CN107429238A - 来自番茄的udp‑糖基转移酶 - Google Patents
来自番茄的udp‑糖基转移酶 Download PDFInfo
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- CN107429238A CN107429238A CN201680017446.2A CN201680017446A CN107429238A CN 107429238 A CN107429238 A CN 107429238A CN 201680017446 A CN201680017446 A CN 201680017446A CN 107429238 A CN107429238 A CN 107429238A
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- leu
- polypeptide
- diterpene
- glycosylation
- glu
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Abstract
本发明涉及具有来源于番茄(Solanum lycopersicum)的UDP‑糖基转移酶活性并且具有SEQ ID NO:1至4中任一项所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列的多肽。本申请还涉及包含编码所述多肽的重组核酸序列的重组宿主及其用于制备糖基化二萜如甜菊醇糖苷的用途。宿主细胞可包含甜菊醇糖苷生物合成途径的另外的酶。
Description
发明领域
本发明涉及一种重组宿主,其包含编码UDP-糖基转移酶(UGT)多肽的重组核酸序列。本发明还涉及一种使用这种重组宿主制备糖基化二萜的方法,并且涉及一种可得自这种方法的发酵液。本发明还涉及一种通过这种方法获得或可从这种发酵液获得的糖基化二萜,并且涉及一种包含两种或更多种此类糖基化二萜的组合物。此外,本发明涉及一种包含这种糖基化二萜或这种组合物的食品、饲料或饮料。本发明还涉及一种使用上述重组宿主将第一糖基化二萜转化为第二糖基化二萜的方法。
发明背景
多年生草本植物甜叶菊(Stevia rebaudiana Bert.)的叶子积聚大量被称为甜菊醇糖苷的具有强烈甜味的化合物。虽然这些化合物的生物功能尚不清楚,但它们作为替代性高效甜味剂具有商业意义。
这些甜的甜菊醇糖苷的功能和感官特性表现为优于许多高效甜味剂的功能和感官特性。此外,研究表明甜菊苷能够降低II型糖尿病患者的血糖水平,并且能够降低轻度高血压患者的血压。
甜菊醇糖苷积聚在甜叶菊叶中,其中它们可占叶干重的10%至20%。甜菊苷和莱鲍迪甙A均是热和pH稳定的,并且适用于碳酸饮料和许多其他食物。甜菊苷比蔗糖甜110与270倍之间,莱鲍迪甙A比蔗糖甜150与320倍之间。此外,莱鲍迪甙D也是在甜叶菊叶中积聚的高效二萜糖苷甜味剂。它可比蔗糖甜约200倍。莱鲍迪甙M是另一种高效二萜糖苷甜味剂。它在某些甜叶菊品种叶中以痕量存在,但已表明其具有优异的味道特征。
传统上已从甜叶菊植物中提取了甜菊醇糖苷。在甜叶菊中,(-)-贝壳杉烯酸(赤霉酸(GA)生物合成中的中间体)被转化成四环二萜甜菊醇,其然后通过多步糖基化途径进行以形成各种甜菊醇糖苷。然而,产率可以是可变的,并且受到农业和环境条件的影响。此外,甜叶菊种植需要大量的土地面积、在收获前的很长时间、密集劳动以及用于提取和纯化糖苷的额外成本。
最近,使用发酵工艺生产甜菊醇糖苷的兴趣日益增长。WO2013/110673和WO2015/007748中描述了可用于产生至少甜菊醇糖苷莱鲍迪甙A和莱鲍迪甙D的微生物。
此类微生物的进一步改进是令人希望的,以便可产生更高量的甜菊醇糖苷和/或另外或新的甜菊醇糖苷和/或更高量的特异性甜菊醇糖苷和/或具有期望比例的不同甜菊醇糖苷的甜菊醇糖苷的混合物。
发明概述
在甜叶菊中,甜菊醇由GGPP合成,所述GGPP由脱氧木酮糖5-磷酸途径形成。两种二萜环化酶(-)-柯巴基二磷酸合酶(CPS)和(-)-贝壳杉烯合酶(KS)的活性导致形成(-)-贝壳杉烯,所述(-)-贝壳杉烯然后在三步反应中通过(-)-贝壳杉烯氧化酶(KO)氧化以形成(-)-贝壳杉烯酸。
在甜叶菊叶中,(-)-贝壳杉烯酸然后通过对映-贝壳杉烯酸13-羟化酶(KAH)羟基化以形成甜菊醇。甜菊醇然后通过一系列UDP-糖基转移酶(UGT)糖基化,从而形成许多甜菊醇糖苷。具体地说,这些分子可被视为甜菊醇分子,其羧基氢原子被葡萄糖分子代替以形成酯,并且羟基氢被葡萄糖和鼠李糖的组合代替以形成缩醛。
这些途径可在重组宿主例如酵母如酵母菌属酵母属(Saccharomyces)和耶氏酵母属(Yarrowia)中重建。
本发明涉及具有UDP-糖基转移酶(UGT)的多肽的鉴定,其与当前已知的那些相比通常具有改进的性质。这些多肽可用于产生重组宿主,所述重组宿主产生更高量的甜菊醇糖苷和/或另外或新的甜菊醇糖苷和/或更高量的特异性甜菊醇糖苷和/或具有期望比例的不同甜菊醇糖苷的甜菊醇糖苷的混合物。
因此,本发明还涉及一种能够产生糖基化二萜,即二萜糖苷如甜菊醇糖苷的重组宿主,所述糖基化二萜如甜菊单糖苷、甜菊双糖苷、甜菊苷、莱鲍迪甙A、莱鲍迪甙B、莱鲍迪甙C、莱鲍迪甙D、莱鲍迪甙E、莱鲍迪甙F、莱鲍迪甙M、甜茶苷、杜克苷A、甜菊醇-13-单糖苷、甜菊醇-19-单糖苷或13-[(β-D-吡喃葡萄糖基)氧基)贝壳衫-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯甜菊醇-19-双糖苷,
因此,本发明涉及一种重组宿主,其包含通常具有UDP-糖基转移酶(UGT)活性如UGT2活性的重组核酸序列,所述重组核酸序列编码多肽,所述多肽具有:
a.SEQ ID NO:1中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
b.SEQ ID NO:2中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
c.SEQ ID NO:3中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;或
d.SEQ ID NO:4中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列。
本发明还涉及:
–一种用于制备糖基化二萜的方法,所述方法包括在合适的发酵培养基中发酵本发明的重组宿主,并且任选地回收糖基化二萜;
–一种发酵液,其包含能够通过本发明的方法获得的糖基化二萜;
–一种通过这种方法获得或能够从这种发酵液获得的糖基化二萜;
–一种包含两种或更多种此类二萜的组合物;
–一种包含这种糖基化二萜的食品、饲料或饮料;
–一种用于将第一糖基化二萜转化为第二糖基化二萜的方法,所述方法包括:
-使所述第一糖基化二萜与本发明的重组宿主、源自这种重组宿主的无细胞提取物或源自其任一者的酶制剂接触;
-从而将所述第一糖基化二萜转化为所述第二糖基化二萜。
附图说明
图1示出了His-标签化的UGT的蛋白质印迹检测。
图2示出了UGT2_1a和RT18的蛋白质印迹。泳道1、2、3、4:0.5、1.0、1.9、3.8μg的UGT2_1a粗酶提取物。泳道5和6:31.9和63.8μg的RT18粗酶提取物。
图3示出了RT18的表达对RebM的产生的影响。
图4示出了RT18的表达对RebD的产生的影响。
图5示出了导致甜菊醇糖苷的生物合成的潜在途径的示意图。
图6示出了导致甜菊醇糖苷的生物合成的潜在途径的示意图。以星号示出的化合物是13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯。
序列表说明
序列的描述列于表10中。本文描述的序列可以参考序列表或参考本文中例如在表10中也列出的数据库登录号进行定义。
发明详述
在本说明书和所附权利要求书中,词语“包含”、“包括”和“具有”以及变化形式应被解释为包含性的。也就是说,这些词语意图表达在上下文允许的情况下可包含未具体叙述的其他要素或整数。
不使用数量词修饰时在本文中用于指代一个或一个以上(即一个或至少一个)的语法对象。举例来说,“要素”可意指一个要素或多于一个要素。
在本文,“莱鲍迪甙”可缩写为“reb”。即,例如莱鲍迪甙A和rebA意图表示同一分子。
在涉及细胞、核酸、蛋白质或载体使用时,术语“重组”指示细胞、核酸、蛋白质或载体已通过引入异源核酸或蛋白质或改变天然核酸或蛋白质来进行修饰,或者指示细胞源自如此修饰的细胞。因此,例如,重组细胞表达在细胞的天然(非重组)形式中未发现的基因或者表达以其他形式异常表达、低表达或完全未表达的天然基因。术语“重组的”与“遗传修饰的”同义。
本发明涉及被鉴定为具有UDP-糖基转移酶(UGT)活性的多肽,所述多肽可以用于重组宿主中,典型地用于生产二萜糖苷,如甜菊醇糖苷。
出于本发明的目的,具有UGT活性的多肽是具有糖基转移酶活性(EC2.4)的多肽,即可以充当催化剂以将单糖单元从活化的核苷酸糖(又称“糖基供体”)转移到糖基受体分子(通常是醇)的多肽。UGT的糖基供体典型地是核苷酸糖尿苷二磷酸葡萄糖(尿嘧啶-二磷酸葡萄糖,UDP-葡萄糖)。适于在本发明的宿主中使用的多肽典型地具有UGT活性和如本文所述的典型地编码这种多肽的多核苷酸序列。典型地,用于在本发明的宿主中使用的多肽是具有UGT2型活性的多肽。
本发明因此提供了包含编码多肽的重组核酸序列的重组宿主,所述多肽包含:
a.SEQ ID NO:1中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
b.SEQ ID NO:2中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
c.SEQ ID NO:3中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;或
d.SEQ ID NO:4中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列。
由重组核酸序列编码的多肽典型地具有UGT活性,如UGT2活性。本发明的重组宿主典型地能够产生糖基化二萜,例如甜菊醇糖苷。
由存在于本发明的重组宿主中的重组核酸编码的多肽可以包含与SEQID NO:1、2、3或4中任一项具有至少约35%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列同一性的氨基酸序列。
因此,本发明涉及:
-包含编码典型地具有UGT活性的多肽的重组核酸序列的重组宿主,所述多肽包含与SEQ ID NO:1具有至少约35%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列同一性的氨基酸序列;
-包含编码典型地具有UGT活性的多肽的重组核酸序列的重组宿主,所述多肽包含与SEQ ID NO:2具有至少约35%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列同一性的氨基酸序列;
-包含编码典型地具有UGT活性的多肽的重组核酸序列的重组宿主,所述多肽包含与SEQ ID NO:3具有至少约35%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列同一性的氨基酸序列;
-包含编码典型地具有UGT活性的多肽的重组核酸序列的重组宿主,所述多肽包含与SEQ ID NO:4具有至少约35%、至少约40%、至少约50%、至少约60%、至少约65%、至少约70%、至少约75%、至少约80%、至少约85%、至少约86%、至少约87%、至少约88%、至少约89%、至少约90%、至少约91%、至少约92%、至少约93%、至少约94%、至少约95%、至少约96%、至少约97%、至少约98%或至少约99%序列同一性的氨基酸序列。
如本文所用,术语“多肽”是指包含通过肽键连接的氨基酸残基并含有多于五个氨基酸残基的分子。氨基酸由单字母或三字母名称标识。如本文所用的术语“蛋白质”与术语“多肽”同义,并且还可指两种或更多种多肽。因此,术语“蛋白质”、“肽”和“多肽”可互换使用。多肽可任选地进行修饰(例如,糖基化、磷酸化、酰化、法尼基化、异戊二烯化、磺化等)以增加官能度。展现活性的多肽可被称为酶。应理解,作为遗传密码简并的结果,可产生编码给定多肽的许多核苷酸序列。
如在本发明中使用的术语“核酸序列”(或“多核苷酸”)是指包含至少5个核苷酸单元的核苷酸聚合物。核酸是指核糖核苷酸聚合物(RNA)、脱氧核苷酸聚合物(DNA)或任一类型的核酸的修饰形式或其合成形式或上述中的任一种的混合聚合物。核酸可包括通过天然存在和/或非天然存在的核酸键连接在一起的天然存在的核酸和修饰的核酸中的任一者或两者。核酸分子可被化学或生物化学修饰或可含有非天然或衍生化的核酸碱基,如本领域的技术人员所容易了解的。此类修饰包括例如标记、甲基化、以类似物替换一个或多个天然存在的核酸、核苷酸间修饰如不带电键联(例如,膦酸甲酯、磷酸三酯、氨基磷酸酯、氨基甲酸酯等)、带电键联(例如,硫代磷酸酯、二硫代磷酸酯等)、悬垂(pendent)部分(例如,多肽)、嵌入剂(例如,吖啶、补骨脂素等)、螯合剂、烷基化剂以及修饰的键联(例如,α异头核酸等)。术语核酸还旨在包括任何拓扑构象,包括单链(有义链和反义链)、双链、部分双链体、三链体、发夹、环形和挂锁构象。还包括在经由氢键合和其他化学相互作用在结合至指定序列的能力方面模拟核酸的合成分子。此类分子在本领域中是已知的并且包括例如其中肽键联取代分子骨架中的磷酸酯键的那些分子。提及核酸序列涵盖其互补物,除非另有说明。因此,提及具有特定序列的核酸分子应理解为涵盖其互补链及其互补序列。互补链也适用于例如反义疗法、杂交探针和PCR引物。术语“核酸”、“多核苷酸”和“多核苷酸序列”可在本文中互换使用。由用于在本发明的重组宿主中使用的重组核酸编码的多肽可以包含信号肽和/或前肽序列。在多肽包含信号肽和/或前肽的情况下,序列同一性可以在成熟多肽序列上计算。
多肽典型地具有UGT活性并且更优选地具有UGT2活性。图5和图6说明了可以由具有UGT2活性的多肽催化的反应的非穷尽性列表。
具有UGT2活性的多肽是可以充当尿苷5'-二磷酸葡萄糖基:甜菊醇-13-O-糖苷转移酶(又称甜菊醇-13-单葡萄糖苷1,2-转葡萄糖基酶)的多肽,其将葡萄糖部分转移到受体分子甜菊醇-13-O-糖苷的13-O-葡萄糖的C-2'。典型地,适合的UGT2多肽还可以充当将葡萄糖部分转移到受体分子甜茶苷的13-O-葡萄糖的C-2’的尿苷5'-二磷酸葡萄糖基:甜茶苷转移酶。也就是说,能够将甜菊醇-13-单糖苷转化为甜菊双糖苷和/或能够将甜茶苷转化为甜菊苷。
具有UGT2活性的多肽也可以或者替代性地催化利用除甜菊醇-13-O-糖苷和甜茶苷以外的甜菊醇糖苷底物的反应,例如,功能性UGT2多肽可利用甜菊苷作为底物,从而将葡萄糖部分转移至19-O-葡萄糖残基的C-2'以产生莱鲍迪甙E。功能性UGT2多肽也可以或者替代性地利用莱鲍迪甙A作为底物,从而将葡萄糖部分转移至19-O-葡萄糖残基的C-2'以产生莱鲍迪甙D。
具有UGT2活性的多肽也可催化利用甜菊醇-19-糖苷或甜茶苷作为底物的反应,例如,功能性UGT2多肽可利用甜菊醇-19-糖苷或甜茶苷作为底物,从而将葡萄糖部分转移至19位以分别产生甜菊醇-19-双糖苷或13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯。
然而,功能性UGT2多肽通常不将葡萄糖部分转移至在C-13位具有1,3-结合的葡萄糖的甜菊醇化合物,即将葡萄糖部分转移至甜菊醇1,3-双糖苷和1,3-甜菊苷通常不会发生。
具有UGT2活性的多肽也可以或者替代性地从除尿苷二磷酸葡萄糖以外的供体转移糖部分。例如,具有UGT2活性的多肽充当尿苷5'-二磷酸D-木糖基:甜菊醇-13-O-糖苷转移酶,其将木糖部分转移至受体分子甜菊醇-13-O-糖苷的13-O-葡萄糖的C-2'。作为另一个实例,具有UGT2活性的多肽可充当尿苷5'-二磷酸L-鼠李糖基:甜菊醇-13-O-糖苷转移酶,其将鼠李糖部分转移至受体分子甜菊醇的13-O-葡萄糖的C-2'。
上述活性中的一种或多种可以用于定义具有UGT2活性的由用于在本发明的重组宿主中使用的重组核酸序列编码的多肽。与UGT2_1a多肽(SEQ ID NO:6)相比,这样的多肽可以在一种或更多种上述活性方面具有改进的UGT2活性。
编码用于在本发明的重组宿主中使用的多肽的多核苷酸可用于将重组细胞中的甜菊醇糖苷的产生导向所需的甜菊醇糖苷,如莱鲍迪甙A、莱鲍迪甙D或莱鲍迪甙M。例如,优先催化甜菊醇-13-单糖苷转化为甜菊双糖苷和/或甜茶苷转化为甜菊苷的UGT2多肽可有助于使产生转向莱鲍迪甙A,而优先催化甜菊苷转化为rebE或甜茶苷转化为在19位具有另外糖的化合物的UGT2多肽可有助于使产生转向莱鲍迪甙M。也就是说,在13位添加糖部分的优先可有助于使产生转向莱鲍迪甙A,而在19位添加糖部分的优先可有助于使产生转向莱鲍迪甙M。
用于在本发明的重组宿主中使用的重组核酸序列可以以核酸构建体的形式提供。术语“核酸构建体”是指单链或双链的核酸分子,其从天然存在的基因中分离或已经被修饰以含有以否则将不会在自然中存在的方式组合和并置的核酸的区段。当核酸构建体含有表达编码序列所需要的所有控制序列时,术语核酸构建体与术语“表达盒”的含义相同,其中所述控制序列可操作地连接至所述编码序列。
用于在本发明的重组宿主中使用的重组核酸序列可以以表达载体的形式提供,其中多核苷酸序列可操作地连接到至少一个控制序列用于在重组宿主细胞中表达多核苷酸序列。
如本文所用的术语“可操作地连接”是指物理地连接并且彼此有功能性关系的两个或多个核酸序列元件。例如,如果启动子能够起始或调控编码序列的转录或表达,则启动子可操作地连接至编码序列,在这种情况下,所述编码序列应被理解为在启动子的“控制下”。通常,当两个核酸序列可操作地连接时,它们将处于相同的取向并且通常也在同一阅读框中。它们通常将是基本上连续的,尽管这可能不是必需的。
表达载体包含编码本文所述多肽的多核苷酸,其可操作地连接至用于在体外或在宿主细胞中表达和/或翻译多核苷酸的适当控制序列(如启动子以及转录和翻译终止信号)。
表达载体可以是能够方便地进行重组DNA程序并能使多核苷酸表达的任何载体(例如,质粒或病毒)。载体的选择通常将取决于所述载体与待引入所述载体的细胞的相容性。载体可以是线性或闭合的环状质粒。载体可以是自主复制型载体,即作为染色体外实体而存在、其复制独立于染色体复制的载体,例如,质粒、染色体外元件、微型染色体或人工染色体。
或者,载体可以是当被引入宿主细胞时整合至基因组中并与其已整合至其中的染色体一起复制的载体。整合型克隆载体可随机或在预定靶基因座处整合在宿主细胞的染色体中。载体可包含一个或多个选择性标记,其允许容易地选择转化的细胞。
标准遗传技术(如在宿主细胞中过表达酶以及宿主细胞的另外遗传修饰)是本领域已知的方法,例如在Sambrook和Russel(2001)"Molecular Cloning:A LaboratoryManual(第3版),Cold Spring Harbor Laboratory,Cold Spring Harbor LaboratoryPress,或F.Ausubel等人编辑,"Current protocols in molecular biology",GreenPublishing and Wiley Interscience,New York(1987)中所描述的。用于真菌宿主细胞的转化和遗传修饰的方法从例如EP-A-0 635 574、WO 98/46772、WO 99/60102和WO 00/37671中获知。
本发明的重组宿主可以包含如本文所述的任何多肽。典型地,本发明的重组宿主能够产生糖基化二萜,如甜菊醇糖苷。例如,本发明的重组宿主可以能够产生例如甜菊醇-13-单糖苷、甜菊醇-19-单糖苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、甜茶苷、甜菊苷、甜菊醇-19-双糖苷、甜菊双糖苷、rebA、rebE、rebD或rebM中的一种或多种。
因此,本发明的重组宿主将典型地包含编码具有UGT1、UGT2、UGT2和UGT4活性的多肽以及在宿主中提供甜菊醇(其然后可以被转化为一种或多种甜菊醇糖苷)的产生的多肽的多核苷酸。
一种多核苷酸可以编码多于一种的这样的多肽。一种多核苷酸可以编码具有多于一种的UGT1、UGT2、UGT3或UGT4活性的或在宿主中提供甜菊醇产生的多肽活性的多肽。因此,根据本发明的重组宿主可以包含一个或多个编码以下项中的一种或多种的重组核苷酸序列:
具有对映-柯巴基焦磷酸合酶活性的多肽;
具有对映-贝壳杉烯合酶活性的多肽;
具有对映-贝壳杉烯氧化酶活性的多肽;以及
具有贝壳杉烯酸13-羟化酶活性的多肽。
重组宿主可以包含一个或多个编码所有四种这样的多肽的重组多核苷酸序列。
出于本发明的目的,具有对映-柯巴基焦磷酸合酶(EC 5.5.1.13)的多肽能够催化化学反应:
所述酶具有一种底物,香叶基香叶基焦磷酸;以及一种产物,对映-柯巴基焦磷酸。所述酶参与赤霉素生物的合成。所述酶属于异构酶家族,特别是分子内裂解酶的类别。所述酶类别的系统名称是对映-柯巴基-二磷酸裂解酶(脱环)。通常使用的其他名称包括具有对映-柯巴基焦磷酸合酶、对映-贝壳杉烯合酶A和对映-贝壳杉烯合成酶A。
编码对映-柯巴基焦磷酸合酶的合适核酸序列可例如包含在WO2015/007748的SEQID.NO:1、3、5、7、17、19、59、61、141、142、151、152、153、154、159、160、182或184中列出的序列。
出于本发明的目的,具有对映-贝壳杉烯合酶活性(EC 4.2.3.19)的多肽是能够催化以下化学反应的多肽:
对映-柯巴基二磷酸对映-贝壳杉烯+二磷酸
因此,所述酶具有一种底物,对映-柯巴基二磷酸;以及两种产物,对映-贝壳杉烯和二磷酸。
所述酶属于裂解酶家族,特别是作用于磷酸盐/酯的碳-氧裂解酶。所述酶类别的系统名称是对映-柯巴基二磷酸二磷酸-裂解酶(环化,对映-贝壳杉烯形成)。常用的其它名称包括对映-贝壳杉烯合酶B、对映-贝壳杉烯合成酶B、对映-柯巴基-二磷酸二磷酸-裂解酶和(环化)。所述酶参与双萜类生物合成。
编码对映-贝壳杉烯合酶的合适核酸序列可例如包含在WO2015/007748的SEQID.NO:9、11、13、15、17、19、63、65、143、144、155、156、157、158、159、160、183或184中列出的序列。
对映-柯巴基二磷酸合酶还可具有与相同蛋白质分子相关联的不同对映-贝壳杉烯合酶活性。由对映-贝壳杉烯合酶催化的反应是赤霉素的生物合成途径中的下一步骤。两种类型的酶活性是不同的,并且定点诱变以抑制蛋白质的对映-贝壳杉烯合酶活性导致对映-柯巴基焦磷酸的积累。
因此,本发明重组宿主中使用的单个核苷酸序列可编码具有对映-柯巴基焦磷酸合酶活性和对映-贝壳杉烯合酶活性的多肽。或者,两种活性可被两个不同的分离的核苷酸序列编码。
出于本发明的目的,具有对映-贝壳杉烯氧化酶活性(EC 1.14.13.78)的多肽是能够催化对映-贝壳杉烯的4-甲基的三次连续氧化以产生贝壳杉烯酸的多肽。这种活性通常需要细胞色素P450的存在。
编码对映-贝壳杉烯氧化酶的合适核酸序列可例如包含在WO2015/007748的SEQID.NO:21、23、25、67、85、145、161、162、163、180或186中列出的序列。
出于本发明的目的,具有贝壳杉烯酸13-羟化酶活性(EC 1.14.13)的多肽是能够催化使用NADPH和O2形成甜菊醇(对映-贝壳杉-16-烯-13-醇-19-酸)的多肽。这种活性也可称为对映-贝壳杉烯酸13-羟化酶活性。
编码贝壳杉烯酸13-羟化酶的合适核酸序列可例如包含在WO2015/007748的SEQID.NO:27、29、31、33、69、89、91、93、95、97、146、164、165、166、167或185中列出的序列。
本发明的重组宿主可包含编码具有NADPH-细胞色素p450还原酶活性的多肽的重组核酸序列。也就是说,本发明的重组宿主可能够表达编码具有NADPH-细胞色素p450还原酶活性的多肽的核苷酸序列。出于本发明的目的,具有NADPH-细胞色素P450还原酶活性(EC1.6.2.4;也称为NADPH:高铁血红蛋白氧化还原酶、NADPH:血红素蛋白氧化还原酶、NADPH:P450氧化还原酶、P450还原酶、POR、CPR、CYPOR)的多肽通常是一种这样的多肽,其为膜结合酶,从而允许电子从含有FAD和FMN的酶NADPH:细胞色素P450还原酶(POR;EC 1.6.2.4)转移至真核细胞的微粒体中的细胞色素P450。
除如本文所述的RT7、RT11、RT15或RT18或相关序列之外,本发明的重组宿主还可以包含一个或多个编码一种或多种UGT多肽的重组核酸序列。可以对这样的另外的UGT进行选择以便产生所希望的二萜糖苷,如甜菊醇糖苷。甜菊醇糖苷形成的示意图示于Humphrey等人,Plant Molecular Biology(2006)61:47-62和Mohamed等人,J.Plant Physiology168(2011)1136-1141中。另外,图5和6示出了甜菊醇糖苷形成的示意图。
本发明的重组宿主可以因此包含一个或多个编码以下项中的一种或多种的重组核酸序列:
(i)具有UGT74G1活性(UGT3活性)的多肽;
(ii)具有UGT85C2活性(UGT1活性)的多肽;以及
(iii)具有UGT76G1活性(UGT4活性)的多肽。
图5和6示出了导致甜菊醇糖苷的生物合成的潜在途径的示意性图示。
本发明的重组宿主通常将包含至少一种编码具有UGT1活性的多肽的重组核酸、至少一种编码具有UGT2活性的多肽的重组核酸、至少一种编码具有UGT3活性的多肽的重组核酸以及至少一种编码具有UGT4活性的多肽的重组核酸。一种核酸可编码两种或更多种此类多肽。
本发明的重组宿主典型地包含表达UGT1、UGT2、UGT3和UGT4多肽中的每种以及具有对映-柯巴基焦磷酸合酶活性的多肽、具有对映-贝壳杉烯合酶活性的多肽、具有对映-贝壳杉烯氧化酶活性的多肽和具有贝壳杉烯酸13-羟化酶活性的多肽中的至少一种的多核苷酸。在这样的重组宿主中,编码这样的多肽的所有多核苷酸都可以是重组的。
编码本文所述的多肽的核酸可用于将重组细胞中的甜菊醇糖苷的产生导向期望的甜菊醇糖苷,如莱鲍迪甙A、莱鲍迪甙D或莱鲍迪甙M。例如,编码优先催化甜菊醇-13-单糖苷转化为甜菊双糖苷和/或甜茶苷转化为甜菊苷的UGT2多肽的重组核酸可有助于使产生转向莱鲍迪甙A,而编码优先催化甜菊苷转化为rebE或甜茶苷转化为在19位具有另外糖的化合物的UGT2多肽的重组核酸可有助于使产生转向莱鲍迪甙M。也就是说,在13位添加糖部分的优先可有助于使产生转向莱鲍迪甙A,而在19位添加糖部分的优先可有助于使产生转向莱鲍迪甙M。本发明的重组宿主可包含编码能够催化向甜菊醇中添加C-13-葡萄糖的多肽的核苷酸序列。也就是说,本发明的重组宿主可包含能够催化将甜菊醇转化为甜菊醇单糖苷的反应的UGT。
本发明的这种重组宿主可包含编码具有由UDP-糖基转移酶(UGT)UGT85C2所示的活性的多肽的核苷酸序列,由此宿主转化后的核苷酸序列赋予所述宿主将甜菊醇转化为甜菊醇单糖苷的能力。
UGT85C2活性是将葡萄糖单元转移至甜菊醇的13-OH。因此,合适的UGT85C2可充当尿苷5'-二磷酸葡糖基:甜菊醇13-OH转移酶和尿苷5'-二磷酸葡糖基:甜菊醇-19-O-糖苷13-OH转移酶。功能性UGT85C2多肽还可催化葡糖基转移酶反应,所述反应利用除甜菊醇和甜菊醇-19-O-糖苷以外的甜菊醇糖苷底物。此类序列可在本文中称为UGT1序列。
本发明的重组宿主可以包含编码具有UGT活性的多肽的核苷酸序列,可以包含编码能够催化将C-19-葡萄糖添加到甜菊双糖苷和/或添加到莱鲍迪甙B的多肽的核苷酸序列。也就是说,本发明的重组宿主可以包含能够催化将甜菊双糖苷转化为甜菊苷和/或莱鲍迪甙B转化为莱鲍迪甙A的反应的UGT。因此,这种重组宿主可以能够将甜菊双糖苷转化为甜菊苷和/或莱鲍迪甙B被转化为莱鲍迪甙A。这种核苷酸序列的表达可以赋予重组宿主产生至少甜菊苷和/或莱鲍迪甙A的能力。
本发明的重组宿主可以因此还包含编码具有由UDP-糖基转移酶(UGT)UGT74G1所示的活性的多肽的核苷酸序列,由此当转化宿主后所述核苷酸序列赋予细胞将甜菊双糖苷转化为甜菊苷的能力。
合适的UGT74G1多肽可能够将葡萄糖单元分别转移至甜菊醇的13-OH或19-COOH。合适的UGT74G1多肽可充当尿苷5'-二磷酸葡糖基:甜菊醇19-COOH转移酶和尿苷5'-二磷酸葡糖基:甜菊醇-13-O-糖苷19-COOH转移酶。功能性UGT74G1多肽还可催化使用除甜菊醇和甜菊醇-13-O-糖苷以外的甜菊醇糖苷底物或者从除尿苷二磷酸葡萄糖以外的供体转移糖部分的糖基转移酶反应。此类序列可在本文中称为UGT3序列。
本发明的重组宿主可包含编码能够催化甜菊苷的C-13位置处的葡萄糖的C-3'的葡糖基化的多肽的核苷酸序列。也就是说,本发明的重组宿主可包含UGT,所述UGT能够催化甜菊苷转化至莱鲍迪甙A的反应。因此,这种重组宿主可能够将甜菊苷转化为莱鲍迪甙A。这种核苷酸序列的表达可赋予宿主产生至少莱鲍迪甙A的能力。
本发明的重组宿主可以因此还包含编码具有由UDP-糖基转移酶(UGT)UGT76G1所示的活性的多肽的核苷酸序列,由此当转化宿主后所述核苷酸序列赋予该宿主将甜菊苷转化为莱鲍迪甙A和/或将甜菊双糖苷转化为莱鲍迪甙B的能力。
合适的UGT76G1向受体分子甜菊醇1,2糖苷的C-13-O-葡萄糖的C-3'添加葡萄糖部分。因此,UGT76G1例如充当尿苷5'-二磷酸葡糖基:甜菊醇13-O-1,2葡糖苷C-3'葡糖基转移酶和尿苷5'-二磷酸葡糖基:甜菊醇-19-O-葡萄糖、13-O-1,2双糖苷C-3'葡糖基转移酶。功能性UGT76G1多肽还可催化葡糖基转移酶反应,所述反应使用含有除葡萄糖以外的糖的甜菊醇糖苷底物,例如甜菊醇鼠李糖苷和甜菊醇木糖苷。此类序列可在本文中称为UGT4序列。UGT4可以替代地或者另外地能够将RebD转化为RebM。
本发明的重组宿主通常包含编码具有上述所有四种UGT活性的多肽的核苷酸序列。给定核酸可编码具有一种或多种上述活性的多肽。例如,核酸编码具有两种、三种或四种上述活性的多肽。优选地,本发明的重组宿主包含UGT1、UGT2和UGT3以及UGT4活性。合适的UGT1、UGT3和UGT4序列在WO2015/007748的表1中进行了描述。
本发明的重组宿主可包含编码具有UGT2活性的额外多肽的重组核酸序列。也就是说,本发明的重组宿主可包含编码本发明的变体UGT2和本发明的一种或多种另外的不同变体或任何另一不同的UGT2的核酸序列。
使用编码RT7、RT11、RT15或RT18多肽(或如本文所述的相关多肽)的核酸序列可以用于改进本发明的重组宿主中的rebA产生。
使用编码RT7、RT11、RT15或RT18多肽(或如本文所述的相关多肽)的核酸序列可以用于改进本发明的重组宿主中的rebM产生。
在本发明的重组宿主中,可上调宿主产生香叶基香叶基二磷酸(GGPP)的能力。在本发明的上下文中上调意味着重组宿主比等同的非重组宿主产生更多的GGPP。
因此,本发明的重组宿主可包含编码羟甲基戊二酰基-辅酶A还原酶、法尼基-焦磷酸合成酶和香叶基香叶基二磷酸合酶的一个或多个核苷酸序列,由此宿主转化后的所述核苷酸序列赋予宿主产生提高水平的GGPP的能力。因此,根据本发明的重组宿主可包含编码羟甲基戊二酰基-辅酶A还原酶、法尼基-焦磷酸合成酶和香叶基香叶基二磷酸合酶中的一种或多种的一个或多个重组核酸序列。
因此,本发明的重组宿主可包含编码以下中的一种或多种的核酸序列:
具有羟甲基戊二酰基-辅酶A还原酶活性的多肽;
具有法尼基-焦磷酸合成酶活性的多肽;
具有香叶基香叶基二磷酸合酶活性的多肽。
本发明的重组宿主可以是例如多细胞生物或其细胞或单细胞生物。本发明的宿主可以是原核、古细菌或真核宿主细胞。
原核宿主细胞可以是但不限于细菌宿主细胞。真核宿主细胞可以是但不限于酵母、真菌、变形虫、藻类、动物、昆虫或植物宿主细胞。
真核宿主细胞可以是真菌宿主细胞。“真菌”包括真菌(Eumycotina)亚门的所有物种(Alexopoulos,C.J.,1962,在Introductory Mycology,John Wiley&Sons,Inc.(约翰威立出版有限公司),纽约)。因此,术语真菌包括丝状真菌和酵母等等。
“丝状真菌”在本文中定义为真核微生物,其包括真菌和卵菌亚门的所有丝状形式(如由Hawksworth等人,1995,同上所定义)。丝状真菌是以由壳多糖、纤维素、葡聚糖、壳聚糖、甘露聚糖以及其它复合多糖构成的菌丝壁为特征。营养体生长是通过菌丝延长,并且碳代谢是专性需氧的。丝状真菌菌株包括但不限于以下各项的菌株:枝顶孢属(Acremonium)、曲霉属(Aspergillus)、伞菌属(Agaricus)、短梗霉属(Aureobasidium)、隐球菌属(Cryptococcus)、棒囊壳属(Corynascus)、金孢子菌属(Chrysosporium)、网孢菌属(Filibasidium)、镰孢菌属(Fusarium)、腐质霉属(Humicola)、稻瘟病菌属(Magnaporthe)、红曲霉属(Monascus)、毛霉菌属(Mucor)、毁丝霉属(Myceliophthora)、被孢霉属(Mortierella)、新美鞭菌属(Neocallimastix)、脉孢菌属(Neurospora)、拟青霉属(Paecilomyces)、青霉菌属(Penicillium)、梨囊鞭菌属(Piromyces)、平革菌属(Phanerochaete)、柄孢壳菌属(Podospora)、密孔菌属(Pycnoporus)、根霉菌属(Rhizopus)、裂褶菌属(Schizophyllum)、粪壳菌属(Sordaria)、踝节菌属(Talaromyces)、篮状菌属(Rasmsonia)、热子囊菌属(Thermoascus)、梭孢壳属(Thielavia)、弯颈霉属(Tolypocladium)、栓菌属(Trametes)以及木霉属(Trichoderma)。可充当宿主细胞的优选丝状真菌菌株属于以下物种:黑曲霉(Aspergillus niger)、米曲霉(Aspergillusoryzae)、烟曲霉(Aspergillus fumigatus)、产黄青霉(Penicillium chrysogenum)、桔青霉(Penicillium citrinum)、枝顶孢霉(Acremonium chrysogenum)、里氏木霉(Trichoderma reesei)、埃默森篮状菌(Rasamsonia emersonii)(先前称为埃默森踝节菌(Talaromyces emersonii))、酱油曲霉(Aspergillus sojae)、鲁克文金孢子菌(Chrysosporium lucknowense)、嗜热毁丝霉(Myceliophtora thermophyla)。用于比较转化和未转化细胞的发酵特征的参考宿主细胞包括例如黑曲霉CBS120.49、CBS 513.88;米曲霉ATCC16868、ATCC 20423、IF0 4177、ATCC 1011、ATCC 9576、ATCC14488-14491、ATCC11601、ATCC12892;烟曲霉AF293(CBS101355);产黄青霉CBS 455.95;桔青霉ATCC 38065;产黄青霉P2;枝顶孢霉ATCC 36225、ATCC 48272;里氏木霉ATCC 26921、ATCC 56765、ATCC26921;酱油曲霉ATCC11906;鲁克文金孢子菌ATCC44006以及所有这些菌株的衍生株。作为丝状真菌宿主细胞特别优选的是黑曲霉CBS 513.88及其衍生株。
真核宿主细胞可以是酵母细胞。优选的酵母宿主细胞可选自以下属:酵母属(例如,酿酒酵母(S.cerevisiae)、贝酵母(S.bayanus)、巴斯德酵母(S.pastorianus)、卡尔斯伯酵母(S.carlsbergensis))、酒香酵母属(Brettanomyces)、克鲁维酵母属(Kluyveromyces)、假丝酵母属(Candida)(例如,克鲁斯假丝酵母(C.krusei)、拉考夫假丝酵母(C.revkaufi)、铁红假丝酵母(C.pulcherrima)、热带假丝酵母(C.tropicalis)、产朊假丝酵母(C.utilis))、伊萨酵母属(Issatchenkia)(例如,东方伊萨酵母(I.orientalis))、毕赤酵母属(Pichia)(例如,巴斯德毕赤酵母(P.pastoris))、裂殖酵母属(Schizosaccharomyces)、汉逊酵母属(Hansenula)、克勒克酵母属(Kloeckera)、管囊酵母属(Pachysolen)、许旺酵母属(Schwanniomyces)、毛孢子菌属(Trichosporon)、耶氏酵母属(例如,解脂耶氏酵母(Y.lipolytica)(先前分类为解脂假丝酵母(Candidalipolytica)))、Yamadazyma。
原核宿主细胞可以是细菌宿主细胞。细菌宿主细胞可以是革兰氏阴性或革兰氏阳性细菌。细菌的实例包括但不限于,属于以下属的细菌:芽孢杆菌属(Bacillus)(例如,枯草芽孢杆菌(B.subtilis)、解淀粉芽孢杆菌(B.amyloliquefaciens)、地衣芽孢杆菌(B.licheniformis)、潘蒂芽孢杆菌(B.puntis)、巨大芽孢杆菌(B.megaterium)、嗜碱芽孢杆菌(B.halodurans)、短小芽孢杆菌(B.pumilus))、不动杆菌(Acinetobacter)、诺卡氏菌属(Nocardia)、黄杆菌属(Xanthobacter)、埃希氏杆菌属(Escherichia)(例如,大肠杆菌(例如,菌株DH 1OB、Stbl2、DH5-α、DB3、DB3.1)、DB4、DB5、JDP682和ccdA-over(例如,美国申请号09/518,188)))、链霉菌属(Streptomyces)、欧文氏菌属(Erwinia)、克雷白氏杆菌属(Klebsiella)、沙雷氏菌属(Serratia)(粘质沙雷氏菌(S.marcessans))、假单胞菌属(Pseudomonas)(例如,铜绿假单胞菌(P.aeruginosa))、沙门氏菌属(Salmonella)(例如,鼠伤寒沙门氏菌(S.typhimurium)、伤寒沙门氏菌(S.typhi))。细菌还包括但不限于光合细菌(例如,绿色非硫细菌(例如,绿弯菌属(Choroflexus)细菌(例如橙黄绿弯菌(C.aurantiacus))、绿丝菌属(Chloronema)(例如,巨大绿丝菌(C.gigateum)))、绿色硫细菌(例如,绿菌属(Chlorobium)细菌(例如,泥生绿菌(C.limicola))、暗网菌属(Pelodictyon)(例如,微黄暗网菌(P.luteolum))、紫色硫细菌(例如,着色菌属(Chromatium)(例如,奥氏着色菌(C.okenii)))以及紫色非硫细菌(例如,红螺菌属(Rhodospirillum)(例如,深红红螺菌(R.rubrum))、红细菌属(Rhodobacter)(例如类球红细菌(R.sphaeroides)、荚膜红细菌(R.capsulatus))和红微菌属(Rhodomicrobium)细菌(例如万尼氏红微菌(R.vanellii)))。
宿主细胞可以是来自非微生物生物体的宿主细胞。此类细胞的实例包括但不限于昆虫细胞(例如,果蝇属(Drosophila)(例如,黑腹果蝇(D.melanogaster))、夜蛾属(Spodoptera)(例如,草地贪夜蛾(S.frugiperda)Sf9或Sf21细胞)和粉纹夜蛾属(Trichoplusa)(例如,High-Five细胞));线虫细胞(例如,秀丽线虫(C.elegans)细胞);禽类细胞;两栖动物细胞(例如,非洲爪蟾(Xenopus laevis)细胞);爬行动物细胞;以及哺乳动物细胞(例如NIH3T3、293、CHO、COS、VERO、C127、BHK、Per-C6、Bowes黑色素瘤和HeLa细胞)。
根据本发明的重组宿主可能够在本领域中已知的任何合适的碳源上生长,并且将其转化为糖基化二萜,例如,甜菊醇糖苷。重组宿主可能够直接转化植物生物质、纤维素、半纤维素、果胶、鼠李糖、半乳糖、岩藻糖、麦芽糖、麦芽糖糊精、核糖、核酮糖或淀粉、淀粉衍生物、蔗糖、乳糖和甘油。因此,优选的宿主表达酶如用于将纤维素转化成葡萄糖单体和将半纤维素转化成木糖和阿拉伯糖单体所需的纤维素酶(内切纤维素酶和外切纤维素酶)和半纤维素酶(例如内切和外切木聚糖酶、阿拉伯糖酶),能够将果胶转化成葡萄糖醛酸和半乳糖醛酸的果胶酶或将淀粉转化成葡萄糖单体的淀粉酶。优选地,宿主能够转化选自由以下各项组成的组的碳源:葡萄糖、木糖、阿拉伯糖、蔗糖、乳糖和甘油。宿主细胞可例如是WO03/062430、WO06/009434、EP1499708B1、WO2006096130或WO04/099381中所描述的真核宿主细胞。
因此,另一方面,本发明还提供了一种用于制备糖基化二萜的方法,所述方法包括发酵本发明的重组宿主,所述重组宿主能够在合适的发酵培养基中产生至少一种糖基化二萜;以及任选地回收所述糖基化二萜。
在用于产生糖基化二萜的方法中使用的发酵培养基可以是允许特定真核宿主细胞生长的任何合适的发酵培养基。发酵培养基的基本要素是本领域的技术人员已知的,并且可适用于所选择的宿主细胞。
优选地,发酵培养基包含选自由以下各项组成的组的碳源:植物生物质、纤维素、半纤维素、果胶、鼠李糖、半乳糖、岩藻糖、果糖、麦芽糖、麦芽糖糊精、核糖、核酮糖或淀粉、淀粉衍生物、蔗糖、乳糖、脂肪酸、甘油三酯和甘油。优选地,发酵培养基还包含氮源,如尿素;或铵盐,如硫酸铵、氯化铵、硝酸铵或磷酸铵。
根据本发明的发酵方法可以分批、分批补料或连续模式进行。也可应用单独的水解和发酵(SHF)方法或同时糖化和发酵(SSF)方法。这些发酵方法模式的组合对于最佳生产率来说也可以是可行的。如果在发酵方法中使用淀粉、纤维素、半纤维素或果胶作为碳源,则SSF方法可以是特别有吸引力的,其中可需要添加水解酶如纤维素酶、半纤维素酶或果胶酶以水解底物。
在用于制备糖基化二萜的方法中使用的重组宿主可以是如上文所定义的任何合适的重组宿主。在所述方法中使用根据本发明的重组真核重组宿主可以是有利的,因为大多数真核细胞不需要用于繁殖的无菌条件并且对噬菌体感染不敏感。此外,真核宿主细胞可在低pH下生长以防止细菌污染。
根据本发明的重组宿主可以是兼性厌氧微生物。兼性厌氧重组宿主可以需氧方式繁殖至高细胞浓度。然后可在高细胞密度下进行这种厌氧阶段,这显著地降低了所需的发酵体积并且可使需氧微生物污染的风险最小化。
用于产生根据本发明的糖基化二萜的发酵方法可以是需氧或厌氧发酵方法。
厌氧发酵方法可在本文中定义为在不存在氧的情况下运行或者基本上不消耗氧(优选小于5、2.5或1mmol/L/h),并且其中有机分子充当电子供体和电子受体两者的发酵方法。根据本发明的发酵方法也可首先在需氧条件下运行,且随后在厌氧条件下运行。
发酵方法也可在限氧或微需氧条件下进行。或者,发酵方法可首先在需氧条件下运行,且随后在限氧条件下运行。限氧发酵方法是其中氧消耗受到从气体到液体的氧传递的限制的过程。氧限制的程度由进入气流的量和组成以及所用发酵设备的实际混合/传质特性决定。
在根据本发明的方法中产生糖基化二萜可在宿主细胞的生长阶段期间、固定(稳定状态)阶段期间或在两个阶段期间发生。在不同的温度下运行发酵方法可以是可行的。
用于产生糖基化二萜的方法可在对于重组宿主来说最佳的温度下进行。对于每种转化的重组宿主而言,最佳生长温度可不同并且是本领域的技术人员已知的。最佳温度可高于野生型生物的最适温度以在非无菌条件下在最低感染敏感性和最低冷却成本的条件下有效生长生物体。或者,所述方法可在对于重组宿主的生长来说不是最佳的温度下进行。
用于产生根据本发明的糖基化二萜的方法可在任何合适的pH值下进行。如果重组宿主是酵母,则发酵培养基中的pH优选具有低于6、优选低于5.5、优选低于5、优选低于4.5、优选低于4、优选低于pH 3.5或低于pH 3.0或低于pH 2.5、优选高于pH 2的值。在这些低pH值下进行发酵的优点是可防止发酵培养基中污染细菌的生长。
这种方法可在工业规模上进行。这种方法的产物是一种或多种糖基化二萜,如一种或多种甜菊醇糖苷。
从发酵培养基中回收糖基化二萜可通过本领域已知的方法进行,例如通过蒸馏、真空萃取、溶剂萃取或蒸发。
在用于产生根据本发明的糖基化二萜的方法中,实现高于5mg/l发酵液、优选高于10mg/l、优选高于20mg/l、优选高于30mg/l发酵液、优选高于40mg/l、更优选高于50mg/l、优选高于60mg/l、优选高于70、优选高于80mg/l、优选高于100mg/l、优选高于1g/l、优选高于5g/l、优选高于10g/l、例如高于20g/l的浓度可以是可行的,但通常达约200g/l、如达约150g/l、如达约100g/l、例如达约70g/l的浓度。此类浓度可以是总发酵液或上清液的浓度。
本发明还提供了一种包含能够通过本发明的用于制备糖基化二萜的方法获得的糖基化二萜的发酵液。
在本发明的重组宿主中表达一种或多种糖基化二萜的情况下,可需要处理此类细胞以释放它们。优选地,在细胞外产生至少一种糖基化二萜,如甜菊醇糖苷,例如rebA或rebM。
本发明还提供了一种通过根据本发明的用于制备糖基化二萜的方法获得的或能够从本发明的发酵液获得的糖基化二萜。这种糖基化二萜可以是非天然存在的糖基化二萜,也就是说不在植物中产生的糖基化二萜。
本发明还提供了一种包含能够通过用于制备糖基化二萜的方法获得的或能够从本发明的发酵液获得的一种或更多种甜菊醇糖苷的组合物。这种组合物可以包含能够通过本发明的用于制备糖基化二萜的方法获得或能够从本发明的发酵液获得的两种或更多种糖基化二萜的组合物。在这种组合物中,一种或多种糖基化二萜可以是非天然存在的糖基化二萜,也就是说不在植物中产生的糖基化二萜。
此外,本发明提供了一种用于将第一糖基化二萜转化为第二糖基化二萜的方法,所述方法包括:
–使所述第一糖基化二萜与本发明的重组宿主、源自这种重组宿主的无细胞提取物或源自其任一者的酶制剂接触;
–从而将所述第一糖基化二萜转化为所述第二糖基化二萜。
在这种方法中,第二糖基化二萜可以是甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
在这种方法中,第一糖基化二萜可以是甜菊醇-13-单糖苷、甜菊醇-19-单糖苷、甜茶苷、甜菊苷、莱鲍迪甙A或13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯,并且第二糖基化二萜是甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
这些是与通过本文所述的具有UGT2活性的多肽催化的反应相关的第一和第二甜菊醇糖苷。
也就是说,本发明涉及一种生物转变或生物转化方法。
通过根据本发明的发酵方法产生的甜菊醇糖苷或组合物可用于对于此类化合物来说已知的任何应用中。特别地,它们可例如用作甜味剂,例如用于食品或饮料中。因此,根据本发明,提供了一种包含本发明的糖基化二萜如甜菊醇糖苷或组合物的食品、饲料或饮料。
例如,本发明的糖基化二萜或组合物可被配制成软饮料、配制为桌面甜味剂、口香糖、乳制品如酸奶(例如原味酸奶)、蛋糕、谷物或基于谷类的食物、营养食品、药物、食用凝胶、糖果产品、化妆品、牙膏或其它口腔组合物等。此外,本发明的糖基化二萜或组合物可用作甜味剂,不仅用于饮料、食品和其它专门用于人消费的产品,而且用于具有改进的特性的动物饲料和草料中。
因此,本发明尤其提供了一种包含根据本发明的方法制备的二萜或糖基化二萜的食品、饲料或饮料。
在食品、饮料、药物、化妆品、桌面产品、口香糖的制造过程中,可使用诸如混合、捏合、溶解、酸洗、渗透、渗滤、喷洒、雾化、灌注和其它方法的常规方法。
本发明的糖基化二萜例如甜菊醇糖苷或组合物可以干或液体的形式使用。它可在食品热处理之前或之后加入。甜味剂的量取决于使用目的。它可单独添加或与其它化合物组合添加。
根据本发明的方法产生的化合物可与一种或多种其它非热量或热量甜味剂掺混。这种掺混可用于改进风味或时间特征或稳定性。广泛范围的非热量和热量甜味剂二者可适用于与本发明的糖基化二萜或组合物掺混。例如,非热量甜味剂如罗汉果苷、莫纳甜、阿斯巴甜、安赛蜜盐、环磺酸盐、三氯蔗糖、糖精盐或赤藓糖醇。适用于与本发明的糖基化二萜或组合物掺混的热量甜味剂包括糖醇和碳水化合物如蔗糖、葡萄糖、果糖和HFCS。还可使用甜味氨基酸,如甘氨酸、丙氨酸或丝氨酸。
本发明的糖基化二萜或组合物可与甜味剂抑制剂如天然甜味剂抑制剂组合使用。它可与鲜味增强剂如氨基酸或其盐组合。
本发明的糖基化二萜或组合物可与多元醇或糖醇、碳水化合物、生理活性物质或功能成分(例如类胡萝卜素、膳食纤维、脂肪酸、皂苷、抗氧化剂、营养食品、类黄酮、异硫氰酸酯、苯酚、植物甾醇或甾烷醇(植物甾醇和植物甾烷醇)、多元醇、益生元、益生菌、植物雌激素、大豆蛋白、硫化物/硫醇、氨基酸、蛋白质、维生素、矿物质和/或基于健康益处如心血管、降胆固醇或抗炎分类的物质组合。
具有本发明的糖基化二萜或组合物的组合物可包括调味剂、芳香组分、核苷酸、有机酸、有机酸盐、无机酸、苦味化合物、蛋白质或蛋白质水解产物、表面活性剂、类黄酮、收敛剂化合物、维生素、膳食纤维、抗氧化剂、脂肪酸和/或盐。
本发明的糖基化二萜或组合物可作为高强度甜味剂应用,以产生具有改进的味道特征的零卡路里、低卡路里或糖尿病人用饮料和食品。它也可用于不能使用糖的饮料、食品、药物和其他产品中。
此外,本发明的糖基化二萜或组合物可用作甜味剂,不仅用于饮料、食品和其它专门用于人消费的产品,而且用于具有改进的特性的动物饲料和草料中。
本发明的糖基化二萜或组合物可用作甜味化合物的产品的实例可以是酒精饮料,如伏特加酒、葡萄酒、啤酒、烈酒、清酒等;天然果汁、提神饮料、碳酸软饮料、减肥饮料、零卡路里饮料、低卡路里饮料和食物、酸奶饮料、速溶果汁、速溶咖啡、粉末型速溶饮料、罐装产品、糖浆、发酵大豆酱、酱油、醋、调味品、蛋黄酱、番茄酱、咖喱、汤、速食肉汤、酱油粉、醋粉、多种类型的饼干、香米饼、咸饼干、面包、巧克力、焦糖、糖果、口香糖、果冻、布丁、蜜饯和腌菜、鲜奶油、果酱、橘子酱、糖花膏、奶粉、冰淇淋、冰糕、包装在瓶中的蔬菜和水果、罐装和煮熟的豆类、在甜味酱中煮熟的肉和食物、农业蔬菜食品、海鲜、火腿、香肠、鱼火腿、鱼香肠、鱼酱、油炸鱼制品、干制海产品、冷冻食品、腌渍海带、腊肉、烟草、医药产品等。原则上它可具有无限应用。
甜味组合物包含饮料,其非限制性实例包括非碳酸化和碳酸饮料,如可乐、姜汁汽水、根汁汽水、苹果汁、水果味软饮料(例如柑橘味软饮料,如柠檬莱姆或橙汁)、软饮料粉等;来自水果或蔬菜的果汁、包括榨汁等的果汁、含有果粒的果汁、水果饮料、果汁饮料、含果汁的饮料、具有水果调味料的饮料、蔬菜汁、含蔬菜的汁以及含水果和蔬菜的混合果汁;运动饮料、能量饮料、接近水的饮料等(例如具有天然或合成调味剂的水);茶类或喜欢型饮料如咖啡、可可、红茶、绿茶、乌龙茶等;含乳成分饮料如乳饮料、含乳成分咖啡、牛奶咖啡、奶茶、果奶饮料、饮用酸奶、乳酸菌饮料等;以及乳制品。
通常,甜味组合物中存在的甜味剂的量取决于甜味组合物的具体类型及其所需的甜度而广泛变化。本领域的普通技术人员可容易确定加入到甜味组合物中的甜味剂的适当量。
本发明的糖基化二萜或组合物可以干或液体形式使用。它可在食品热处理之前或之后加入。甜味剂的量取决于使用目的。它可单独添加或与其它化合物组合添加。
在食品、饮料、药物、化妆品、桌面产品、口香糖的制造过程中,可使用诸如混合、捏合、溶解、酸洗、渗透、渗滤、喷洒、雾化、灌注和其它方法的常规方法。
因此,本发明的组合物可通过本领域的技术人员已知的提供成分的均匀或均质混合物的任何方法来制备。这些方法包括干混、喷雾干燥、团聚、湿法制粒、压实、共结晶等。
呈固体形式时,本发明的糖基化二萜或组合物可以适于递送到待甜化的食物中的任何形式提供给消费者,所述形式包括小袋、小包、散装袋或盒、方块、片剂、喷雾或可溶解的条。所述组合物可以单位剂量或散装形式递送。
对于液体甜味剂体系和组合物而言,应开发方便范围的流体、半流体、糊状和膏状形式、使用任何形状或形式的适当包装材料的适当包装,其便于携带或分配或储存或运输含有任何上述甜味剂产品或上述产品的组合的任何组合。
所述组合物可包含多种填充剂、功能成分、着色剂、调味剂。
术语“序列同源性”或“序列同一性”或“同源性”或“同一性”在本文中可互换使用。出于本发明的目的,在此定义为了确定两个氨基酸序列或两个核酸序列的序列同源性或序列同一性的百分比,出于最佳比较目的比对所述序列。为了优化两个序列之间的比对,可在比较的两个序列中的任一个中引入空位。这种比对可在所比较的序列的全长上进行。或者,比对可在更短的长度上进行,例如在约20、约50、约100或更多个核酸/碱基或氨基酸上进行。序列同一性是在所报告的比对区域上两个序列之间的相同匹配的百分比。
两个序列之间的序列比较和序列同一性百分比的确定可使用数学算法来完成。本领域的技术人员将意识到以下事实:若干不同的计算机程序可用于比对两个序列并确定两个序列之间的同一性(Kruskal,J.B.(1983)An overview of sequence comparison InD.Sankoff and J.B.Kruskal,(编辑),Time warps,string edits and macromolecules:the theory and practice of sequence comparison,第1-44页Addison Wesley)。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可使用用于两个序列的比对的Needleman和Wunsch算法来确定(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两者均可通过所述算法进行比对。Needleman-Wunsch算法已在计算机程序NEEDLE中实现。出于本发明的目的,使用了来自EMBOSS包的NEEDLE程序(2.8.0版或更高版本,EMBOSS:The European Molecular Biology Open SoftwareSuite(2000)Rice,P.Longden,I.和Bleasby,A.Trends in Genetics 16,(6)第276-277页,http://emboss.bioinformatics.nl/)。对于蛋白质序列而言,EBLOSUM62用于取代矩阵。对于核苷酸序列而言,使用EDNAFULL。所使用的任选参数是空位开放罚分为10,以及空位延伸罚分为0.5。技术人员将理解的是,所有这些不同的参数将产生稍微不同的结果,但是当使用不同的算法时,两个序列的总体同一性百分比没有显著改变。
在通过如上所述的程序NEEDLE进行比对后,查询序列与本发明的序列之间的序列同一性的百分比计算如下:在两个序列中显示相同氨基酸或相同核苷酸的比对中的相应位置的数目除以在减去比对中的总空位数后比对的总长度。如本文定义的同一性可通过使用NOBRIEF选项从NEEDLE获得,并且在程序的输出中标记为“最长同一性”。
本发明的核酸和蛋白质序列可进一步用作“查询序列”以进行针对公共数据库的检索,以例如鉴定其它家族成员或相关序列。此类搜索可使用Altschul等人(1990)J.Mol.Biol.215:403—10的NBLAST和XBLAST程序(2.0版)进行。BLAST核苷酸搜索可用NBLAST程序(得分=100、字长=12)来进行,以获得与本文所述的核酸分子同源的核苷酸序列。BLAST蛋白质搜索可用XBLAST程序(得分=50、字长=3)来进行,以获得与本文所述的蛋白分子同源的氨基酸序列。为了获得用于比较目的的空位比对,可利用如在Altschul等人,(1997)Nucleic Acids Res.25(17):3389-3402中描述的空位BLAST。当利用BLAST和空位BLAST程序时,可使用相应程序(例如XBLAST和NBLAST)的默认参数。参见美国国家生物技术信息中心http://www.ncbi.nlm.nih.gov/的主页。
本发明的一些实施方式:
1.一种包含编码多肽的重组核酸序列的重组宿主,所述多肽具有:
a.SEQ ID NO:1中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
b.SEQ ID NO:2中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
c.SEQ ID NO:3中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;或
d.SEQ ID NO:4中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列。
2.根据实施方案1所述的重组宿主,其能够产生糖基化二萜,如甜菊醇糖苷。
3.根据实施方案1或2所述的重组宿主,其包含一个或多个重组核苷酸序列,所述重组核苷酸序列编码:
具有对映-柯巴基焦磷酸合酶活性的多肽;
具有对映-贝壳杉烯合酶活性的多肽;
具有对映-贝壳杉烯氧化酶活性的多肽;以及
具有贝壳杉烯酸13-羟化酶活性的多肽。
4.根据前述实施方案中任一项所述的重组宿主,其包含重组核酸序列,所述重组核酸序列编码具有NADPH-细胞色素p450还原酶活性的多肽。
5.根据前述实施方案中任一项所述的重组宿主,其包含编码以下中的一种或多种的重组核酸序列:
(i)具有UGT74G1活性(UGT3活性)的多肽;
(ii)具有UGT85C2活性(UGT1活性)的多肽;以及
(iii)具有UGT76G1活性(UGT4活性)的多肽。
6.根据前述实施方案中任一项所述的重组宿主,其包含重组核酸序列,所述重组核酸序列编码具有UGT2活性的额外多肽。
7.根据前述实施方案中任一项所述的重组宿主,其中所述宿主属于以下属中的一种:酵母属、曲霉属、毕赤酵母属、克鲁维酵母属、假丝酵母属、汉逊酵母属、腐质霉属、伊萨酵母属、毛孢子菌属、酒香酵母属、管囊酵母属、耶氏酵母属、Yamadazyma或埃希氏杆菌属。
8.根据实施方案7所述的重组宿主,其中所述重组宿主是酿酒酵母细胞、解脂耶氏酵母细胞、克鲁斯假丝酵母细胞、东方伊萨酵母细胞或大肠杆菌细胞。
9.根据前述实施方案中任一项所述的重组宿主,其中所述宿主产生香叶基香叶基二磷酸(GGPP)的能力被上调。
10.根据前述实施方案中任一项所述的重组宿主,其包含一个或多个重组核酸序列,所述重组核酸序列编码羟甲基戊二酰基-辅酶A还原酶、法尼基-焦磷酸合成酶和香叶基香叶基二磷酸合酶。
11.根据前述实施方案中任一项所述的重组宿主,其包含核酸序列,所述核酸序列编码以下中的一种或多种:
具有羟甲基戊二酰基-辅酶A还原酶活性的多肽;
具有法尼基-焦磷酸合成酶活性的多肽;
具有香叶基香叶基二磷酸合酶活性的多肽。
12.一种用于制备糖基化二萜的方法,所述方法包括在合适的发酵培养基中发酵根据实施方案2至11中任一项所述的重组宿主,并且任选地回收所述糖基化二萜。
13.根据实施方案12所述的方法,其用于制备糖基化二萜,其中所述方法以工业规模进行。
14.一种发酵液,其包含能够通过根据实施方案12或13所述的方法获得的糖基化二萜。
15.一种糖基化二萜,其通过根据实施方案12或13所述的方法获得或能够从根据实施方案14所述的发酵液获得。
16.一种组合物,其包含通过根据实施方案12或13所述的方法获得或能够从根据实施方案14所述的发酵液获得的两种或更多种糖基化二萜。
17.一种食品、饲料或饮料,其包含根据实施方案15的糖基化二萜或根据实施方案16的组合物。
18.一种用于将第一糖基化二萜转化为第二糖基化二萜的方法,所述方法包括:
–使所述第一糖基化二萜与根据实施方案1至11中任一项所述的重组宿主、源自这种重组宿主的无细胞提取物或源自上述任一者的酶制剂接触;
–从而将所述第一糖基化二萜转化为所述第二糖基化二萜。
19.根据实施方案18所述的方法,其中所述第二糖基化二萜是甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
20.根据实施方案19所述的方法,其中所述第一糖基化二萜是甜菊醇-13-单糖苷、甜菊醇-19-单糖苷、甜茶苷、甜菊苷、莱鲍迪甙A或13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯,并且所述第二糖基化二萜是甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
在本文对专利文件或作为现有技术给出的其他材料的引用不应被认为承认该文件或材料是已知的或它包含的信息是任何这些权利要求的优先权日时公知常识的一部分。
在本文所述的每个参考文献的披露均通过引用以其全部内容并入本文。
本发明通过以下实施例来进一步说明:
实施例
实施例1:E.coli表达载体的构建
从番茄cDNA扩增编码来自番茄(Solanum lycopersicon)的UGT的全长开放阅读框。将1μg自番茄果实分离的总RNA用作起始材料,以根据制造商的说明书使用SMARTTM RACEcDNA扩增试剂盒(克罗泰克公司(Clontech))制备cDNA。
对于扩增,使用Phusion“校对聚合酶”(费泽姆公司(Finnzymes))和表1中提及的引物。
表1:用于扩增番茄和甜菊UGT片段的引物
将扩增的片段和载体pACYC-DUET1(诺瓦根公司(Novagen))用限制酶BamHI和PstI(针对番茄UGT片段)或BamHI和HindIII(针对UGT2_1a和UGT85C2)消化,随后纯化所需DNA片段,然后将其连接并且最后使用标准程序转化到大肠杆菌XL-1blue中。在含有50μg/mL氯霉素的LB板上对重组细菌进行选择。在重组菌落在液体培养基(含50μg/mL氯霉素的3mL LB培养液,250rpm,37℃)中过夜生长之后,使用Qiaprep Spin Miniprep试剂盒(凯杰公司(Qiagen))分离质粒DNA。通过Sanger测序用载体引物对分离的质粒材料进行检查。
这种克隆策略产生构建体,自其中能够表达具有N-末端His6-标签的UGT。
实施例2:通过UGT85C2合成甜菊单糖苷
为了从甜菊醇(西格玛(Sigma)U4625)和UDP-葡萄糖(西格玛4625)酶促地制备甜菊单糖苷,将以下化合物在4ml的总反应体积中混合。对于UGT85C2的粗酶提取物的制备,参见实施例3。
μl | |
0.1M Tris-缓冲液中的100mM 2-巯基乙醇 | 160 |
10%DMSO中的100mM UDP-葡萄糖 | 800 |
100%DMSO中的100mM甜菊醇 | 40 |
粗酶提取物UGT85C2 | 400 |
在30℃和100rpm下过夜进行糖基化反应。
随后使用已经根据制造商的说明书预处理的Oasis亲水亲油平衡(HLB)3cc提取柱(沃特斯公司(Waters))纯化反应。将酶促反应装载到HLB柱上,并允许通过重力流进入该柱。随后将柱用6mL的水洗涤。通过使3ml的100%甲醇通过柱来洗脱产物。将甲醇洗脱物在真空离心下干燥并且将沉淀溶解于80μl DMSO中。这产生50mM甜菊单糖苷制剂。
实施例3:不同番茄UGT和甜叶菊UGT2_1a的体外比较
将对照质粒pACYC-DUET-1和UGT构建体转化到大肠杆菌BL21DE3(英杰公司(Invitrogen))中。对于表达,制备重组大肠杆菌菌株的3mL过夜培养物(含适当抗生素、50ug氯霉素/mL和1%葡萄糖的LB培养基)。将200μL的该培养物转移到100mL锥形瓶中的含适当抗生素的20mL的LB培养基中,并且在37℃、250rpm下温育,直到A600是0.4至0.6。随后添加IPTG至1mM的终浓度并且将培养物在18℃和250rpm下温育过夜。第二天,通过离心(10min 8000xg)收获细胞,除去培养基,并且将细胞重悬于1mL重悬缓冲液(100mM Tris-HCl pH=7.5、1.4mM 2-巯基乙醇;4℃,15%甘油)中。通过在速度6.5下,在FastPrep FP120机器(萨万特公司(Savant))中,用200mg 0.1mm氧化锆/氧化硅珠(BioSpec公司)振荡10秒进行两次来破坏细胞。随后通过离心(10min 13,000xg,4℃)除去不溶性颗粒。所得上清液被称为粗酶提取物。
实施例4:通过UGT葡糖基化甜菊单糖苷和莱鲍迪甙A
对于酶测定,在2ml埃彭多夫管中制备总共50μl的混合物:
2%DMSO中的0.1M Tris | 37.5μl |
0.1M tris中的100mM 2-巯基乙醇 | 2μl |
10%DMSO中的100mM UDP-葡萄糖 | 5μl |
100%DMSO中的50mM甜菊单糖苷 | 0.5μl |
粗UGT酶提取物 | 5μl |
将管在30℃和100rpm下温育过夜。
对于莱鲍迪甙A(RebA)情况下的测定,用50%DMSO中的0.5μl 50mM RebA(ChromDex ASB-00018225)替换甜菊单糖苷。
实施例5:LC-MS分析
LC-PDA-QTOF-MS系统用于分析反应产物。在温育之后,通过添加用0.13%甲酸酸化的MQ水中的150μl的100%甲醇使体外酶测定混合物(50μl)停止。将样品声处理15min,在2500rpm下离心10min并且通过0.45μm过滤器(Minisart SRP4,生物技术公司(BiotechGmbH),德国)过滤。对于层析分离,使用来自菲罗门公司(Phenomenex)(托伦斯,加利福尼亚州,美国)的Luna C18(2)预柱(2.0x 4mm)和分析柱(2.0x 150mm,粒度3μm)。将五微升的每个过滤样品注入系统中,以便使用甲酸:水(1:1000,v/v;洗脱液A)和甲酸:乙腈(1:1000,v/v;洗脱液B)作为洗脱溶剂进行LC-PDA-MS分析。流量设为0.19mL/min,并且跨越45min的时段梯度从80%洗脱液A和20%洗脱液B到45%洗脱液A和55%洗脱液B。将柱温维持在40℃下并且将样品温度维持在20℃下。使用沃特斯2996PDA(λ范围从240至600nm)测量UV吸光度并且使用QTOF Ultima V4.00.00质谱仪(沃特斯公司,MS技术(MStechnologies))以负模式进行ESI-MS分析。10eV的碰撞能量用于在m/z范围100至1,500内的全扫描LC-MS。亮氨酸脑啡肽([M–H]–=554.2620)用于在线质量校准(锁定质量)。
通过其保留时间及其表观质量鉴定化合物并且与存在于莱鲍迪甙-A杂质混合物-6(Cerilliant S-017)中的标准甜菊苷进行比较(表2)。
表2:莱鲍迪甙-A杂质混合物-6中的甜菊苷的保留时间和质量
Rt(min) | m/z | |
RebD | 12.95 | 1127.47 |
RebA | 18.76 | 965.42 |
甜菊苷 | 18.94 | 803.37 |
甜茶苷 | 22.84 | 803.37 |
RebB | 25.15 | 641.31 |
甜菊双糖苷 | 25.58 | 641.31 |
甜菊醇 | 44.73 | 317.21 |
在表3和4中给出了体外测试的结果。为了半量化体外测定的所产生化合物,从总离子计数层析谱测量每个相关峰的峰表面积。清楚地,UGT2_1a能够从甜菊单糖苷产生甜菊双糖苷(Rt=25.6)。UGT RT18也主要产生甜菊双糖苷。其他RT优先地产生其他甜菊醇糖苷(表3)。
表3:在甜菊单糖苷与不同的UGT酶体外反应之后通过LC-MS检测到的产物。作为底
物,使用甜菊单糖苷(Rt=30.4min;m/z 959=[2M-H])。在LC-MS层析谱中示出了峰表面积。
Rt:以分钟计的保留时间。在25.6min时检测到甜菊双糖苷。
当测试作为底物的RebA时,清楚的是与UGT2_1a相比,RT18显示出从RebA相对强的RebD形成(Rt=12.9min),而其他UGT优先地产生不同的RebA-糖苷(表4)。
表4:在RebA与不同的UGT酶体外反应之后通过LC-MS检测到的产物。作为底物,使
用RebA(Rt=18.74min;m/z 1011=[M-H+甲酸])。在LC-MS层析谱中示出了峰表面积。Rt:以
分钟计的保留时间。在Rt=12.9min时检测到RebD。
m/z=565 | m/z=1127 | m/z=1127 | m/z=1127 | m/z=1127 | m/z=1127 | |
Rt=12.6 | Rt=12.9 | Rt=14.1 | Rt=14.25 | Rt=14.9 | Rt=17.4 | |
Blanc | 6 | 12 | ||||
UGT2_1a | 1037 | 16 | ||||
RT18 | 98 | 3596 | 494 | |||
RT15 | 376 | 8946 | 234 | |||
RT11 | 33 | 7684 | 159 | |||
RT7 | 1212 | 2169 | 31 |
因此,RT18可以从甜菊单糖苷形成甜菊双糖苷,并且从RebA形成RebD。
实施例6:粗酶提取物中的UGT蛋白含量
我们观察到与UGT2_1a相比,RT18粗酶提取物的形成甜菊双糖苷的活性要低2-3倍。为了能够比较两种酶在粗提取物中每酶分子的活性,我们分析了粗酶提取物的总蛋白含量。
首先,根据制造商的说明书,使用冻干牛血清白蛋白BioRad 500-0007作为标准品,使用蛋白质染色试剂浓缩物(BIO-RAD 500-0006)针对蛋白质含量对提取物进行比较。在此基础上,观察到UGT2_1a粗提取物含有是RT18粗提取物两倍的蛋白质(表5)。
表5:粗酶提取物的总蛋白含量。蛋白质浓度以μg/μl给出。
总蛋白(μg/μl) | |
pACYC-DUET-1 | 3.35 |
UGT2_1a | 5.08 |
RT18 | 2.66 |
RT15 | 3.63 |
RT11 | 3.33 |
RT7 | 2.06 |
随后,为了比较粗提取物中的酶浓度,进行蛋白质印迹实验。将50μg的总蛋白引入50ul样品缓冲液(20mM Tris pH 6.8、6%甘油、0.4%SDS、20mM二硫苏糖醇、0.01%溴酚蓝)中并煮5分钟。随后,将10μl样品(=10μg总蛋白)装载到含SDS的12.5%聚丙烯酰胺凝胶上并且在20mA下跑2小时胶。将蛋白质从凝胶转移到标准印迹缓冲液(3g/L Tris、14.4g/L甘氨酸、10%乙醇)中的硝酸纤维素膜(伯乐公司(BIO-RAD))上持续1小时(100V)。随后将硝酸纤维素用TBST缓冲液(20mM Tris-Cl缓冲液pH 7.5、150mM NaCl、0.05%Tween 20)洗涤5分钟,并且用含2%脱脂奶粉(ELK)的TBST缓冲液封闭1小时。通过与含2%ELK和1:4000稀释的偶联至过氧化物酶(西格玛公司,圣路易斯,A7058)的抗His单克隆抗体的TBST一起温育1小时来检测酶的存在。在用TBST以五分钟洗涤四次之后,通过用于膜(西格玛T0565)的TMB液体底物系统检测过氧化物酶。在His标签化的蛋白质(这里:UGT)存在于印迹中的位置处检测到紫色。当以此方式比较所有五个粗酶提取物时(图1),清楚的是UGT2_1a被表达至良好的可检测水平,而RT18蛋白无法检测到。还以不同强度检测到了其他UGT(RT15、RT11、RT7)。
为了比较RT18和UGT2_1a的粗酶提取物中的UGT含量,进行另一蛋白质印迹。对于UGT2_1a,装载0.5、1.0、1.9、3.8μg蛋白质;而对于RT18,装载31.9和63.8μg。如上所述检测UGT。印迹(图2)显示1.9μg UGT2_1a提取物和63.8μg RT18中His标签化的UGT蛋白的量相同,如通过目测估计的。这指示RT18粗提取物中的UGT蛋白的浓度比UGT2_1a粗提取物中的低20-50倍。因此,如表3和4记录的,RT18的活性当使用甜菊单糖苷作为底物时为UGT2_1a的10倍以上,并且当使用RebA作为底物时为50倍以上。
实施例7:MSMS分析
为了提供更多的以甜菊单糖苷作为底物UGT2_1a和RT18的产物是相同的证据,通过串联质谱分析(LC-MS2)将RT18的甜菊双糖苷产物与来自UGT2_1a的甜菊双糖苷产物和来自RT11的甜菊醇-二葡萄糖苷产物进行进一步比较。将来自RT18和UGT2_1a酶测定的甲醇提取物注入与LTQ离子阱-轨道阱FTMS混合型质谱仪(赛默公司(Thermo))系统耦合的AccelaHPLC-PDA(赛默公司)中。使用针对LC-QTOF MS分析(参见上文)所述的相同LC条件并且使用负离子模式进行数据定向MSMS,其中分离宽度为3.00道尔顿并且归一化碰撞能量为35.0。甜菊醇葡萄糖苷的保留时间与对LC-QTOF MS系统的分析稍有不同(参见上文,表3)。
对具有m/z 641.30的化合物(在RT18和UGT2_1a样品中在23.0min时洗脱以及在RT11样品中在22.2min时洗脱)进行片段化处理。
在m/z 641.30的离子的片段化质谱中,在所有三个样品中观察到片段m/z 479.26[M-H-葡萄糖]和m/z 317.21[M-H-2葡萄糖]。记录所有三种化合物的m/z 317.21与m/z479.26离子之间的比率。对于RT18和UGT2_1a二者的化合物,m/z 317与m/z 479的比率为2:10;而对于RT11化合物,m/z 317与m/z479的比率为4:10。因此,MS2分析没有区分来自RT18和UGT2_1a的甜菊双糖苷产物,但是区分了来自这两者的RT11甜菊醇二葡萄糖苷产物。这些结果进一步证实RT18的主要产物对应甜菊双糖苷。
实施例8.甜菊醇糖苷生产菌株中的RT18表达
为了证实RT18酶的体内活性对甜菊醇糖苷产生的影响,用三个不同强度的启动子组装RT18(SEQ ID NO:19)(表6),并且使用描述于WO 2013/110673和WO 2015/007748中的方法转化到产生甜菊醇糖苷的解脂耶氏酵母(Yarrowia lipolitica)菌株中。这种耶氏酵母菌株的基因型在表7中给出。
表6.用于RT18表达的不同强度启动子
表7.亲本菌株的基因型(拷贝数;SEQ ID NO)。
对于阳性转化体,用来自YEPh-D琼脂的菌落材料接种预培养物。使预培养物在以葡萄糖为碳源的200μl YEP中生长。将预培养物在Infors培养箱中在30℃、750rpm和80%湿度下温育72小时。将40μl的预培养物用于接种2.5ml主培养物。将主培养物在Infors培养箱中在30℃、550rpm、80%湿度下温育120小时。120h之后,将主培养物在2750rpm下旋转沉降10min。将上清液用水和乙腈稀释,并且使用LC/MS测量。
结果示于图3和4中。可以看出与亲本相比,表达RT18的菌株产生更高量的RebM和RebD。另外,表达越强,产生的RebD和RebM越多。更高RebD的形成说明RT18在催化甜菊醇糖苷的19位上的葡萄糖糖基化中是有效的(参见图6),例如催化从RebA形成RebD。RebD可以然后通过UGT4催化被进一步转化为RebM。
实施例9.甜菊醇糖苷生产菌株中的RT18和UGT4表达
与RT18相比,其他UDP-糖基转移酶的表达对产物谱将具有影响。例如,在表达RT18的菌株中过量产生的RebD可以通过UGT4的活性被进一步转化为RebM。为了评估RT18与UGT4的过表达的影响,将RT18和UGT4的表达载体使用描述于WO 2013/110673和WO 2015/007748中的方法转化到产生甜菊醇糖苷的解脂耶氏酵母菌株中。这种亲本菌株的基因型在表8中给出。
表8.用于转化RT18和UGT4的菌株的基因型(拷贝数;SEQ ID NO)
对于阳性转化体,用来自YEPh-D琼脂的菌落材料接种预培养物。使预培养物在以葡萄糖为碳源的200μl YEP中生长。将预培养物在Infors培养箱中在30℃、750rpm和80%湿度下温育72小时。将40μl的预培养物用于接种2.5ml主培养物。将主培养物在Infors培养箱中在30℃、550rpm、80%湿度下温育120小时。120h之后,将主培养物在2750rpm下旋转沉降10min。将上清液用水和乙腈稀释,并且使用LC/MS测量。
结果示于表9中,其中列出了两种菌株的甜菊醇糖苷相对于总甜菊醇糖苷的百分比。可以看出表达RT18与另外的UGT4的菌株有效地将更高百分比的甜菊醇糖苷转化为更高的糖基化甜菊醇糖苷。特别地,RebB、甜菊苷和RebA在表达RT18和UGT4的菌株中较低,而RebM的丰度大大增加。这说明了RT18表达在将甜菊醇糖苷产生导向更高的糖基化产物如RebM中的有效性。
表9.亲本菌株和表达RT18和额外拷贝的UGT4的菌株中的甜菊醇糖苷相对于总甜菊醇糖苷的百分比。
表10:序列表说明
序列表
<110> 帝斯曼知识产权资产管理有限公司
<120> 来自番茄的UDP-糖基转移酶
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<150> US62/136759
<151> 2015-03-23
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Met Asp Gly Ser Asn Glu Lys Ser Ile Arg Val Leu Met Phe Pro Trp
1 5 10 15
Leu Gly His Gly His Ile Ser Pro Phe Phe Glu Leu Ala Lys Lys Leu
20 25 30
Val Lys Arg Asn Phe Thr Ile Phe Leu Val Ser Thr Pro Ala Asn Phe
35 40 45
Ile Ser Ile Lys Gln Lys Leu Ile His Glu Asn Leu Cys Asp Lys Ile
50 55 60
His Leu Phe Asp Leu Arg Leu Pro Ser Leu Pro Asp Leu Pro Pro His
65 70 75 80
Tyr His Thr Thr Asn Gly Leu Pro Pro His Leu Met Ser Thr Leu Lys
85 90 95
Lys Ala Phe Ala Lys Ser Arg Pro Ile Phe Thr Gln Ile Met Asn Thr
100 105 110
Ile Glu Pro Asp Leu Leu Leu Tyr Asp Leu Leu Gln Pro Trp Ala Pro
115 120 125
Lys Val Ala Lys Glu Lys Asn Ile Pro Ser Val Val Phe Val Thr Ser
130 135 140
Ser Ala Thr Met Phe Ser Tyr Met Phe His Asn Phe Arg Tyr Pro Asn
145 150 155 160
Ser Gln Phe Pro Phe Ser Ser Ile Tyr Tyr Arg Asp Tyr Glu Leu Thr
165 170 175
Arg Leu Ile Lys Asn Gln Glu Met Glu Thr Ile Glu Gln His Gln Arg
180 185 190
Asp Asn Lys Ser Val Lys Met Cys Phe Lys Arg Ser Thr Asn Ile Val
195 200 205
Leu Ile Lys Gly Phe Lys Glu Ile Asp Gly Gln Tyr Cys Glu Tyr Ile
210 215 220
Ser Ser Leu Thr Lys Lys Arg Val Val Pro Val Gly Pro Leu Val Gln
225 230 235 240
Glu Gln Thr Ser Glu Asp Asn Asn Ser Gln Ile Leu Thr Trp Leu Asn
245 250 255
Gln Lys Ser Lys Gly Ser Thr Ile Phe Val Ser Phe Gly Ser Glu Tyr
260 265 270
Phe Leu Ser Gln Glu Asp Arg Glu Glu Ile Ala His Gly Leu Glu Gln
275 280 285
Ser Arg Val Asn Phe Ile Trp Val Val Arg Phe Pro Lys Gly Glu Lys
290 295 300
Leu Lys Leu Glu Gln Ala Leu Pro Arg Asp Phe Phe Lys Lys Val Gly
305 310 315 320
Glu Arg Gly Met Val Val Glu Asp Trp Ala Pro Gln Ala Lys Ile Leu
325 330 335
Gly Asn Pro Asn Ile Gly Gly Phe Val Ser His Cys Gly Trp Asn Ser
340 345 350
Val Leu Glu Ser Met Lys Ile Gly Val Pro Ile Ile Ala Met Pro Met
355 360 365
His Leu Asp Gln Pro Leu Asn Ala Arg Leu Val Glu Glu Val Gly Ile
370 375 380
Gly Leu Glu Val Val Arg Asp Lys Asp Gly Lys Leu Asp Gly Glu Gln
385 390 395 400
Ile Ser Glu Ile Ile Asn Lys Val Val Leu Glu Lys Glu Gly Glu Ser
405 410 415
Ile Arg Glu Lys Ala Lys Lys Met Ser Glu Thr Ile Arg Val Lys Gly
420 425 430
Asp Glu Glu Ile Asp Asp Val Val Gln Glu Leu Val Asn Leu Cys Lys
435 440 445
Thr Arg Ser Asn Val Val
450
<210> 4
<211> 446
<212> PRT
<213> 番茄()
<400> 4
Met Ser Thr Thr Leu Lys Val Leu Met Phe Pro Phe Leu Ala Tyr Gly
1 5 10 15
His Ile Ser Pro Tyr Leu Asn Val Ala Lys Lys Leu Ala Asp Arg Gly
20 25 30
Phe Leu Ile Tyr Leu Cys Ser Thr Pro Ile Asn Leu Lys Ser Thr Ile
35 40 45
Asn Lys Ile Pro Glu Lys Tyr Ala Asp Ser Ile Gln Leu Ile Glu Leu
50 55 60
His Leu Pro Glu Leu Pro Glu Leu Pro Pro His Tyr His Thr Thr Asn
65 70 75 80
Gly Leu Pro Pro Asn Leu Asn His Ile Leu Arg Arg Ala Leu Lys Met
85 90 95
Ser Lys Pro Asn Phe Ser Lys Ile Met Gln Asn Leu Lys Pro Asp Leu
100 105 110
Leu Ile Tyr Asp Ile Leu Gln Gln Trp Ala Glu Asp Val Ala Thr Glu
115 120 125
Leu Asn Ile Pro Ala Val Lys Leu Leu Thr Ser Gly Val Ala Val Phe
130 135 140
Ser Tyr Phe Phe Asn Leu Thr Lys Lys Pro Glu Val Glu Phe Pro Tyr
145 150 155 160
Pro Ala Ile Tyr Leu Arg Lys Ile Glu Leu Val Arg Trp Cys Glu Thr
165 170 175
Leu Ser Lys His Asn Lys Glu Gly Glu Glu His Asp Asp Gly Leu Ala
180 185 190
Tyr Gly Asn Met Gln Ile Met Leu Met Ser Thr Ser Lys Ile Leu Glu
195 200 205
Ala Lys Tyr Ile Asp Tyr Cys Ile Glu Leu Thr Asn Trp Lys Val Val
210 215 220
Pro Val Gly Ser Leu Val Gln Asp Ser Ile Thr Asn Asp Ala Ala Asp
225 230 235 240
Asp Asp Met Glu Leu Ile Asp Trp Leu Gly Thr Lys Asp Glu Asn Ser
245 250 255
Thr Val Phe Val Ser Phe Gly Ser Glu Tyr Phe Leu Ser Lys Glu Asp
260 265 270
Val Glu Glu Val Ala Phe Gly Leu Glu Leu Ser Asn Val Asn Phe Ile
275 280 285
Trp Val Val Arg Phe Pro Lys Gly Glu Glu Lys Asn Leu Glu Asp Val
290 295 300
Leu Pro Lys Gly Phe Phe Glu Arg Ile Gly Glu Arg Gly Arg Val Leu
305 310 315 320
Asp Lys Phe Ala Pro Gln Pro Arg Ile Leu Asn His Pro Ser Thr Gly
325 330 335
Gly Phe Ile Ser His Cys Gly Trp Asn Ser Ala Met Glu Ser Ile Asp
340 345 350
Phe Gly Val Pro Ile Val Ala Met Pro Met Gln Leu Asp Gln Pro Met
355 360 365
Asn Ala Arg Leu Ile Val Glu Leu Gly Val Ala Val Glu Ile Val Arg
370 375 380
Asp Asp Asp Gly Lys Ile Tyr Arg Gly Glu Ile Ala Glu Thr Leu Lys
385 390 395 400
Gly Val Ile Thr Gly Glu Ile Gly Glu Ile Leu Arg Ala Lys Val Arg
405 410 415
Asp Ile Ser Lys Asn Leu Lys Ala Ile Lys Asp Glu Glu Met Asp Val
420 425 430
Ala Ala Gln Glu Leu Ile Gln Leu Cys Arg Asn Ser Asn Lys
435 440 445
<210> 5
<211> 473
<212> PRT
<213> 甜叶菊()
<400> 5
Met Ala Thr Ser Asp Ser Ile Val Asp Asp Arg Lys Gln Leu His Val
1 5 10 15
Ala Thr Phe Pro Trp Leu Ala Phe Gly His Ile Leu Pro Tyr Leu Gln
20 25 30
Leu Ser Lys Leu Ile Ala Glu Lys Gly His Lys Val Ser Phe Leu Ser
35 40 45
Thr Thr Arg Asn Ile Gln Arg Leu Ser Ser His Ile Ser Pro Leu Ile
50 55 60
Asn Val Val Gln Leu Thr Leu Pro Arg Val Gln Glu Leu Pro Glu Asp
65 70 75 80
Ala Glu Ala Thr Thr Asp Val His Pro Glu Asp Ile Pro Tyr Leu Lys
85 90 95
Lys Ala Ser Asp Gly Leu Gln Pro Glu Val Thr Arg Phe Leu Glu Gln
100 105 110
His Ser Pro Asp Trp Ile Ile Tyr Asp Tyr Thr His Tyr Trp Leu Pro
115 120 125
Ser Ile Ala Ala Ser Leu Gly Ile Ser Arg Ala His Phe Ser Val Thr
130 135 140
Thr Pro Trp Ala Ile Ala Tyr Met Gly Pro Ser Ala Asp Ala Met Ile
145 150 155 160
Asn Gly Ser Asp Gly Arg Thr Thr Val Glu Asp Leu Thr Thr Pro Pro
165 170 175
Lys Trp Phe Pro Phe Pro Thr Lys Val Cys Trp Arg Lys His Asp Leu
180 185 190
Ala Arg Leu Val Pro Tyr Lys Ala Pro Gly Ile Ser Asp Gly Tyr Arg
195 200 205
Met Gly Leu Val Leu Lys Gly Ser Asp Cys Leu Leu Ser Lys Cys Tyr
210 215 220
His Glu Phe Gly Thr Gln Trp Leu Pro Leu Leu Glu Thr Leu His Gln
225 230 235 240
Val Pro Val Val Pro Val Gly Leu Leu Pro Pro Glu Ile Pro Gly Asp
245 250 255
Glu Lys Asp Glu Thr Trp Val Ser Ile Lys Lys Trp Leu Asp Gly Lys
260 265 270
Gln Lys Gly Ser Val Val Tyr Val Ala Leu Gly Ser Glu Val Leu Val
275 280 285
Ser Gln Thr Glu Val Val Glu Leu Ala Leu Gly Leu Glu Leu Ser Gly
290 295 300
Leu Pro Phe Val Trp Ala Tyr Arg Lys Pro Lys Gly Pro Ala Lys Ser
305 310 315 320
Asp Ser Val Glu Leu Pro Asp Gly Phe Val Glu Arg Thr Arg Asp Arg
325 330 335
Gly Leu Val Trp Thr Ser Trp Ala Pro Gln Leu Arg Ile Leu Ser His
340 345 350
Glu Ser Val Cys Gly Phe Leu Thr His Cys Gly Ser Gly Ser Ile Val
355 360 365
Glu Gly Leu Met Phe Gly His Pro Leu Ile Met Leu Pro Ile Phe Gly
370 375 380
Asp Gln Pro Leu Asn Ala Arg Leu Leu Glu Asp Lys Gln Val Gly Ile
385 390 395 400
Glu Ile Pro Arg Asn Glu Glu Asp Gly Cys Leu Thr Lys Glu Ser Val
405 410 415
Ala Arg Ser Leu Arg Ser Val Val Val Glu Lys Glu Gly Glu Ile Tyr
420 425 430
Lys Ala Asn Ala Arg Glu Leu Ser Lys Ile Tyr Asn Asp Thr Lys Val
435 440 445
Glu Lys Glu Tyr Val Ser Gln Phe Val Asp Tyr Leu Glu Lys Asn Ala
450 455 460
Arg Ala Val Ala Ile Asp His Glu Ser
465 470
<210> 6
<211> 481
<212> PRT
<213> 甜叶菊()
<400> 6
Met Asp Ala Met Ala Thr Thr Glu Lys Lys Pro His Val Ile Phe Ile
1 5 10 15
Pro Phe Pro Ala Gln Ser His Ile Lys Ala Met Leu Lys Leu Ala Gln
20 25 30
Leu Leu His His Lys Gly Leu Gln Ile Thr Phe Val Asn Thr Asp Phe
35 40 45
Ile His Asn Gln Phe Leu Glu Ser Ser Gly Pro His Cys Leu Asp Gly
50 55 60
Ala Pro Gly Phe Arg Phe Glu Thr Ile Pro Asp Gly Val Ser His Ser
65 70 75 80
Pro Glu Ala Ser Ile Pro Ile Arg Glu Ser Leu Leu Arg Ser Ile Glu
85 90 95
Thr Asn Phe Leu Asp Arg Phe Ile Asp Leu Val Thr Lys Leu Pro Asp
100 105 110
Pro Pro Thr Cys Ile Ile Ser Asp Gly Phe Leu Ser Val Phe Thr Ile
115 120 125
Asp Ala Ala Lys Lys Leu Gly Ile Pro Val Met Met Tyr Trp Thr Leu
130 135 140
Ala Ala Cys Gly Phe Met Gly Phe Tyr His Ile His Ser Leu Ile Glu
145 150 155 160
Lys Gly Phe Ala Pro Leu Lys Asp Ala Ser Tyr Leu Thr Asn Gly Tyr
165 170 175
Leu Asp Thr Val Ile Asp Trp Val Pro Gly Met Glu Gly Ile Arg Leu
180 185 190
Lys Asp Phe Pro Leu Asp Trp Ser Thr Asp Leu Asn Asp Lys Val Leu
195 200 205
Met Phe Thr Thr Glu Ala Pro Gln Arg Ser His Lys Val Ser His His
210 215 220
Ile Phe His Thr Phe Asp Glu Leu Glu Pro Ser Ile Ile Lys Thr Leu
225 230 235 240
Ser Leu Arg Tyr Asn His Ile Tyr Thr Ile Gly Pro Leu Gln Leu Leu
245 250 255
Leu Asp Gln Ile Pro Glu Glu Lys Lys Gln Thr Gly Ile Thr Ser Leu
260 265 270
His Gly Tyr Ser Leu Val Lys Glu Glu Pro Glu Cys Phe Gln Trp Leu
275 280 285
Gln Ser Lys Glu Pro Asn Ser Val Val Tyr Val Asn Phe Gly Ser Thr
290 295 300
Thr Val Met Ser Leu Glu Asp Met Thr Glu Phe Gly Trp Gly Leu Ala
305 310 315 320
Asn Ser Asn His Tyr Phe Leu Trp Ile Ile Arg Ser Asn Leu Val Ile
325 330 335
Gly Glu Asn Ala Val Leu Pro Pro Glu Leu Glu Glu His Ile Lys Lys
340 345 350
Arg Gly Phe Ile Ala Ser Trp Cys Ser Gln Glu Lys Val Leu Lys His
355 360 365
Pro Ser Val Gly Gly Phe Leu Thr His Cys Gly Trp Gly Ser Thr Ile
370 375 380
Glu Ser Leu Ser Ala Gly Val Pro Met Ile Cys Trp Pro Tyr Ser Trp
385 390 395 400
Asp Gln Leu Thr Asn Cys Arg Tyr Ile Cys Lys Glu Trp Glu Val Gly
405 410 415
Leu Glu Met Gly Thr Lys Val Lys Arg Asp Glu Val Lys Arg Leu Val
420 425 430
Gln Glu Leu Met Gly Glu Gly Gly His Lys Met Arg Asn Lys Ala Lys
435 440 445
Asp Trp Lys Glu Lys Ala Arg Ile Ala Ile Ala Pro Asn Gly Ser Ser
450 455 460
Ser Leu Asn Ile Asp Lys Met Val Lys Glu Ile Thr Val Leu Ala Arg
465 470 475 480
Asn
<210> 7
<211> 32
<212> DNA
<213> 人工序列()
<220>
<223> RT7正向引物
<400> 7
attaggatcc aatgggaaca caagtaacag ag 32
<210> 8
<211> 37
<212> DNA
<213> 人工序列()
<220>
<223> RT7反向引物
<400> 8
aatactgcag ttaattagta ctaatcttac aaaattg 37
<210> 9
<211> 37
<212> DNA
<213> 人工序列()
<220>
<223> RT11正向引物
<400> 9
attaggatcc aatggaagcc aagaaaaata aaatgag 37
<210> 10
<211> 35
<212> DNA
<213> 人工序列()
<220>
<223> RT11反向引物
<400> 10
aatactgcag tcatttgttg ctgcaaagag ccatc 35
<210> 11
<211> 34
<212> DNA
<213> 人工序列()
<220>
<223> RT15正向引物
<400> 11
attaggatcc aatggatggt tcgaatgaaa agtc 34
<210> 12
<211> 35
<212> DNA
<213> 人工序列()
<220>
<223> RT15反向引物
<400> 12
aatactgcag ctagacaaca tttgatctag tcttg 35
<210> 13
<211> 38
<212> DNA
<213> 人工序列()
<220>
<223> RT18正向引物
<400> 13
attaggatcc aatgagtact actttaaagg tattgatg 38
<210> 14
<211> 36
<212> DNA
<213> 人工序列()
<220>
<223> RT反向引物
<400> 14
aatactgcag attcacttat tactattcct acaaag 36
<210> 15
<211> 31
<212> DNA
<213> 人工序列()
<220>
<223> UGT2_1a正向引物
<400> 15
attaggatcc aatggccact tctgactcca t 31
<210> 16
<211> 32
<212> DNA
<213> 人工序列()
<220>
<223> UGT2_1a反向引物
<400> 16
aataaagctt ttagctttcg tggtcaatgg ca 32
<210> 17
<211> 32
<212> DNA
<213> 人工序列()
<220>
<223> UGT85C2正向引物
<400> 17
attaggatcc aatggacgct atggccacca ct 32
<210> 18
<211> 32
<212> DNA
<213> 人工序列()
<220>
<223> UGT85C2反向引物
<400> 18
aataaagctt ttagtttcga gccaagacag tg 32
<210> 19
<211> 1341
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的RT18开放阅读框
<400> 19
atgtccacca ccctcaaggt cctcatgttc cccttcctcg cttacggcca catctctccc 60
tacctcaacg ttgccaagaa gctcgccgac cgaggcttcc tcatctacct ctgttccacc 120
cccatcaacc tcaagtccac catcaacaag atccccgaga agtacgccga ctccatccag 180
ctcatcgaac tccatctccc cgagcttccc gagctgcctc cccactacca caccaccaac 240
ggtctgcctc ccaacctcaa ccacatcctc cgacgagccc tcaagatgtc caagcccaac 300
ttctccaaga tcatgcagaa cctgaagccc gatctgctca tctacgacat tctccagcag 360
tgggccgagg atgtcgccac cgagcttaac atccccgccg tcaagctgct cacctctggt 420
gttgctgttt tctcttactt cttcaacctc accaagaagc ccgaggtcga gttcccctac 480
cccgctatct acctccgaaa gatcgagctg gtccgatggt gcgagactct gtccaagcac 540
aacaaggaag gtgaggagca cgacgacggc ctcgcctacg gcaacatgca gatcatgctc 600
atgtccactt ccaagatcct cgaggccaag tacattgact actgcattga gctgaccaac 660
tggaaggtcg tccccgtcgg ctctctcgtc caggactcca tcaccaacga cgccgctgac 720
gacgacatgg aactcattga ctggctcggt actaaggacg agaactccac cgtctttgtc 780
tcttttggct ccgagtactt cctctccaaa gaggacgttg aagaggttgc cttcggtctg 840
gagctgtcca acgtcaactt catctgggtt gtccgattcc ccaagggtga ggagaagaac 900
ctcgaggacg ttctgcccaa gggcttcttc gagcgaatcg gtgagcgagg ccgagtcctc 960
gacaagtttg ctccccagcc ccgaattctc aaccacccct ctaccggtgg tttcatctct 1020
cactgtggct ggaactccgc catggagtcc attgactttg gtgtccccat tgtcgccatg 1080
cccatgcagc tcgaccagcc catgaacgcc cgactcattg tcgagcttgg tgttgccgtc 1140
gagattgtcc gagatgatga tggtaagatc taccgaggtg agattgctga gactctcaag 1200
ggtgtcatca ccggcgagat tggtgagatc ctccgagcca aggtccgaga catctccaag 1260
aacctcaagg ccatcaagga cgaggagatg gacgttgctg cccaggagct gatccagctc 1320
tgccgaaact ccaataaata a 1341
<210> 20
<211> 866
<212> DNA
<213> 解脂耶氏酵母()
<400> 20
catgctcact tttgttgtcc tgatgatctc ccgttatttc gccgctcctc tggaaaccat 60
ccgcccgcaa atcccctctg cccatcttga caatgcacaa tgcatcattc tcagcctgca 120
tgaatgcgaa agatggcaat attggtggag gaggcgacgg cggtaaacaa tggagataga 180
aaccacaaaa gaaacctgga aacccaaaat ggactcacga caactccccc actcccccac 240
tccccatctc cccctgggca tcagttgccc atcggtatct caactgtcgc actagttagc 300
gcaaccatca catactttag acgccaaaca atgggacaac tcatcgcgcc gaactatggg 360
cagattttaa ctcgcacaac attaccccaa ctctaaaagg taacctcgac cggaaaacgg 420
gaagacagga tcagcaaccg tgatcgacag aatcttcagg gcactacagt tgatagacat 480
aggttatgtt ggtaggtcta gacgggcctc ggggaattga ccccaccagt tgcaagtcac 540
gtgcccctga tacagctagt ttagcacatc tgcccactac gtctggacgc accatggtgg 600
tgccagtcgc gtgaactcaa acacccacta gcctcgggaa ggattcagtt aaatccgcac 660
cttatttcca acacaaagaa gcggttggcg gacaaagaac atgtcctttc tggggcactg 720
tacattccag gactctgttc aaggtcaaat atacaaaaca cagatagaga aacatagaca 780
gctgcggcct tataaatacc tgggcgcact tctctctttt tccctcctca tcacacattc 840
gttcaccact aagtcactcg ttcaaa 866
<210> 21
<211> 999
<212> DNA
<213> 解脂耶氏酵母()
<400> 21
ctactgttgc tacgattccc ccattgcaac cacagtttgg ggttaccccg cattatatta 60
gcatgattac gaaagagata agtatcatat ggaacatgtg aagggtagta tgcaggtccg 120
gcggagaaag agaatgacgt tttcattaag cgattcgctt ggcggcttgt gggggatgtg 180
acgatactta cggtaaagac cctgtgtgag agctggtact cgctcgttac ttcgctgatc 240
tgttgggccg tcaatcgaat ctcgtggaac ttgcattctt cttaactgtg tctatacaag 300
acacctaatg aaacatacaa gctaccgaaa tcattttact cgtactgacc ggtacggtac 360
ttgcacaagt agtgaaactt ccgaaaatag ccagcctcat gcatcatcgc ttcacccctt 420
ctgttgacct caaaagcatt ccaacggtaa aaaattataa cgccgccaac tggatggttg 480
tgacggcgtt gaccaccaat gtgtgggggc tggcggtagg accgagctta ttcgtcccaa 540
taagctcttt ggatttgatt ctttggggtg tgtggtaaaa ttcacatggg gaagaacacg 600
gtggcagttt gaggcagagg cccagcgtgt agttcctagg gcatgaatat accgaactca 660
tggcgcagaa ttgagctgaa tgcgcaaaaa gctacaggat caaccgcgtt agaaatgccg 720
caaatgtcca ctaattcccc ggactgttcc aaatgattct gtggggataa atctcaaact 780
gggttaggct ttgtcacgtt tctttgtgtc gtgtcggttc gtccggggca atgtgcccac 840
gcttggctgt ctccctacac ctcggtaaaa actatcacat gctgcccctc tcgagcaagc 900
attaaatgca tatagtcaat ctaacgacat atatataggt agggtgcatc ctccggttta 960
gctccccaga atatctctta ttcattacac aaaaacaac 999
<210> 22
<211> 1000
<212> DNA
<213> 解脂耶氏酵母()
<400> 22
gtgcaatcac atgttgctac tgtacctgct gtggaccacg cacggcggaa cgtaccgtac 60
aaatattttc ttgctcacat gactctctct cggccgcgca cgccggtggc aaattgctct 120
tgcattggct ctgtctctag acgtccaaac cgtccaaagt ggcagggtga cgtgatgcga 180
cgcacgaagg agatggcccg gtggcgagga accggacacg gcgagccggc gggaaaaaag 240
gcggaaaacg aaaagcgaag ggcacaatct gacggtgcgg ctgccaccaa cccaaggagg 300
ctattttggg tcgctttcca tttcacattc gccctcaatg gccactttgc ggtggtgaac 360
atggtttctg aaacaacccc ccagaattag agtatattga tgtgtttaag attgggttgc 420
tatttggcca ttgtggggga gggtagcgac gtggaggaca ttccagggcg aattgagcct 480
agaaagtggt agcattccaa ccgtctaagt cgtccgaatt gatcgctata actatcacct 540
ctctcacatg tctacttccc caaccaacat ccccaacctc ccccacacta aagttcacgc 600
caataatgta ggcactcttt ctgggtgtgg gacagcagag caatacggag gggagattac 660
acaacgagcc acaattgggg agatggtagc catctcactc gacccgtcga cttttggcaa 720
cgctcaatta cccaccaaat ttgggctgga gttgagggga ccgtgttcca gcgctgtagg 780
accagcaaca cacacggtat caacagcaac caacgccccc gctaatgcac ccagtactgc 840
gcaggtgtgg gccaggtgcg ttccagatgc gagttggcga accctaagcc gacagtgtac 900
tttttgggac gggcagtagc aatcgtgggc ggaaaccccg gtgtatataa aggggtggag 960
aggacggatt attagcacca acacacacac ttatactaca 1000
<210> 23
<211> 1503
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的tHMG
<400> 23
atgacccagt ctgtgaaggt ggttgagaag cacgttccta tcgtcattga gaagcccagc 60
gagaaggagg aggacacctc ttctgaagac tccattgagc tgactgtcgg aaagcagccc 120
aagcccgtga ccgagacccg ttctctggac gacttggagg ctatcatgaa ggcaggtaag 180
accaagctcc tggaggacca cgaggttgtc aagctctctc tcgaaggcaa gctccctttg 240
tatgctcttg agaagcagct tggtgacaac acccgagctg ttggcatccg acgatctatc 300
atctcccagc agtctaatac caagactctt gagacctcaa agctccctta cctgcactac 360
gactacgacc gtgtttttgg agcctgttgc gagaacgtta ttggttacat gcctctcccc 420
gttggtgttg ctggccccat gaacattgat ggcaagaact accacattcc tatggccacc 480
actgagggtt gtcttgttgc ctcaaccatg cgaggttgca aggccatcaa cgccggtggc 540
ggtgttacca ctgtgcttac tcaggacggt atgacacgag gtccttgtgt ttccttcccc 600
tctctcaagc gggctggagc cgctaagatc tggcttgatt ccgaggaggg tctcaagtcc 660
atgcgaaagg ccttcaactc cacctctcga tttgctcgtc tccagtctct tcactctacc 720
cttgctggta acctgctgtt tattcgattc cgaaccacca ctggtgatgc catgggcatg 780
aacatgatct ccaagggcgt cgaacactct ctggccgtca tggtcaagga gtacggcttc 840
cctgatatgg acattgtgtc tgtctcgggt aactactgca ctgacaagaa gcccgcagcg 900
atcaactgga tcgaaggccg aggcaagagt gttgttgccg aagccaccat ccctgctcac 960
attgtcaagt ctgttctcaa aagtgaggtt gacgctcttg ttgagctcaa catcagcaag 1020
aatctgatcg gtagtgccat ggctggctct gtgggaggtt tcaatgcaca cgccgcaaac 1080
ctggtgaccg ccatctacct tgccactggc caggatcctg ctcagaatgt cgagtcttcc 1140
aactgcatca cgctgatgag caacgtcgac ggtaacctgc tcatctccgt ttccatgcct 1200
tctatcgagg tcggtaccat tggtggaggt actattttgg agccccaggg tgctatgctg 1260
gagatgcttg gcgtgcgagg tcctcacatc gagacccccg gtgccaacgc ccaacagctt 1320
gctcgcatca ttgcttctgg agttcttgca gcggagcttt cgctgtgttc tgctcttgct 1380
gccggccatc ttgtgcaaag tcatatgacc cacaaccgtt cccaggctcc tactccggcc 1440
aagcagtctc aggccgatct gcagcgtctc caaaacggtt cgaatatctg cattcggtca 1500
tag 1503
<210> 24
<211> 984
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的GGS
<400> 24
atggattata acagcgcgga tttcaaggag atctggggca aggccgccga caccgcgctg 60
ctgggaccgt acaactacct cgccaacaac cggggccaca acatcagaga acacttgatc 120
gcagcgttcg gagcggttat caaggtggac aagagcgatc tcgaaaccat ttcgcacatc 180
accaagattt tgcataactc gtcgctgctt gttgatgacg tggaagacaa ctcgatgctc 240
cgacgaggcc tgccggcagc ccattgtctg tttggagtcc cccaaaccat caactccgcc 300
aactacatgt actttgtggc tctgcaggag gtgctcaagc tcaagtctta tgatgccgtc 360
tccattttca ccgaggaaat gatcaacttg catagaggtc agggtatgga tctctactgg 420
agagaaacac tcacttgccc ctcggaagac gagtatctgg agatggtggt gcacaagacc 480
ggaggactgt ttcggctggc tctgagactt atgctgtcgg tggcatcgaa acaggaggac 540
catgaaaaga tcaactttga tctcacacac cttaccgaca cactgggagt catttaccag 600
attctggatg attacctcaa cctgcagtcc acggaattga ccgagaacaa gggattctgc 660
gaagatatca gcgaaggaaa gttttcgttt ccgctgattc acagcatccg gaccaacccg 720
gataaccacg agattctcaa cattctcaaa cagcgaacaa gcgacgcttc actcaaaaag 780
tacgccgtgg actacatgag aacagaaacc aagagtttcg actactgcct caagagaatc 840
caggccatgt cactcaaggc aagttcgtac attgatgatc tcgcagcagc cggccacgat 900
gtctccaagt tgcgagccat tttgcattat tttgtgtcca cctctgactg tgaggagaga 960
aagtactttg aggatgcgca gtga 984
<210> 25
<211> 2232
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的来自甜叶菊的CPS
<400> 25
atgtgcaagg ctgtttccaa ggagtactcc gatctgctcc agaaggacga ggcctctttc 60
accaagtggg acgacgacaa ggtcaaggac cacctcgaca ccaacaagaa cctctacccc 120
aacgacgaga tcaaggagtt tgtcgagtcc gtcaaggcca tgttcggctc catgaacgac 180
ggcgagatta atgtctctgc ttacgacacc gcctgggttg ctctggtcca ggatgtcgac 240
ggttccggct ctcctcagtt cccttcctct ctcgagtgga tcgccaacaa ccagctgtcc 300
gacggttctt ggggtgacca cctgctcttc tctgctcacg accgaatcat caacaccctg 360
gcctgtgtca ttgctctgac ctcttggaac gtccacccct ccaagtgcga gaagggtctg 420
aacttcctcc gagagaacat ctgcaagctc gaggacgaga acgccgagca catgcccatt 480
ggcttcgagg tcaccttccc ctctctgatt gacattgcca agaagctcaa cattgaggtc 540
cccgaggaca cccccgctct caaggagatc tacgctcgac gagacatcaa gctcaccaag 600
atccccatgg aggttctcca caaggtcccc accactctcc tccactctct cgagggtatg 660
cccgatctcg agtgggagaa gctgctcaag ctgcagtgca aggacggctc tttcctcttc 720
tccccctctt ccactgcctt cgccctcatg cagaccaagg acgagaagtg tctccagtac 780
ctcaccaaca ttgtcaccaa gttcaacggt ggtgtcccca acgtctaccc cgttgacctc 840
tttgagcaca tctgggttgt tgaccgactc cagcgactcg gtatcgcccg atacttcaag 900
tccgagatca aggactgtgt cgagtacatc aacaagtact ggaccaagaa cggtatctgc 960
tgggcccgaa acacccacgt ccaggacatt gacgacaccg ccatgggctt ccgagttctg 1020
cgagcccacg gctacgatgt cacccccgat gtctttcgac agtttgagaa ggacggcaag 1080
tttgtctgtt tcgccggtca gtccacccag gccgtcaccg gtatgttcaa cgtctaccga 1140
gcttctcaga tgctcttccc cggtgagcga atcctcgagg acgccaagaa gttctcctac 1200
aactacctca aggagaagca gtccaccaac gagctgctcg acaagtggat cattgccaag 1260
gatctgcccg gtgaggttgg ctacgccctc gacatcccct ggtacgcctc tctgccccga 1320
ctggagactc gatactacct cgagcagtac ggtggtgagg acgatgtctg gatcggtaag 1380
accctgtacc gaatgggcta cgtttccaac aacacctacc tcgagatggc caagctcgac 1440
tacaacaact acgttgccgt cctccagctc gagtggtaca ccatccagca gtggtacgtc 1500
gacattggta tcgagaagtt cgagtccgac aacatcaagt ccgtccttgt ctcctactac 1560
ctcgctgctg cctccatctt cgagcccgag cgatccaagg agcgaattgc ctgggccaag 1620
accaccatcc tcgtcgacaa gatcacctcc atcttcgact cctcccagtc ctccaaggaa 1680
gatatcaccg ccttcattga caagttccga aacaagtcct cctccaagaa gcactccatc 1740
aacggcgagc cctggcacga ggtcatggtt gctctcaaga aaactctcca cggctttgcc 1800
ctcgacgctc tgatgaccca ctctcaggac atccaccccc agctccacca ggcctgggag 1860
atgtggctca ccaagctcca ggacggtgtt gatgtcactg ctgagctcat ggtccagatg 1920
atcaacatga ccgccggccg atgggtttcc aaggagctcc tcacccaccc ccagtaccag 1980
cgactctcca ctgtcaccaa ctctgtctgc cacgacatca ccaagctcca caacttcaag 2040
gagaactcca ccaccgtcga ctccaaggtc caggagctgg tccagctcgt tttctccgac 2100
acccccgatg atctcgacca ggacatgaag cagaccttcc tgactgtcat gaaaactttc 2160
tactacaagg cctggtgcga ccccaacacc atcaacgacc acatctccaa ggtctttgag 2220
attgtgattt aa 2232
<210> 26
<211> 2274
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的来自甜叶菊的tKS
<400> 26
atgacctccc acggcggcca gaccaacccc accaacctca tcattgacac caccaaggag 60
cgaatccaga agcagttcaa gaacgtcgag atctccgttt cctcctacga caccgcctgg 120
gtcgccatgg tcccctctcc caactccccc aagtctccct gcttccccga gtgtctcaac 180
tggctcatca acaaccagct caacgacggc tcttggggtc tggtcaacca cacccacaac 240
cacaaccacc ccctcctcaa ggactctctc tcttccactc tcgcctgcat tgttgctctc 300
aagcgatgga acgttggcga ggaccagatc aacaagggtc tgtctttcat tgagtccaac 360
ctcgcctccg ccaccgagaa gtcccagccc tcccccattg gctttgatat catcttcccc 420
ggtctgctcg agtacgccaa gaacctcgat atcaacctgc tctccaagca gaccgacttc 480
tctctcatgc tgcacaagcg agagctcgag cagaagcgat gccactccaa cgagatggac 540
ggctacctgg cctacatttc cgagggtctg ggtaacctct acgactggaa catggtcaag 600
aagtaccaga tgaagaacgg ttccgttttc aactccccct ctgccaccgc tgctgccttc 660
atcaaccacc agaaccccgg ctgtctcaac tacctcaact ctctgctcga caagtttggt 720
aacgccgtcc ccactgtcta cccccacgat ctcttcatcc gactctccat ggtcgacacc 780
attgagcgac tcggtatttc ccaccacttc cgagtcgaga tcaagaacgt tctcgatgag 840
acttaccgat gctgggttga gcgagatgag cagatcttca tggacgttgt cacctgtgct 900
ctggccttcc gactcctccg aatcaacggt tacgaggttt cccccgaccc cctcgccgag 960
atcaccaacg agctggctct caaggacgag tacgccgccc tcgagactta ccacgcttct 1020
cacattctgt accaagagga tctgtcctcc ggcaagcaga ttctcaagtc cgccgacttc 1080
ctcaaggaga tcatctccac tgactccaac cgactctcca agctcatcca caaggaagtc 1140
gagaacgctc tcaagttccc catcaacacc ggtctggagc gaatcaacac ccgacgaaac 1200
atccagctct acaacgtcga caacacccga attctcaaga ccacctacca ctcttccaac 1260
atctccaaca ccgactacct gcgactcgcc gtcgaggact tctacacctg ccagtccatc 1320
taccgagagg agctcaaggg tctggagcga tgggttgtcg agaacaagct cgaccagctc 1380
aagtttgccc gacaaaagac tgcctactgc tacttctccg ttgctgccac cctctcttct 1440
cccgagctct ccgacgcccg aatctcttgg gccaagaacg gtatcctgac cactgttgtc 1500
gacgacttct ttgacattgg tggcaccatt gacgagctga ccaacctcat ccagtgcgtc 1560
gagaagtgga acgtcgacgt tgacaaggac tgttgttccg agcacgtccg aatcctcttc 1620
ctggctctca aggacgccat ctgctggatc ggtgacgagg ccttcaagtg gcaggctcga 1680
gatgtcactt cccacgtcat ccagacctgg ctcgagctca tgaactccat gctgcgagag 1740
gccatctgga cccgagatgc ctacgtcccc accctcaacg agtacatgga gaacgcctac 1800
gtcagctttg ctctcggtcc cattgtcaag cccgccatct actttgtcgg tcccaagctg 1860
tccgaggaga ttgtcgagtc ctccgagtac cacaacctct tcaagctcat gtccacccag 1920
ggccgactcc tcaacgatat ccactccttc aagcgagagt tcaaggaagg taagctcaac 1980
gccgttgctc tgcacctgtc caacggtgag tccggcaagg tcgaggaaga ggtcgtcgag 2040
gagatgatga tgatgatcaa gaacaagcga aaggagctca tgaagctcat cttcgaggag 2100
aacggctcca ttgtcccccg agcctgcaag gacgccttct ggaacatgtg ccacgtcctc 2160
aacttcttct acgccaacga cgacggtttc accggcaaca ccattctcga caccgtcaag 2220
gacatcatct acaaccctct ggttctggtc aacgagaacg aggagcagag gtaa 2274
<210> 27
<211> 1578
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的来自藤仓赤霉菌的KO
<400> 27
atgtccaagt ccaactccat gaactccacc tcccacgaga ctctcttcca gcagctcgtt 60
ctcggcctcg accgaatgcc cctcatggac gtccactggc tcatctacgt tgcctttggt 120
gcctggctct gctcctacgt catccacgtt ctgtcctctt cctccactgt caaggtcccc 180
gtcgtcggtt accgatccgt tttcgagccc acctggctcc tccgactgcg attcgtctgg 240
gagggtggtt ccatcattgg ccagggctac aacaagttca aggactccat cttccaggtc 300
cgaaagctcg gtaccgacat tgtcatcatc cctcccaact acattgacga ggtccgaaag 360
ctctcccagg acaagacccg atccgtcgag cccttcatca acgactttgc cggccagtac 420
acccgaggta tggtctttct gcagtccgat ctccagaacc gagtcatcca gcagcgactc 480
acccccaagc ttgtctctct caccaaggtc atgaaggaag agctcgacta cgctctgacc 540
aaggagatgc ccgacatgaa gaacgacgag tgggttgagg tcgacatctc ttccatcatg 600
gtccgactca tctctcgaat ctccgcccga gttttcctcg gccccgagca ctgccgaaac 660
caggagtggc tcaccaccac cgccgagtac tccgagtctc tcttcatcac cggcttcatc 720
ctccgagttg tcccccacat tctccgaccc ttcattgctc ctctgctgcc ctcttaccga 780
accctgctgc gaaacgtttc ttccggccga cgagtcattg gtgatatcat ccgatcccag 840
cagggtgacg gtaacgagga catcctctct tggatgcgag atgctgccac tggtgaggag 900
aagcagatcg acaacattgc ccagcgaatg ctcattctgt ctctcgcctc catccacacc 960
accgccatga ccatgaccca cgccatgtac gatctgtgtg cctgccccga gtacattgag 1020
cccctccgag atgaggtcaa gtccgtcgtt ggtgcttctg gctgggacaa gaccgctctc 1080
aaccgattcc acaagctcga ctctttcctc aaggagtccc agcgattcaa ccccgttttc 1140
ctgctcacct tcaaccgaat ctaccaccag tccatgaccc tctccgatgg taccaacatc 1200
ccctccggta cccgaattgc tgtcccctct cacgccatgc tccaggactc cgcccacgtc 1260
cccggtccca ctcctcccac tgagttcgac ggtttccgat actccaagat ccgatccgac 1320
tccaactacg cccagaagta cctcttctcc atgaccgact cttccaacat ggcctttggc 1380
tacggtaagt acgcctgccc cggccgattc tacgcctcca acgagatgaa gctgactctg 1440
gccattctgc tcctccagtt tgagttcaag ctccccgacg gtaagggccg accccgaaac 1500
atcaccatcg actccgacat gatccccgac ccccgagctc gactctgtgt ccgaaagcga 1560
tctctgcgtg acgagtaa 1578
<210> 28
<211> 1578
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的KAH_4
<400> 28
atggagtctc tggttgtcca caccgtcaac gccatctggt gcattgtcat tgtcggtatc 60
ttctccgtcg gctaccacgt ctacggccga gctgttgtcg agcagtggcg aatgcgacga 120
tctctcaagc tccagggtgt caagggtcct cctccctcca tcttcaacgg taacgtttcc 180
gagatgcagc gaatccagtc cgaggccaag cactgctccg gtgacaacat catctcccac 240
gactactctt cttctctgtt cccccacttt gaccactggc gaaagcagta cggccgaatc 300
tacacctact ccactggcct caagcagcac ctctacatca accaccccga gatggtcaag 360
gagctctccc agaccaacac cctcaacctc ggccgaatca cccacatcac caagcgactc 420
aaccccattc tcggtaacgg tatcatcacc tccaacggcc cccactgggc ccaccagcga 480
cgaatcattg cctacgagtt cacccacgac aagatcaagg gtatggtcgg tctgatggtc 540
gagtccgcca tgcccatgct caacaagtgg gaggagatgg tcaagcgagg tggtgagatg 600
ggctgtgaca tccgagtcga cgaggacctc aaggatgtct ccgctgacgt cattgccaag 660
gcctgtttcg gctcttcctt ctccaagggc aaggccatct tctccatgat ccgagatctg 720
ctcaccgcca tcaccaagcg atccgtcctc ttccgattca acggtttcac cgacatggtt 780
ttcggctcca agaagcacgg tgacgttgac attgacgctc tcgagatgga gctcgagtcc 840
tccatctggg agactgtcaa ggagcgagag attgagtgca aggacaccca caagaaggac 900
ctcatgcagc tcattctcga gggtgccatg cgatcttgtg acggtaacct gtgggacaag 960
tctgcttacc gacgattcgt tgtcgacaac tgcaagtcca tctactttgc cggccacgac 1020
tccaccgccg tttccgtttc ttggtgcctc atgctgctcg ctctcaaccc ctcttggcag 1080
gtcaagatcc gagatgagat tctgtcctcc tgcaagaacg gtatccccga cgccgagtcc 1140
atccccaacc tcaagaccgt caccatggtc atccaggaga ctatgcgact ctaccctccc 1200
gctcccattg tcggccgaga ggcctccaag gacattcgac tcggtgatct ggttgtcccc 1260
aagggtgtct gtatctggac cctcatcccc gctctgcacc gagatcccga gatctggggt 1320
cccgacgcca acgacttcaa gcccgagcga ttctccgagg gtatctccaa ggcctgcaag 1380
tacccccagt cctacatccc ctttggcctc ggcccccgaa cctgtgtcgg caagaacttt 1440
ggtatgatgg aggtcaaggt cctcgtttct ctgattgtct ccaagttctc cttcactctg 1500
tctcccacct accagcactc tccctcccac aagctgctcg tcgagcccca gcacggtgtt 1560
gtcatccgag ttgtataa 1578
<210> 29
<211> 2133
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的KAH_4
<400> 29
atgtcctcct cttcttcttc ttccacctcc atgattgatc tcatggctgc catcatcaag 60
ggtgagcccg tcattgtctc cgaccccgcc aacgcctccg cctacgagtc cgttgctgcc 120
gagctgtcct ccatgctcat cgagaaccga cagtttgcca tgatcgtcac cacctccatt 180
gctgttctca ttggctgcat tgtcatgctc gtctggcgac gatctggctc cggtaactcc 240
aagcgagtcg agcccctcaa gcccctggtc atcaagcccc gagaagagga gatcgacgac 300
ggccgaaaga aggtcaccat cttctttggc acccagaccg gtactgctga gggcttcgcc 360
aaggctctcg gtgaggaagc caaggctcga tacgaaaaga cccgattcaa gattgtcgac 420
ctcgatgatt acgctgccga tgacgacgag tacgaggaga agctcaagaa agaggacgtt 480
gccttcttct tcctcgccac ctacggtgac ggtgagccca ccgacaacgc tgcccgattc 540
tacaagtggt tcaccgaggg taacgaccga ggcgagtggc tcaagaacct caagtacggt 600
gttttcggtc tgggcaaccg acagtacgag cacttcaaca aggttgccaa ggttgtcgac 660
gacatcctcg tcgagcaggg tgcccagcga ctcgtccagg tcggcctcgg tgatgatgac 720
cagtgcatcg aggacgactt cactgcctgg cgagaggctc tgtggcccga gctcgacacc 780
attctgcgag aggaaggtga caccgccgtt gccaccccct acaccgccgc cgtcctcgag 840
taccgagtct ccatccacga ctccgaggat gccaagttca acgacatcaa catggccaac 900
ggtaacggct acaccgtctt tgacgcccag cacccctaca aggccaacgt cgccgtcaag 960
cgagagctcc acacccccga gtccgaccga tcttgtatcc acctcgagtt tgacattgct 1020
ggttccggtc tgacctacga gactggtgac cacgttggtg tcctctgtga caacctgtcc 1080
gagactgtcg acgaggctct gcgactcctc gacatgtccc ccgacactta cttctctctg 1140
cacgccgaga aagaggacgg tactcccatc tcttcttctc tgccccctcc cttccctccc 1200
tgcaacctgc gaaccgctct gacccgatac gcctgcctcc tctcttctcc caagaagtct 1260
gctctcgttg ctctggccgc ccacgcctcc gaccccaccg aggctgagcg actcaagcac 1320
ctcgcctctc ccgctggcaa ggacgagtac tccaagtggg ttgtcgagtc ccagcgatct 1380
ctgctcgagg tcatggccga gttcccctcc gccaagcccc ctctcggtgt tttcttcgcc 1440
ggtgttgctc cccgactcca gccccgattc tactccatct cctcttcccc caagatcgcc 1500
gagactcgaa tccacgttac ctgtgctctg gtctacgaga agatgcccac cggccgaatc 1560
cacaagggtg tctgctccac ctggatgaag aacgccgttc cctacgagaa gtccgagaac 1620
tgttcctctg ctcccatctt tgtccgacag tccaacttca agctcccctc cgactccaag 1680
gtccccatca tcatgattgg ccccggtacc ggcctcgccc ccttccgagg cttcctgcag 1740
gagcgactcg ccctcgtcga gtccggtgtc gagctcggcc cctccgtcct cttctttggc 1800
tgccgaaacc gacgaatgga cttcatctac gaagaggagc tccagcgatt cgtcgagtcc 1860
ggtgctctcg ccgagctctc cgttgccttc tcccgagagg gtcccaccaa ggagtacgtc 1920
cagcacaaga tgatggacaa ggcctccgac atctggaaca tgatctccca gggcgcctac 1980
ctctacgtct gcggtgacgc caagggtatg gcccgagatg tccaccgatc tctgcacacc 2040
attgcccagg agcagggctc catggactcc accaaggccg agggtttcgt caagaacctc 2100
cagacctccg gccgatacct ccgagatgtc tgg 2133
<210> 30
<211> 1446
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的UGT1
<400> 30
atggacgcca tggccaccac cgagaagaag ccccacgtca tcttcatccc cttccccgcc 60
cagtcccaca tcaaggccat gctcaagctc gcccagctcc tccaccacaa gggcctccag 120
atcacctttg tcaacaccga cttcatccac aaccagttcc tcgagtcctc cggcccccac 180
tgtctggacg gtgctcccgg tttccgattt gagactatcc ccgatggtgt ctcccactcc 240
cccgaggcct ccatccccat ccgagagtct ctgctccgat ccattgagac taacttcctc 300
gaccgattca ttgatctcgt caccaagctc cccgatcctc ccacctgtat catctccgac 360
ggtttcctgt ccgttttcac cattgatgct gccaagaagc tcggtatccc cgtcatgatg 420
tactggactc tggctgcctg tggtttcatg ggtttctacc acatccactc tctgatcgag 480
aagggctttg ctcctctcaa ggacgcctcc tacctcacca acggttacct cgacaccgtc 540
attgactggg tccccggtat ggagggtatc cgactcaagg acttccccct cgactggtcc 600
accgacctca acgacaaggt tctcatgttc accaccgagg ctccccagcg atcccacaag 660
gtttcccacc acatcttcca caccttcgac gagctcgagc cctccatcat caagactctg 720
tctctgcgat acaaccacat ctacaccatt ggccccctcc agctcctcct cgaccagatc 780
cccgaggaga agaagcagac cggtatcacc tctctgcacg gctactctct cgtcaaggaa 840
gagcccgagt gcttccagtg gctccagtcc aaggagccca actccgttgt ctacgtcaac 900
tttggctcca ccaccgtcat gtctctcgag gacatgaccg agtttggctg gggtctggcc 960
aactccaacc actacttcct gtggatcatc cgatccaacc tcgtcattgg cgagaacgcc 1020
gttctgcctc ccgagctcga ggagcacatc aagaagcgag gcttcattgc ctcttggtgc 1080
tcccaggaga aggttctcaa gcacccctcc gtcggtggtt tcctgaccca ctgcggctgg 1140
ggctccacca ttgagtctct gtccgctggt gtccccatga tctgctggcc ctactcctgg 1200
gaccagctca ccaactgccg atacatctgc aaggagtggg aggttggtct ggagatgggt 1260
accaaggtca agcgagatga ggtcaagcga ctcgtccagg agctcatggg cgagggtggt 1320
cacaagatgc gaaacaaggc caaggactgg aaggagaagg cccgaattgc cattgccccc 1380
aacggctctt cttctctcaa cattgacaag atggtcaagg agatcactgt tctcgctcga 1440
aactaa 1446
<210> 31
<211> 1419
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的UGT2变体
<400> 31
atggccacct ccgactccat tgttgacgac cgaaagaagc tccacattgt catgttcccc 60
tggctcgcct ttggccacat catcccctat ctcgagcttt ccaagctcat tgcccagaag 120
ggccacaagg tttccttcct ctccaccacc aagaacattg accgactctc ctcccacatc 180
tctcccctca tcaactttgt caagctcacc ctcccccgag tccaggagct gcccgaggac 240
gccgaggcca ccactgatgt ccaccccgag gatatcccct acctcaagaa ggcctccgac 300
ggcctccagc ccgaggtcac tgagttcctc gagcagcact ctcccgactg gatcatctac 360
gactacaccc actactggct ccccgagatt gccaagtctc tcggtgtctc tcgagcccac 420
ttctccgtca ccaccccctg ggccattgct tacatgggtc ccactgccga tgccatgatc 480
aacggttccg actaccgaac cgagcttgag gacttcaccg tccctcccaa gtggttcccc 540
ttccccacca ccgtctgctg gcgaaagcac gatctggccc gactcgtccc ctacaaggct 600
cccggtatct ccgacggtta ccgaatgggc ctcgtcatca agggctgcga ctgtctgctc 660
tccaagacct accacgagtt cggtactcag tggctccgac ttctcgagga gctgcaccga 720
gtccccgtca tccccgttgg tctgctccct ccctccatcc ccggctctga caaggacgac 780
tcttgggttt ccatcaagga gtggctcgac ggccaggaga agggctccgt tgtctacgtt 840
gctctcggtt ccgaggttct cgtcacccag gaagaggttg tcgagcttgc tcacggtctg 900
gagctgtccg gtctgccctt cttctgggcc taccgaaagc ccaagggtcc cgccaagtcc 960
gactccgtcg agcttcccga tggtttcgtc gagcgagtcc gagatcgagg tctggtctgg 1020
acctcttggg ctccccagct ccgaatcctc tcccacgagt ccgttgctgg tttcctcacc 1080
cactgcggtt ccggctccat tgtcgagggc ctcatgttcg gccaccctct catcatgctc 1140
cccatcttcg gtgaccagcc cctcaacgcc cgactccttg aggacaagca ggtcggtatc 1200
gagatccccc gaaacgagga agatggttct ttcacccgag actctgttgc cgagtctctg 1260
cgactcgtca tggtcgagga agagggtaag atctaccgag agaaggccaa ggagatgtcc 1320
aagctctttg gcgacaagga cctccaggac cagtacgtcg acgactttgt cgagtacctc 1380
cagaagcacc gacgagctgt tgccattgac cacgaaagc 1419
<210> 32
<211> 1383
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的UGT3的
<400> 32
atggccgagc agcagaagat caagaagtct ccccacgttc tgctcatccc cttccctctg 60
cagggccaca tcaacccctt catccagttc ggcaagcgac tcatctccaa gggtgtcaag 120
accactctgg tcaccaccat ccacaccctc aactccactc tcaaccactc caacaccacc 180
accacctcca tcgagatcca ggccatctcc gacggctgtg acgagggtgg tttcatgtct 240
gctggtgagt cttacctcga gactttcaag caggtcggtt ccaagtctct ggctgacctc 300
atcaagaagc tccagtccga gggtaccacc attgacgcca tcatctacga ctccatgacc 360
gagtgggttc tcgatgtcgc catcgagttt ggtattgacg gtggctcctt cttcacccag 420
gcctgtgtcg tcaactctct ctactaccac gtccacaagg gtctgatctc tctgcccctc 480
ggcgagactg tctccgtccc cggtttcccc gttctgcagc gatgggagac tcctctcatt 540
ctccagaacc acgagcagat ccagtccccc tggtcccaga tgctcttcgg ccagttcgcc 600
aacattgacc aggcccgatg ggttttcacc aactccttct acaagctcga ggaagaggtc 660
attgagtgga cccgaaagat ctggaacctc aaggtcattg gccccaccct cccctccatg 720
tacctcgaca agcgactcga tgacgacaag gacaacggtt tcaacctcta caaggccaac 780
caccacgagt gcatgaactg gctcgacgac aagcccaagg agtccgttgt ctacgttgcc 840
tttggctctc tggtcaagca cggccccgag caggttgagg agatcacccg agctctgatt 900
gactccgatg tcaacttcct gtgggtcatc aagcacaagg aagagggtaa gctccccgag 960
aacctgtccg aggtcatcaa gaccggcaag ggcctcattg ttgcctggtg caagcagctc 1020
gacgttctcg cccacgagtc cgtcggctgc tttgtcaccc actgcggttt caactccacc 1080
ctcgaggcta tctctctcgg tgtccccgtt gttgccatgc cccagttctc cgaccagacc 1140
accaacgcca agctcctcga tgagattctc ggtgtcggtg tccgagtcaa ggctgacgag 1200
aacggtattg tccgacgagg taacctggct tcttgtatca agatgatcat ggaggaagag 1260
cgaggtgtca tcatccgaaa gaacgccgtc aagtggaagg atctggccaa ggttgctgtc 1320
cacgagggtg gctcttccga caacgacatt gtcgagtttg tctccgagct catcaaggcc 1380
taa 1383
<210> 33
<211> 1377
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的UGT4
<400> 33
atggagaaca agaccgagac taccgtccga cgacgacgac gaatcattct cttccccgtc 60
cccttccagg gccacatcaa ccccattctg cagctcgcca acgttctgta ctccaagggc 120
ttctccatca ccatcttcca caccaacttc aacaagccca agacctccaa ctacccccac 180
ttcactttcc gattcatcct cgacaacgac ccccaggacg agcgaatctc caacctgccc 240
acccacggtc ctctggctgg tatgcgaatc cccatcatca acgagcacgg tgctgacgag 300
ctccgacgag agctcgagct gctcatgctc gcctccgaag aggacgagga agtctcctgt 360
ctgatcaccg atgctctgtg gtactttgcc cagtccgtcg ccgactctct caacctgcga 420
cgactcgttc tcatgacctc ctctctgttc aacttccacg cccacgtttc tctgccccag 480
tttgacgagc tcggttacct cgaccccgat gacaagaccc gactcgagga gcaggcttcc 540
ggtttcccca tgctcaaggt caaggacatc aagtccgcct actccaactg gcagattctc 600
aaggagattc tcggcaagat gatcaagcag accaaggcct cctccggtgt catctggaac 660
tccttcaagg agctcgagga gtccgagctc gagactgtca tccgagagat ccccgctccc 720
tctttcctca tccccctgcc caagcacctc accgcttcct cctcttctct gctcgaccac 780
gaccgaaccg tctttcagtg gctcgaccag cagccccctt cctccgtcct ctacgtttcc 840
ttcggctcca cctccgaggt cgacgagaag gacttcctcg agattgctcg aggcctcgtt 900
gactccaagc agtccttcct gtgggttgtc cgacccggct ttgtcaaggg ctccacctgg 960
gttgagcccc tgcccgatgg tttcctcggt gagcgaggcc gaattgtcaa gtgggtcccc 1020
cagcaggaag ttctggccca cggtgccatt ggtgccttct ggacccactc cggctggaac 1080
tccactctcg agtccgtctg cgagggtgtc cccatgatct tctccgactt tggcctcgac 1140
cagcccctca acgcccgata catgtccgat gttctcaagg tcggtgtcta cctcgagaac 1200
ggctgggagc gaggtgagat tgccaacgcc atccgacgag tcatggtcga cgaggaaggt 1260
gagtacatcc gacagaacgc ccgagtcctc aagcagaagg ccgatgtctc tctcatgaag 1320
ggtggttctt cttacgagtc tctcgagtct ctcgtttcct acatctcttc tttgtaa 1377
<210> 34
<211> 1419
<212> DNA
<213> 人工序列()
<220>
<223> 针对在解脂耶氏酵母中表达优化的UGT2变体
<400> 34
atggctactt ccgactccat tgtcgacgac cgaaagaagc tccacattgt catgttcccc 60
tggctcgcct ttggccacat cattccctac ctcgagcttt ccaagctcat tgcccagaag 120
ggccacaagg tttctttcct ctccaccacc aagaacattg accgactctc ctcccacatc 180
tctcctctca tcaacgttgt ccagctcacc ctcccccgag tccaggagct gcccgaggac 240
gccgaggcca ccaccgatgt ccaccccgag gatatcccct acctcaagaa ggcctccgac 300
ggtctgcagc ccgaggtcac cgagttcctc gagcagcact ctcccgactg gatcatctac 360
gactacaccc actactggct cccctccatt gccaccaagc acggtgtctc tcgagcccac 420
ttctccgtca ccaccccctg ggccattgcc tacatgggcc ccactgctga cgccatgatc 480
aacggttccg atggccgaac cacccccgag gacttcactg tccctcccaa gtggttcccc 540
ttccccacca aggtctgctg gcgaaagcac gatctggccc gactcgttcc ctacaaggcc 600
cccggtatct ccgacggcta ccgaatgggt ctggtcatca agggctgcga ctgtctgctc 660
tccaagacct accacgagtt tggcacccag tggctccgac tcctcgagac tctccaccga 720
aagcccgtca tccccgtcgg tctgctccct ccctccatcc ccggctccga caaggacgac 780
tcttgggttt ccatcaagga gtggctcgac ggccaggaga agggctctgt tgtctacgtt 840
gctctcggtt ccgaggttct cgtcacccag gacgaggttg ttgagctggc ccacggtctg 900
gagctgtccg gcctcccctt cgtctgggct taccgaaacc ccaagggtcc cgccaagtcc 960
gactccgtcg agcttcccga tggtttcgtc gagcgagtcc gagatcgagg tctggtctgg 1020
acctcttggg ctccccagct ccgaatcctc tcccacgagt ccgtctgtgg tttcctcacc 1080
cactgcggtt ccggctccat cgtcgagggt ctgatgttcg gccaccccct catcatgctc 1140
cccatcttcg gtgaccagcc cctcaacgcc cgactccttg aggacaagca ggtcggtatc 1200
gagatccccc gaaacgaaga ggacggttcc ttcacccgag actctgttgc tgagtctctc 1260
cgactcgtca tggtcgagga agagggtaag atctaccgag agaaggccaa ggagatgtcc 1320
aagctgttcg gtgacaagga tctccaggac cagtacgtcg acgactttgt cgagtacctc 1380
cagaagcacc gacgagctgt tgccattgac cacgagtct 1419
Claims (20)
1.一种包含编码多肽的重组核酸序列的重组宿主,该多肽包含:
a.SEQ ID NO:1中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
b.SEQ ID NO:2中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;
c.SEQ ID NO:3中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列;或
d.SEQ ID NO:4中所示的氨基酸序列或与其具有至少约30%序列同一性的氨基酸序列。
2.根据权利要求1所述的重组宿主,其能够产生糖基化二萜。
3.根据权利要求1或2所述的重组宿主,其包含一个或更多个重组核苷酸序列,所述重组核苷酸序列编码:
具有对映-柯巴基焦磷酸合酶活性的多肽;
具有对映-贝壳杉烯合酶活性的多肽;
具有对映-贝壳杉烯氧化酶活性的多肽;以及
具有贝壳杉烯酸13-羟化酶活性的多肽。
4.根据前述权利要求中任一项所述的重组宿主,其包含重组核酸序列,所述重组核酸序列编码具有NADPH-细胞色素p450还原酶活性的多肽。
5.根据前述权利要求中任一项所述的重组宿主,其包含编码以下中的一种或更多种的重组核酸序列:
(i)具有UGT74G1活性(UGT3活性)的多肽;
(ii)具有UGT85C2活性(UGT1活性)的多肽;以及
(iii)具有UGT76G1活性(UGT4活性)的多肽。
6.根据前述权利要求中任一项所述的重组宿主,其包含重组核酸序列,所述重组核酸序列编码具有UGT2活性的额外多肽。
7.根据前述权利要求中任一项所述的重组宿主,其中所述宿主属于以下属中的一种:酵母属(Saccharomyces)、曲霉属(Aspergillus)、毕赤酵母属(Pichia)、克鲁维酵母属(Kluyveromyces)、假丝酵母属(Candida)、汉逊酵母属(Hansenula)、腐质霉属(Humicola)、伊萨酵母属(Issatchenkia)、毛孢子菌属(Trichosporon)、酒香酵母属(Brettanomyces)、管囊酵母属(Pachysolen)、耶氏酵母属(Yarrowia)、Yamadazyma或埃希氏杆菌属(Escherichia)。
8.根据权利要求7所述的重组宿主,其中所述重组宿主是酿酒酵母(Saccharomycescerevisiae)细胞、解脂耶氏酵母(Yarrowia lipolitica)细胞、克鲁斯假丝酵母(Candidakrusei)细胞、东方伊萨酵母(Issatchenkia orientalis)细胞或大肠杆菌(Escherichiacoli)细胞。
9.根据前述权利要求中任一项所述的重组宿主,其中所述宿主产生香叶基香叶基二磷酸(GGPP)的能力被上调。
10.根据前述权利要求中任一项所述的重组宿主,其包含一个或更多个编码羟甲基戊二酰基-辅酶A还原酶、法尼基-焦磷酸合成酶和香叶基香叶基二磷酸合酶的重组核酸序列。
11.根据前述权利要求中任一项所述的重组宿主,其包含编码以下中的一种或更多种的核酸序列:
具有羟甲基戊二酰基-辅酶A还原酶活性的多肽;
具有法尼基-焦磷酸合成酶活性的多肽;
具有香叶基香叶基二磷酸合酶活性的多肽。
12.一种用于制备糖基化二萜的方法,所述方法包括在合适的发酵培养基中发酵根据权利要求2至11中任一项所述的重组宿主,并且任选地回收所述糖基化二萜。
13.根据权利要求12所述的方法,其用于制备糖基化二萜,其中所述方法以工业规模进行。
14.一种发酵液,其包含能够通过根据权利要求12或13所述的方法获得的糖基化二萜。
15.一种糖基化二萜,其通过根据权利要求12或13所述的方法获得或能够从根据权利要求14所述的发酵液获得。
16.一种组合物,其包含通过根据权利要求12或13所述方法获得或能够从根据权利要求14所述的发酵液获得的两种或更多种糖基化二萜。
17.一种食品、饲料或饮料,其包含根据权利要求15所述的糖基化二萜或根据权利要求16所述的组合物。
18.一种用于将第一糖基化二萜转化为第二糖基化二萜的方法,所述方法包括:
–使所述第一糖基化二萜与根据权利要求1至11中任一项所述的重组宿主、源自这种重组宿主的无细胞提取物或源自上述任一者的酶制剂接触;
–从而将所述第一糖基化二萜转化为所述第二糖基化二萜。
19.根据权利要求18所述的方法,其中所述第二糖基化二萜是:甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
20.根据权利要求19所述的方法,其中所述第一糖基化二萜是甜菊醇-13-单糖苷、甜菊醇-19-单糖苷、甜茶苷、甜菊苷、莱鲍迪甙A或13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯,并且所述第二糖基化二萜是甜菊醇-19-双糖苷、甜菊双糖苷、甜菊苷、13-[(β-D-吡喃葡萄糖基)氧基)贝壳杉-16-烯-18-酸2-O-β-D-吡喃葡萄糖基-β-D-吡喃葡萄糖基酯、RebE或RebD。
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PCT/EP2016/056449 WO2016151046A1 (en) | 2015-03-23 | 2016-03-23 | Udp-glycosyltransferases from solanum lycopersicum |
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EP (2) | EP3274448B1 (zh) |
CN (1) | CN107429238A (zh) |
BR (1) | BR112017020308A2 (zh) |
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WO2018144679A2 (en) * | 2017-02-03 | 2018-08-09 | Codexis, Inc. | Engineered glycosyltransferases and steviol glycoside glucosylation methods |
WO2018224698A1 (en) | 2017-08-23 | 2018-12-13 | Dsm Ip Assets B.V. | Yoghurt comprising rebaudioside m |
AU2019304965A1 (en) * | 2018-07-16 | 2021-02-11 | Manus Bio, Inc. | Production of steviol glycosides through whole cell biotransformation |
JP6911205B2 (ja) * | 2018-12-07 | 2021-07-28 | サントリーホールディングス株式会社 | 組成物 |
US20230174993A1 (en) * | 2020-05-13 | 2023-06-08 | Ginkgo Bioworks, Inc. | Biosynthesis of mogrosides |
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CN112979354A (zh) * | 2019-12-02 | 2021-06-18 | 韩玉才 | 一种食用菌废料制备有机肥的配方及方法 |
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US20180057850A1 (en) | 2018-03-01 |
EP3274448B1 (en) | 2021-08-11 |
EP3988653A3 (en) | 2022-07-27 |
CA2979957A1 (en) | 2016-09-29 |
BR112017020308A2 (pt) | 2018-07-10 |
EP3274448A1 (en) | 2018-01-31 |
EP3988653A2 (en) | 2022-04-27 |
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