tyr Gln Thr Lys Asp Asn Asp Phe Pro
355 360 365
Asn Asn Ile Ser Cys Ser Asn Phe Phe Met Phe Cys Leu Phe Pro Val
370 375 380
Leu Val Tyr Gln Ile Asn Tyr Pro Arg Thr Ser Arg Ile Arg Trp Arg
385 390 395 400
Tyr Val Leu Glu Lys Val Cys Ala Ile Ile Gly Thr Ile Phe Leu Met
405 410 415
Met Val Thr Ala Gln Phe Phe Met His Pro Val Ala Met Arg Cys Ile
420 425 430
Gln Phe His Asn Thr Pro Thr Phe Gly Gly Trp Ile Pro Ala Thr Gln
435 440 445
Glu Trp Phe His Leu Leu Phe Asp Met Ile Pro Gly Phe Thr Val Leu
450 455 460
Tyr Met Leu Thr Phe Tyr Met Ile Trp Asp Ala Leu Leu Asn Cys Val
465 470 475 480
Ala Glu Leu Thr Arg Phe Ala Asp Arg Tyr Phe Tyr Gly Asp Trp Trp
485 490 495
Asn Cys Val Ser Phe Glu Glu Phe Ser Arg Ile Trp Asn Val Pro Val
500 505 510
His Lys Phe Leu Leu Arg His Val Tyr His Ser Ser Met Gly Ala Leu
515 520 525
His Leu Ser Lys Ser Gln Ala Thr Leu Phe Thr Phe Phe Leu Ser Ala
530 535 540
Val Phe His Glu Met Ala Met Phe Ala Ile Phe Arg Arg Val Arg Gly
545 550 555 560
Tyr Leu Phe Met Phe Gln Leu Ser Gln Phe Val Trp Thr Ala Leu Ser
565 570 575
Asn Thr Lys Phe Leu Arg Ala Arg Pro Gln Leu Ser Asn Val Val Phe
580 585 590
Ser Phe Gly Val Cys Ser Gly Pro Ser Ile Ile Met Thr Leu Tyr Leu
595 600 605
Thr Leu
610
<210> 2
<211> 1833
<212> DNA
<213> 酿酒酵母(Saccharomyces cerevisiae)
<400> 2
atgacggaga ctaaggattt gttgcaagac gaagagtttc ttaagatccg cagactcaat 60
tccgcagaag ccaacaaacg gcattcggtc acgtacgata acgtgatcct gccacaggag 120
tccatggagg tttcgccacg gtcgtctacc acgtcgctgg tggagccagt ggagtcgact 180
gaaggagtgg agtcgactga ggcggaacgt gtggcaggga agcaggagca ggaggaggag 240
taccctgtgg acgcccacat gcaaaagtac ctttcacacc tgaagagcaa gtctcggtcg 300
aggttccacc gaaaggatgc tagcaagtat gtgtcgtttt ttggggacgt gagttttgat 360
cctcgcccca cgctcctgga cagcgccatc aacgtgccct tccagacgac tttcaaaggt 420
ccggtgctgg agaaacagct caaaaattta cagttgacaa agaccaagac caaggccacg 480
gtgaagacta cggtgaagac tacggagaaa acggacaagg cagatgcccc cccaggagaa 540
aaactggagt cgaacttttc agggatctac gtgttcgcat ggatgttctt gggctggata 600
gccatcaggt gctgcacaga ttactatgcg tcgtacggca gtgcatggaa taagctggaa 660
atcgtgcagt acatgacaac ggacttgttc acgatcgcaa tgttggactt ggcaatgttc 720
ctgtgcactt tcttcgtggt tttcgtgcac tggctggtga aaaagcggat catcaactgg 780
aagtggactg ggttcgttgc agtgagcatc ttcgagttgg ctttcatccc cgtgacgttc 840
cccatttacg tctactactt tgatttcaac tgggtcacga gaatcttcct gttcctgcac 900
tccgtggtgt ttgttatgaa gagccactcg tttgcctttt acaacgggta tctttgggac 960
ataaagcagg aactcgagta ctcttccaaa cagttgcaaa aatacaagga atctttgtcc 1020
ccagagaccc gcgagattct gcaaaaaagt tgcgactttt gccttttcga attgaactac 1080
cagaccaagg ataacgactt ccccaacaac atcagttgca gcaatttctt catgttctgt 1140
ttgttccccg tcctcgtgta ccagatcaac tacccaagaa cgtcgcgcat cagatggagg 1200
tatgtgttgg agaaggtgtg cgccatcatt ggcaccatct tcctcatgat ggtcacggca 1260
cagttcttca tgcacccggt ggccatgcgc tgtatccagt tccacaacac gcccaccttc 1320
ggcggctgga tccccgccac gcaagagtgg ttccacctgc tcttcgacat gattccgggc 1380
ttcactgttc tgtacatgct cacgttttac atgatatggg acgctttatt gaattgcgtg 1440
gcggagttga ccaggtttgc ggacagatat ttctacggcg actggtggaa ttgcgtttcg 1500
tttgaagagt ttagcagaat ctggaacgtc cccgttcaca aatttttact aagacacgtg 1560
taccacagct ccatgggcgc attgcatttg agcaagagcc aagctacatt atttactttt 1620
ttcttgagtg ccgtgttcca cgaaatggcc atgttcgcca ttttcagaag ggttagagga 1680
tatctgttca tgttccaact gtcgcagttt gtgtggactg ctttgagcaa caccaagttt 1740
ctacgggcaa gaccgcagtt gtccaacgtt gtcttttcgt ttggtgtctg ttcagggccc 1800
agtatcatta tgacgttgta cctgacctta tga 1833
<210> 3
<211> 642
<212> PRT
<213> 酿酒酵母(Saccharomyces cerevisiae)
<400> 3
Met Asp Lys Lys Lys Asp Leu Leu Glu Asn Glu Gln Phe Leu Arg Ile
1 5 10 15
Gln Lys Leu Asn Ala Ala Asp Ala Gly Lys Arg Gln Ser Ile Thr Val
20 25 30
Asp Asp Glu Gly Glu Leu Tyr Gly Leu Asp Thr Ser Gly Asn Ser Pro
35 40 45
Ala Asn Glu His Thr Ala Thr Thr Ile Thr Gln Asn His Ser Val Val
50 55 60
Ala Ser Asn Gly Asp Val Ala Phe Ile Pro Gly Thr Ala Thr Glu Gly
65 70 75 80
Asn Thr Glu Ile Val Thr Glu Glu Val Ile Glu Thr Asp Asp Asn Met
85 90 95
Phe Lys Thr His Val Lys Thr Leu Ser Ser Lys Glu Lys Ala Arg Tyr
100 105 110
Arg Gln Gly Ser Ser Asn Phe Ile Ser Tyr Phe Asp Asp Met Ser Phe
115 120 125
Glu His Arg Pro Ser Ile Leu Asp Gly Ser Val Asn Glu Pro Phe Lys
130 135 140
Thr Lys Phe Val Gly Pro Thr Leu Glu Lys Glu Ile Arg Arg Arg Glu
145 150 155 160
Lys Glu Leu Met Ala Met Arg Lys Asn Leu His His Arg Lys Ser Ser
165 170 175
Pro Asp Ala Val Asp Ser Val Gly Lys Asn Asp Gly Ala Ala Pro Thr
180 185 190
Thr Val Pro Thr Ala Ala Thr Ser Glu Thr Val Val Thr Val Glu Thr
195 200 205
Thr Ile Ile Ser Ser Asn Phe Ser Gly Leu Tyr Val Ala Phe Trp Met
210 215 220
Ala Ile Ala Phe Gly Ala Val Lys Ala Leu Ile Asp Tyr Tyr Tyr Gln
225 230 235 240
His Asn Gly Ser Phe Lys Asp Ser Glu Ile Leu Lys Phe Met Thr Thr
245 250 255
Asn Leu Phe Thr Val Ala Ser Val Asp Leu Leu Met Tyr Leu Ser Thr
260 265 270
Tyr Phe Val Val Gly Ile Gln Tyr Leu Cys Lys Trp Gly Val Leu Lys
275 280 285
Trp Gly Thr Thr Gly Trp Ile Phe Thr Ser Ile Tyr Glu Phe Leu Phe
290 295 300
Val Ile Phe Tyr Met Tyr Leu Thr Glu Asn Ile Leu Lys Leu His Trp
305 310 315 320
Leu Ser Lys Ile Phe Leu Phe Leu His Ser Leu Val Leu Leu Met Lys
325 330 335
Met His Ser Phe Ala Phe Tyr Asn Gly Tyr Leu Trp Gly Ile Lys Glu
340 345 350
Glu Leu Gln Phe Ser Lys Ser Ala Leu Ala Lys Tyr Lys Asp Ser Ile
355 360 365
Asn Asp Pro Lys Val Ile Gly Ala Leu Glu Lys Ser Cys Glu Phe Cys
370 375 380
Ser Phe Glu Leu Ser Ser Gln Ser Leu Ser Asp Gln Thr Gln Lys Phe
385 390 395 400
Pro Asn Asn Ile Ser Ala Lys Ser Phe Phe Trp Phe Thr Met Phe Pro
405 410 415
Thr Leu Ile Tyr Gln Ile Glu Tyr Pro Arg Thr Lys Glu Ile Arg Trp
420 425 430
Ser Tyr Val Leu Glu Lys Ile Cys Ala Ile Phe Gly Thr Ile Phe Leu
435 440 445
Met Met Ile Asp Ala Gln Ile Leu Met Tyr Pro Val Ala Met Arg Ala
450 455 460
Leu Ala Val Arg Asn Ser Glu Trp Thr Gly Ile Leu Asp Arg Leu Leu
465 470 475 480
Lys Trp Val Gly Leu Leu Val Asp Ile Val Pro Gly Phe Ile Val Met
485 490 495
Tyr Ile Leu Asp Phe Tyr Leu Ile Trp Asp Ala Ile Leu Asn Cys Val
500 505 510
Ala Glu Leu Thr Arg Phe Gly Asp Arg Tyr Phe Tyr Gly Asp Trp Trp
515 520 525
Asn Cys Val Ser Trp Ala Asp Phe Ser Arg Ile Trp Asn Ile Pro Val
530 535 540
His Lys Phe Leu Leu Arg His Val Tyr His Ser Ser Met Ser Ser Phe
545 550 555 560
Lys Leu Asn Lys Ser Gln Ala Thr Leu Met Thr Phe Phe Leu Ser Ser
565 570 575
Val Val His Glu Leu Ala Met Tyr Val Ile Phe Lys Lys Leu Arg Phe
580 585 590
Tyr Leu Phe Phe Phe Gln Met Leu Gln Met Pro Leu Val Ala Leu Thr
595 600 605
Asn Thr Lys Phe Met Arg Asn Arg Thr Ile Ile Gly Asn Val Ile Phe
610 615 620
Trp Leu Gly Ile Cys Met Gly Pro Ser Val Met Cys Thr Leu Tyr Leu
625 630 635 640
Thr Phe
<210> 4
<211> 1929
<212> DNA
<213> 酿酒酵母(Saccharomyces cerevisiae)
<400> 4
atggacaaga agaaggatct actggagaac gaacaatttc tccgcatcca aaagctcaac 60
gctgccgatg cgggcaaaag acaatctata acagtggacg acgagggcga actatatggg 120
ttagacacct ccggcaactc accagccaat gaacacacag ctaccacaat tacacagaat 180
cacagcgtgg tggcctcaaa cggagacgtc gcattcatcc caggaactgc taccgaaggc 240
aatacagaga ttgtaactga agaagtgatt gagaccgatg ataacatgtt caagacccat 300
gtgaagactt taagctccaa agagaaggca cggtataggc aagggtcctc taactttata 360
tcgtatttcg atgatatgtc atttgaacac aggcccagta tattagatgg gtcagttaac 420
gagcccttca agaccaaatt cgtgggacct actttagaaa aggagatcag aagaagggag 480
aaagagctaa tggccatgcg caaaaattta caccaccgca agtcctcccc agatgctgtc 540
gactcagtag ggaaaaatga tggcgccgcc ccaactactg ttccaactgc cgccacctca 600
gaaacggtgg tcaccgttga aaccaccata atttcatcca atttctccgg gttgtacgtg 660
gcgttttgga tggctattgc atttggtgct gtcaaggctt taatagacta ttattaccag 720
cataatggta gcttcaagga ttcggagatc ttgaaattta tgactacgaa tttgttcact 780
gtggcatccg tagatctttt gatgtatttg agcacttatt ttgtcgttgg aatacaatac 840
ttatgcaagt ggggggtctt gaaatggggc actaccggct ggatcttcac ctcaatttac 900
gagtttttgt ttgttatctt ctacatgtat ttaacagaaa acatcctaaa actacactgg 960
ctgtccaaga tcttcctttt tttgcattct ttagttttat tgatgaaaat gcattctttc 1020
gccttctaca atggctatct atggggtata aaggaagaac tacaattttc caaaagcgct 1080
cttgccaaat acaaggattc tataaatgat ccaaaagtta ttggtgctct tgagaaaagc 1140
tgtgagtttt gtagttttga attgagctct cagtctttaa gcgaccaaac tcaaaaattc 1200
cccaacaata tcagtgcaaa aagctttttt tggttcacca tgtttccaac cctaatttac 1260
caaattgaat atccaagaac taaggaaatc agatggagct acgtattaga aaagatctgc 1320
gccatcttcg gtaccatttt cttaatgatg atagatgctc aaatcttgat gtatcctgta 1380
gcaatgagag cattggctgt gcgcaattct gaatggactg gtatattgga tagattattg 1440
aaatgggttg gattgctcgt tgatatcgtc ccagggttta tcgtgatgta catcttggac 1500
ttctatttga tttgggatgc cattttgaac tgtgtggctg aattgacaag atttggcgac 1560
agatatttct acggtgactg gtggaattgt gttagttggg cagacttcag tagaatttgg 1620
aacatcccag tgcataagtt tttgttaaga catgtttacc atagttcaat gagttcattc 1680
aaattgaaca agagtcaagc aactttgatg acctttttct taagttccgt cgttcatgaa 1740
ttagcaatgt acgttatctt caagaaattg aggttttact tgttcttctt ccaaatgctg 1800
caaatgccat tagtagcttt aacaaatact aaattcatga ggaacagaac cataatcgga 1860
aatgttattt tctggctcgg tatctgcatg ggaccaagtg tcatgtgtac gttgtacttg 1920
acattctaa 1929
<210> 5
<211> 241
<212> PRT
<213> 玉米黑粉菌(Ustilago maydis)
<400> 5
Met Ala Ser His Arg Pro Arg Ser Asn Lys Ala Ala Asn Gly Ala Ser
1 5 10 15
Thr Ser Pro Lys Arg Ser Trp Ile Ile Val Ser Ala Ala Leu Val Gly
20 25 30
Phe Cys Ala Leu Ile Ala Ala Leu Asp Ser Ile Arg Ser Ser Phe Tyr
35 40 45
Ile Phe Asp His Lys Ala Ile Tyr Lys Ile Ala Ser Thr Ala Val Ala
50 55 60
Asn His Pro Gly Asn Ala Thr Ala Ile Phe Asp Asp Val Leu Asp Asn
65 70 75 80
Leu Arg Ala Asp Pro Lys Leu Ala Pro Tyr Ile Asn Lys Asn His Phe
85 90 95
Ser Asp Glu Ser Glu Trp Met Phe Asn Asn Ala Gly Gly Ala Met Gly
100 105 110
Ser Met Phe Ile Ile His Ala Ser Val Thr Glu Tyr Leu Ile Phe Phe
115 120 125
Gly Thr Pro Val Gly Thr Glu Gly His Thr Gly Arg His Thr Ala Asp
130 135 140
Asp Tyr Phe Asn Ile Leu Thr Gly Asn Gln Tyr Ala Phe Pro Ala Gly
145 150 155 160
Ala Leu Lys Ala Glu His Tyr Pro Ala Gly Ser Val His His Leu Arg
165 170 175
Arg Gly Thr Val Lys Gln Tyr Met Met Pro Glu Asp Gly Cys Trp Ala
180 185 190
Leu Glu Leu Ala Gln Gly Trp Ile Pro Pro Met Leu Pro Phe Gly Leu
195 200 205
Ala Asp Val Leu Ser Ser Thr Leu Asp Leu Pro Thr Phe Gly Ile Thr
210 215 220
Val Trp Ile Thr Ala Arg Glu Met Val Gly Asn Leu Leu Ile Gly Lys
225 230 235 240
Phe
<210> 6
<211> 726
<212> DNA
<213> 玉米黑粉菌(Ustilago maydis)
<400> 6
atggcatcgc atagaccacg cagcaacaag gctgccaatg gtgcttcgac ttcacccaaa 60
cgcagctgga taattgtctc agctgcgctc gttggcttct gcgctctcat cgccgctctc 120
gattcgatcc gatccagctt ctacatcttt gaccacaagg caatctacaa gatcgcatcg 180
actgcggtcg ccaaccatcc aggcaatgcg acggccatct ttgatgatgt cctcgacaac 240
cttcgtgccg accccaagct cgcgccttac atcaacaaga atcatttcag cgacgagtca 300
gaatggatgt tcaacaatgc cggtggtgct atgggtagca tgttcatcat tcatgcttcc 360
gtcaccgagt acctgatctt ctttggcact cccgtcggaa ccgagggtca cactggtcgt 420
cacacagccg atgactactt caacatcctt accggtaacc aatacgcttt cccagctggt 480
gcgctcaagg cggagcacta ccctgccgga tcagtgcacc atcttcgccg cggaacggtc 540
aagcagtaca tgatgcctga agacggctgc tgggcgctcg agcttgctca gggctggatc 600
ccacccatgc ttccctttgg tctcgccgat gtgctcagct cgacgctcga cctgcccacc 660
tttggtatca ctgtctggat cactgcacga gaaatggttg gcaatctgct catcggcaag 720
ttttga 726
<210> 7
<211> 384
<212> PRT
<213> 巴斯德毕赤酵母(Pichia pastoris)
<400> 7
Met Asp Ile Ala Leu Glu Ile Leu Asp Thr Phe Val Phe Asp Lys Val
1 5 10 15
Tyr Ala Lys Leu Leu Pro Ile Ser Leu Val Gln His Leu Pro Asp Gly
20 25 30
Tyr Leu Lys Thr Leu Gly His Leu Thr Gly Ala Asn Asn Thr Met Glu
35 40 45
Ser Leu Phe Gly Ile Ala Pro Asn Val Asp Gln Ala Ser Lys Asn His
50 55 60
Trp Leu Arg Thr Val Asn Asp Ser Ile Ala Leu Ala Arg Pro Gly Glu
65 70 75 80
Arg Leu Val Tyr Gly Val Asn Ala Pro Leu His Phe Phe Asp Glu Thr
85 90 95
Ala Tyr Thr Tyr Ala Ser Ile Leu Gly Arg Ser Asn Ile Ile Arg Gln
100 105 110
Phe Thr Thr Leu Met Ile Leu Met Ile Leu Phe Gly Trp Gly Leu Tyr
115 120 125
Leu Ser Val Ala Ser Phe Ser Tyr Tyr Phe Val Phe Asp Lys Ala Ile
130 135 140
Phe Asn His Pro Arg Tyr Leu Lys Asn Gln Met Ser Leu Glu Ile His
145 150 155 160
Gln Ala Leu Thr Ala Ile Pro Thr Met Val Leu Leu Thr Val Pro Trp
165 170 175
Phe Leu Ile Glu Leu Arg Gly Tyr Ser Lys Leu Tyr Phe Asp Val Asn
180 185 190
Glu Ser Thr Gly Gly Trp Lys Ala Ile Ile Trp Gln Ile Pro Cys Phe
195 200 205
Ile Met Phe Thr Asp Cys Cys Ile Tyr Phe Ile His Arg Trp Leu His
210 215 220
Trp Pro Ser Val Tyr Lys Arg Leu His Lys Pro His His Lys Trp Ile
225 230 235 240
Val Cys Thr Pro Phe Ala Ser His Ala Phe His Pro Val Asp Gly Tyr
245 250 255
Ala Gln Ser Leu Pro Tyr His Leu Tyr Gly Met Leu Phe Pro Leu His
260 265 270
Lys Val Ser Tyr Leu Ile Leu Phe Gly Leu Val Asn Phe Trp Thr Val
275 280 285
Met Ile His Asp Gly Glu Tyr Leu Ser Arg Asp Pro Ile Val Asn Gly
290 295 300
Ala Ala Cys His Thr Val His His Leu Tyr Phe Asn Tyr Asn Tyr Gly
305 310 315 320
Gln Phe Thr Thr Leu Trp Asp Arg Leu Gly Gly Ser Tyr Arg Met Pro
325 330 335
Asp Lys Glu Leu Phe Asp Lys Asn Lys Lys Lys Asp Val Lys Thr Trp
340 345 350
Arg Ser Gln Val Lys Gln Ala Asp Ser Ile Arg Glu Asp Leu Glu Gly
355 360 365
Lys Glu Asp Phe Arg Glu Tyr Gly Thr Glu Glu Lys Leu Lys Ser Thr
370 375 380
<210> 8
<211> 1155
<212> DNA
<213> 巴斯德毕赤酵母(Pichia pastoris)
<400> 8
atggacattg ctttggagat tctagacact tttgtctttg acaaagtcta tgcaaaacta 60
ctgcccattt ctctggtgca acatttgcca gatggctatt tgaagacttt gggacatttg 120
actggtgcca acaacaccat ggaatcactg ttcggaatag ctccaaacgt tgaccaagcg 180
tctaagaacc actggctgag aacagtgaat gactctattg ccttagcccg tcccggtgag 240
cgtctggtct acggtgtcaa cgctccttta cacttttttg acgaaacagc gtatacatac 300
gcatcgatct tgggacgctc caatatcatt cgacaattca caactttgat gattctgatg 360
attctttttg gctggggttt gtatttatct gtggcttcat tttcatacta ctttgttttt 420
gataaagcca ttttcaatca cccaagatac ctcaaaaacc agatgtctct ggagatccat 480
caagcgttga ctgctatacc tacgatggtt ttgcttacag ttccatggtt tttgattgag 540
ttgcgtggat actctaaatt atactttgat gtaaatgagt ctactggagg atggaaggct 600
attatttggc aaattccttg cttcattatg tttaccgatt gttgtatcta ctttattcat 660
cgttggttgc actggccatc cgtgtataag cgtttgcaca agcctcacca caagtggatt 720
gtttgtacac cttttgctag tcatgccttc catccagttg atggttatgc acaatcacta 780
ccttaccatt tgtatggaat gttgtttcca ctacacaagg tgagctatct gatcttattt 840
gggcttgtga acttttggac tgttatgatc catgatggag aatacctgtc cagagaccct 900
atagtcaatg gagctgcttg tcatacagtg catcacctat acttcaacta caattacggc 960
cagttcacaa cactttggga ccgtcttggt ggatcataca gaatgccaga caaggaactc 1020
tttgataaga acaagaagaa agatgtaaag acatggcgtt cacaagtcaa gcaggccgat 1080
tcgataagag aagacttaga gggaaaagaa gatttccgtg agtatggaac tgaggaaaaa 1140
cttaaaagca catag 1155
<210> 9
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 9
tgttctgtac atgctcacgt tttac 25
<210> 10
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 10
cacacggtct cacaagacaa cgttggacaa ctgc 34
<210> 11
<211> 37
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 11
cacacggtct caatcaaacg aaaagacaac gttggac 37
<210> 12
<211> 66
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 12
cttgtcgttt ggtgtctgtt cagggcccag tatcattatg acgttgtacc tgaccttatg 60
actgca 66
<210> 13
<211> 58
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 13
gtcataaggt caggtacaac gtcataatga tactgggccc tgaacagaca ccaaacga 58
<210> 14
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 14
tgatgtctgt tcagggccca gtatcattat gacgttgtac ctgaccttat gactgca 57
<210> 15
<211> 49
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 15
gtcataaggt caggtacaac gtcataatga tactgggccc tgaacagac 49
Claims (14)
1. 一种具有甾醇酰基转移酶活性的经修饰的选自EC 2.3.1.26的酶,所述经修饰的选自EC 2.3.1.26的酶具有在根据SEQ ID NO:1的多肽中的选自592或595位的氨基酸取代,其中根据 SEQ ID NO:1 的多肽中的592位或在哺乳动物、酵母或植物甾醇酰基转移酶 1中相应位置处的氨基酸是亮氨酸,或根据 SEQ ID NO:1 的多肽中的595 位或在哺乳动物、酵母或植物甾醇酰基转移酶 1 中相应位置处的氨基酸是天冬氨酸。
2.根据权利要求1所述的经修饰的酶,所述经修饰的酶催化包括7-脱氢胆固醇7-DHC和酵母甾醇在内的甾醇的酯化,其中与使用相应的未修饰酶的催化中的7-DHC与酵母甾醇的比率相比,所述甾醇酯中7-DHC与酵母甾醇的比率增加了至少约15%。
3. 根据权利要求1或2所述的经修饰的酶,其中所述氨基酸取代选自F592L 或G595D。
4.一种产生甾醇的酵母细胞,所述酵母细胞包含根据权利要求1至3中任一项所述的经修饰的酶。
5.根据权利要求4所述的酵母细胞,所述酵母细胞用于产生包含7-DHC和酵母甾醇的甾醇混合物,其中与表达未修饰的酶的酵母细胞相比,7-DHC与酵母甾醇的比率增加了至少约15%。
6.根据权利要求4或5所述的酵母细胞,其中ERG5和ERG6被灭活。
7. 根据权利要求4或5所述的酵母细胞,其中所述细胞表达选自具有甾醇Δ24还原酶活性的EC 1.3.1.72的异源酶。
8.根据权利要求4或5所述的酵母细胞,其中所述酵母细胞选自由以下项组成的组:酵母属、裂殖酵母属、毕赤酵母属、克鲁维酵母属、汉逊酵母属和耶氏酵母属。
9.一种用于降低包含酵母甾醇和7-DHC的甾醇混合物中的酵母甾醇的百分比的方法,所述方法包括在合适的条件下培养根据权利要求4至8中任一项所述的酵母细胞。
10.一种用于提高包含7-DHC和酵母甾醇的甾醇混合物中7-DHC的百分比的方法,所述方法包括在合适的条件下培养根据权利要求4至8中任一项所述的酵母细胞,以及任选地从所述甾醇混合物中分离和/或纯化所述7-DHC。
11.一种用于产生7-DHC的方法,所述方法包括使用根据权利要求4至8中任一项所述的酵母细胞将乙酰辅酶A酶促转换成包含酵母甾醇和7-DHC的甾醇混合物,其中所述甾醇混合物中7-DHC的百分比为至少70%。
12.根据权利要求11所述的方法,其中还将所述7-DHC转换成维生素D3。
13.根据权利要求11或12所述的方法,其中将所述7-DHC进一步转换成25-羟基维生素D3。
14.根据权利要求1至3中任一项所述的经修饰的酶或根据权利要求4至8中任一项所述的酵母细胞在用于产生7-DHC的方法中的用途,其中所述7-DHC是从包含酵母甾醇和7-DHC的甾醇混合物中分离出的,并且其中与分别使用相应的未修饰的酶和酵母细胞的方法相比,7-DHC与酵母甾醇的比率增加了至少约15%。
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AU7092900A (en) | 1999-08-30 | 2001-03-26 | Monsanto Technology Llc | Plant sterol acyltransferases |
DE10203352A1 (de) | 2002-01-29 | 2003-07-31 | Basf Ag | Verfahren zur Herstellung von 7-Dehydrocholesterol und/oder dessen biosynthetischen Zwischen- und/oder Folgeprodukten in transgenen Organismen |
JP5697294B2 (ja) | 2003-12-24 | 2015-04-08 | デュポン ニュートリション バイオサイエンシーズ エーピーエス | 糖脂質アシル基転移酵素変異体及びその製造方法 |
PT2489731E (pt) | 2007-07-26 | 2014-09-15 | Amgen Inc | Enzimas aciltransferase de lecitina-colesterol modificadas |
JP2012024084A (ja) | 2010-06-25 | 2012-02-09 | Mitsubishi Chemicals Corp | 新規酵母およびそれを用いたδ5,7−ステロール及びハイドロコルチゾンの製造方法 |
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CN101052706A (zh) * | 2004-07-16 | 2007-10-10 | 代尔夫特技术大学 | 发酵木糖的真核细胞的代谢工程 |
CA2773030A1 (en) * | 2009-08-26 | 2011-03-03 | Organobalance Gmbh | Genetically modified organisms for the production of lipids |
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WO2011067144A1 (en) * | 2009-12-03 | 2011-06-09 | Dsm Ip Assets B.V. | Production of non-yeast sterols by yeast |
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WO2017108799A1 (en) * | 2015-12-23 | 2017-06-29 | Dsm Ip Assets B.V. | Production of sterols in modified yeast |
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