CN113166789A - 岩藻糖基化寡糖lnfp-v的合成 - Google Patents
岩藻糖基化寡糖lnfp-v的合成 Download PDFInfo
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Abstract
本发明提供了一种通过使用重组细菌细胞生物技术生产LNFP‑V的方法。LNFP‑V通过使用具有α1,3/4‑岩藻糖基转移酶活性的多肽来生产,该多肽包含与SEQ ID No.1或3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
Description
技术领域
本发明涉及生物技术领域,特别是涉及使用遗传修饰的微生物,特别是大肠杆菌(E.coli)的重组岩藻糖基化寡糖LNFP-V的微生物生产,以及所述遗传修饰的细胞的构建。
背景技术
近年来,由于哺乳动物乳中包含的包括寡糖在内的复合碳水化合物在活生物体中发生的许多生物过程中的作用,其合成的商业化努力显著增加。人乳寡糖(HMO)正成为营养和治疗行业的重要商业目标。现在已报道了200多种HMO,并且已阐明了130多种HMO结构(Urashima等人:“乳寡糖(Milk Oligosaccharides)”.《Nova Biomedical Books》,纽约(2011);Chen Adv.Carbohydr.Chem.Biochem.72,113(2015))。尽管最近具有更简单结构的HMO(例如工业规模的三糖2'-岩藻糖基乳糖)的合成和纯化已由多家制造商使用包含利用遗传修饰的微生物的生物技术方法完成,但对于更复杂结构的HMO而言,同样的任务仍然具有挑战性。
乳酰-N-岩藻五糖V(LNFP-V)是一种中性五糖,于1976年首次从人乳中分离出来。其结构被确定为四糖乳-N-四糖(LNT),在葡萄糖残基上用α1,3-偶联物(Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc,方案1;Ginsburg等人,Arch.Biochem.Biophys.175,565(1976))进行岩藻糖基化。
方案1.LNFP-V的结构
人乳中LNFP-V的平均浓度为0.18g/l(Erney等人,J.PediatricGastroenterol.Nutr.30,181(2000))。由于其浓度低,从人乳中分隔和分离LNFP-V似乎不经济。迄今为止,还没有关于LNFP-V的酶促或化学全合成的报道。关于生物技术方法,使用重组大肠杆菌在实验室规模的发酵过程中从乳糖生产LNFP-V,所述重组大肠杆菌包含分别编码和表达β1,3-N-乙酰氨基葡萄糖转移酶、β1,3-半乳糖基转移酶和α1,3/4-岩藻糖基转移酶的质粒携带的异源基因IgtA、galTK和fucTIII(M.Randriantsoa:Synthesemicrobiologique des antigenes glucidiques des groupes sanguins,These soutenuea I’Universite Joseph Fourier,Grenoble,2008)。
Bioorg.Med.Chem.23,6799(2015)和WO 2016/008602的作者公开了一种不含质粒的重组大肠杆菌,其包含分别编码和表达β1,3-N-乙酰氨基葡萄糖转移酶、β1,3-半乳糖基转移酶和α1,3/4-岩藻糖基转移酶的基因IgtA、wbgO和fucTIII,其在培养后能够产生六糖LNDFH-II,但没有形成LNFP-V的报道。
最近,据报道,LNFP-V对艰难梭菌的毒素A的碳水化合物结合结构域显示出结合亲和力(Nguyen等人,J.Microbiol.Biotechnol.26,659(2016))。已知艰难梭菌是医院腹泻的主要原因(Kyne等人,Clin.Infect.Dis.34,346(2002))。
因此,需要一种允许以安全且成本效益好的方式生产足够量的分离的LNFP-V的方法。
发明内容
本发明提供了通过使用重组细菌细胞的生物技术生产LNFP-V的方法。
因此,在第一方面,本发明涉及遗传修饰的微生物或细胞,优选细菌细胞,更优选大肠杆菌细胞,其包含选自由β1,3-N-乙酰氨基葡萄糖转移酶、β1,3-半乳糖基转移酶和α1,3/4-岩藻糖基转移酶组成的三种功能活性异源糖基转移酶,其中α1,3/4-岩藻糖基转移酶由选自幽门螺杆菌(H.pylori)的fucT基因、幽门螺杆菌的futA基因及其功能变体/突变体的核酸序列编码,并且其中编码所述异源糖基转移酶的核酸序列整合到微生物或细胞的基因组中。优选地,由于天然β-半乳糖苷酶基因,优选lacZ的缺失或失活,重组微生物或细胞缺乏细胞内β-半乳糖苷酶活性。
本发明的第二方面涉及用于生产LNFP-V的方法,该方法包括:
-提供如本发明的第一方面所公开的遗传修饰的微生物或细胞,
-在乳糖存在下培养所述微生物或细胞,和
-从所述微生物或细胞、从培养基或从两者分离LNFP-V。
本发明的第三方面涉及一种蛋白质(多肽),其包含由SEQ ID No.7表征的氨基酸序列或由其组成。包含由SEQ ID No.7表征的氨基酸序列或由其组成的蛋白质(多肽)具有α1,3/4-岩藻糖基转移酶活性。
本发明的第四方面涉及具有α1,3/4-岩藻糖基转移酶活性的多肽在生产LNFP-V中的用途,该多肽选自:
-多肽,其包含与SEQ ID No.1的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成,和
-多肽,其包含与SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
附图说明
下文中将参考附图进一步详细描述本发明,其中显示了US6974687(GenBank ID:BD182026)中描述的幽门螺杆菌β1,3-半乳糖基转移酶序列与本发明的实施例中使用的galTK编码的GalTKβ1,3-半乳糖基转移酶序列的比对。
具体实施方式
在岩藻糖基化的乳-N-四糖(LNT)的酶促合成中,注意力主要集中在将岩藻糖连接到N-乙酰氨基葡萄糖上,从而构建携带Lewis A人抗原的结构。Bioorg.Med.Chem.23,6799(2015)和WO 2016/008602的作者构建了能够合成LNT的遗传修饰的大肠杆菌,并且在细胞中引入了异源α1,3/4-岩藻糖基转移酶(由质粒或基因组整合的来自幽门螺杆菌菌株DSM6709的α1,3/4-岩藻糖基转移酶fucTIII基因表达(Rabbani等人,《糖生物学(Glycobiology)》15,1076(2005))。培养后,检测和表征的主要产物是双岩藻糖基化的LNT(乳-N-二岩藻六糖II,LNDFH-II),其在N-乙酰氨基葡萄糖上带有第一个岩藻糖残基,在葡萄糖上带有第二岩藻糖基团。在检测到的产物中未鉴定出单岩藻糖基化的LNT。
其他作者(M.Randriantsoa:Synthese microbiologique desantigenesglucidiques des groupes sanguins,These soutenue a I’UniversiteJosephFourier,Grenoble,2008)证明了表达异源β1,3-N-乙酰氨基葡萄糖转移酶、异源β1,3-半乳糖基转移酶和来自质粒的上述相同异源α1,3/4-岩藻糖基转移酶的遗传修饰的大肠杆菌菌株能够产生单岩藻糖基化的乳-N-四糖LNFP-V,并且伴有LNT和LNDFH-II。
出人意料的是,本发明人通过引入选择的编码α1,3/4-岩藻糖基转移酶的异源基因,成功地构建了产生大量LNFP-V作为主要代谢产物的基因组修饰菌株。
因此,本发明涉及能够从乳糖产生LNFP-V的遗传修饰的微生物或细胞,有利地为细菌细胞,优选为大肠杆菌,并且包含:
-基因组整合的异源核酸序列,其编码具有β1,3-N-乙酰氨基葡萄糖转移酶活性的多肽,
-基因组整合的异源核酸序列,其编码具有β1,3-半乳糖基转移酶活性的多肽,和
-基因组整合的异源核酸序列,其编码具有α1,3/4-岩藻糖基转移酶活性的多肽,
其中具有α1,3/4-岩藻糖基转移酶活性的多肽选自:
-多肽,其包含与SEQ ID No.1的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成,和
-多肽,其包含与SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
因此,本文公开的能够从乳糖产生LNFP-V的遗传修饰的微生物或细胞含有并表达三种编码蛋白质的异源糖基转移酶(称为β1,3-N-乙酰氨基葡萄糖转移酶、β1,3-半乳糖基转移酶和α1,3/4-岩藻糖基转移酶)基因,所述蛋白质对于从乳糖合成LNFP-V是合适和必需的,并且所述异源糖基转移酶基因整合到微生物或细胞的基因组中。表达的异源α1,3/4-岩藻糖基转移酶是一种多肽,其包含与SEQ ID No.1或SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
在某些实施方式中,表达的异源α1,3/4-岩藻糖基转移酶包含与SEQ ID No.1或SEQ ID No.3(视情况而定)具有至少92%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的多肽或由其组成。
SEQ ID No.1的多肽是幽门螺杆菌NCTC 11639(GenBank ID:AAB81031.1,Ge等人,J.Biol.Chem.272,21357(1997),参见下文SEQ ID No.2)的天然α1,3/4-岩藻糖基转移酶的截短形式,在本文中称为“截短的FucT”。截短的FucT缺少构成由SEQ ID No.2表征的整个原始蛋白质的C-末端的37个氨基酸(Ma等人,J.Biol.Chem.281,6385(2006))。截短的FucT由幽门螺杆菌NCTC 11639的相应截短的fucT基因编码(有关整个fucT,参见GenBank ID:AF008596.1)。
在一个实施方式中,包含SEQ ID No.1的氨基酸序列的多肽是幽门螺杆菌NCTC11639(GenBank ID:AAB81031.1,Ge等人,J.Biol.Chem.272,21357(1997))的α1,3/4-岩藻糖基转移酶的全长,其特征在于SEQ ID No.2,在本文中称为FucT。FucT由幽门螺杆菌NCTC11639(GenBank ID:AF008596.1)的fucT基因编码。
SEQ ID No.3的多肽是幽门螺杆菌ATCC 26695(GenBank ID:NP_207177.1)的α1,3/4-岩藻糖基转移酶,在本文中称为FutA。FutA由幽门螺杆菌NCTC 26695的futA基因编码。
在一个实施方式中,表达的异源α1,3/4-岩藻糖基转移酶包含与SEQ ID No.4相同的多肽或优选由其组成。根据SEQ ID No.4的蛋白质是FutA的功能变体,其中128位的Ala(A)被Asn(N)置换,且129位的His(H)被Glu(E)置换(Choi等人.Biotechnol.Bioengirt.113,1666(2016))。根据SEQ ID No.4的蛋白质在本文中称为FutA_mut,并且在本文中将编码FutA_mut的核酸序列称为futA_mut。
在一个实施方式中,表达的异源α1,3/4-岩藻糖基转移酶包含与SEQ ID No.7相同的多肽或优选由其组成。根据SEQ ID No.7的蛋白质是FutA的功能变体,其中128位的Ala(A)被Asn(N)置换,129位的His(H)被Glu(E)置换,148位的Asp(D)被Gly(G)置换,且221位的Tyr(Y)被Cys(C)置换。根据SEQ ID No.7的蛋白质在本文中称为FutA_mut2,并且在本文中将编码FutA_mut2的核酸序列称为futA_mut2。
在优选的实施方式中,表达的异源α1,3/4-岩藻糖基转移酶包含与SEQ ID No.1、SEQ ID No.2、SEQ ID No.3、SEQ ID No.4或SEQ ID No.7相同的多肽或优选由其组成。
上述遗传修饰的微生物或细胞优选包含功能性GDP-岩藻糖代谢途径和/或乳糖导入系统,该乳糖导入系统包括由乳糖通透酶介导的主动转运机制,优选由lacY基因编码的通透酶。
在本文中,术语“微生物”或“细胞”意指生物细胞,例如细菌或酵母细胞,其可被遗传改造以在不同表达水平表达其天然或外源基因,它们是染色体(染色体的)基因或质粒整合(质粒携带)基因。
术语“宿主细胞”、“重组微生物或细胞”或“遗传修饰的微生物或细胞”可互换使用,以表示细胞,优选细菌细胞,与其天然存在的(野生型)变体相比,在其基因组中至少含有一种人工改变。通过这种改变,要么通过整合到基因组中或经由质粒添加的方式将核酸构建体添加到细胞中,要么从细胞的基因组中删除或改变核酸序列。无论如何,如此转化的细胞具有与改变之前不同的基因型,因此,修饰的细胞显示出修饰的特征(一种或多种)。优选地,当培养或发酵时,由于引入异源核酸序列或编码在野生型细胞中不表达的酶的天然核酸序列的修饰,遗传修饰的细胞可进行至少一种附加的或改变的生化反应,或者由于编码在野生型细胞中发现的酶的核酸序列的缺失、添加或修饰,遗传修饰的细胞不能进行生化反应。遗传修饰的细胞可通过众所周知的常规基因工程技术来构建(例如Green和Sambrook:《分子克隆:实验室手册》,第4版,冷泉港实验室出版社(Molecular Cloning:Alaboratory Manual,4th ed.,Cold Spring Harbor Laboratory Press)(2012);分子生物学的最新规程(Current protocols in molecular biology)(Ausubel等人编辑),JohnWiley and Sons(2010)。
在两种或更多种核酸或氨基酸序列的上下文中,术语“[某个]%的序列同一性”意指当在比较窗口或指定的核酸或氨基酸序列上进行比较和比对以获得最大对应性时,两种或更多种序列具有给定百分比的核苷酸或氨基酸残基(即序列具有至少90%(%)的同一性)。核酸或氨基酸序列的同一性百分比可使用具有默认参数的BLAST 2.0序列比较算法或通过手动比对和目视检查来测量(参见例如http://www.ncbi.nlm.nih.gov/BLAST/)。该定义也适用于测试序列的互补序列以及具有缺失和/或添加以及具有取代的序列。适用于确定同一性百分比、序列相似性和比对的算法的一个示例是BLAST 2.2.20+算法,该算法在Altschul等人Nucl.Acids Res.25,3389(1997)中有所描述。BLAST 2.2.20+用于确定本发明的核酸和蛋白质的序列同一性百分比。进行BLAST分析的软件可通过国家生物技术信息中心(http://www.ncbi.nlm.nih.gov/)公开获得。序列比对算法的示例是CLUSTAL Omega(http://www.ebi.ac.uk/Tools/msa/clustalo/)、EMBOSS Needle(http://www.ebi.ac.uk/Tools/psa/emboss_needle/)、MAFFT(http://mafft.cbrc.jp/alignment/server/)或MUSCLE(http://www.ebi.ac.uk/Tools/msa/muscle/)。
在一个优选的实施方式中,本发明的遗传修饰的细胞已被转化成含有核酸构建体,该核酸构建体包含具有糖基转移酶活性的蛋白质、酶或多肽的编码序列,优选一种或更多种构建体,所述构建体包含一种或更多种异源转移酶的一种或更多种编码核酸序列,优选至少一种编码β1,3-N-乙酰氨基葡萄糖转移酶的序列,至少一种编码β1,3-半乳糖基转移酶的序列和至少一种编码α1,3/4-岩藻糖基转移酶的序列,并且能够表达构建体中包含的编码核酸序列。
本发明的遗传修饰的微生物或细胞可选自细菌和酵母,优选细菌。细菌优选选自:大肠杆菌(Escherichia coli)、芽孢杆菌属(Bacillus spp.)(例如枯草芽孢杆菌(Bacillus subtilis))、幽门弯曲杆菌(Campylobacter pylori)、幽门螺杆菌(Helicobacter pylori)、根癌农杆菌(Agrobacterium tumefaciens)、金黄色葡萄球菌(Staphylococcus aureus)、水生嗜热菌(Thermophilus aquaticus)、茎瘤固氮根瘤菌(Azorhizobiumcaulinodans)、豆科根瘤菌(Rhizobium leguminosarum)、淋病奈瑟氏球菌(Neisseria gonorrhoeae)、脑膜炎奈瑟氏球菌(Neisseria meningitis)、乳酸杆菌属(Lactobacillus spp.)、乳球菌属(Lactococcus spp.)、肠球菌属(Enterococcus spp.)、双岐杆菌属(Bifidobacterium spp.)、芽孢乳杆菌属(Sporolactobacillus spp.)、小单孢子菌属(Micromomospora spp.)、微球菌属(Micrococcus spp.)、红球菌属(Rhodococcusspp.)、假单胞菌属(Pseudomonas),其中大肠杆菌是优选的。
术语“能够从乳糖生产LNFP-V的遗传修饰的微生物或细胞”意指所述细胞具有经由连续的糖基化步骤由乳糖(一种二糖)合成LNFP-V(一种五糖)所必需的酶活性,其中乳糖在第一步糖基化中被糖基化为三糖,然后在第二步糖基化中三糖被糖基化为四糖,最后在第三步糖基化中四糖被糖基化为LNFP-V。糖基化步骤由各自的糖基转移酶介导。在糖基转移酶介导的糖基化中,所论述的糖基转移酶将合适的供体分子的单糖(该供体分子是活化的单糖核苷酸)转移到受体分子。根据本发明的必需的糖基转移酶是:β1,3-N-乙酰氨基葡萄糖转移酶、β1,3-半乳糖基转移酶和α1,3/4-岩藻糖基转移酶;并且相应的供体分别是:UDP-GlcNAc、UDP-Gal和GDP-Fuc。
细胞产生UDP-GlcNAc和UDP-Gal是在酶的作用下发生的,这些酶参与它们的天然从头生物合成途径,以分步反应顺序从简单的碳源如甘油、果糖、蔗糖或葡萄糖开始(关于单糖代谢的综述,参见例如FI.FI.Freeze和A.D.Elbein:第四章:糖基化前体(Glycosylation precursors),收录于:糖生物学基础(Essentials of Glycobiology),第二版(编辑A.Varki等人,冷泉港实验室出版社(2009)。具体而言,UDP-GlcNAc是由果糖-6-磷酸通过三个步骤从头产生的,这三个步骤由三个基因编码的酶催化,这三个基因是glmS、glmM和glmU,它们在其天然启动子下表达。类似地,UDP-Gal由葡萄糖-6-磷酸酶通过三个步骤从头产生,这三个步骤由基因pgm、galU和galE编码的酶催化,这些基因也在其天然启动子下表达。GDP-Fuc代谢途径见下文。根据生产LNFP-V的某个合成顺序,乳糖被N-乙酰氨基葡萄糖基化为乳-N-三糖II(GlcNAcβ1-3Galβ1-4Glc),然后半乳糖基化为LNT(Galβ1-3GlcNAcβ1-3Galβ1-4Glc),最后被岩藻糖基化为LNFP-V。然而,岩藻糖基化有可能在N-乙酰氨基葡萄糖基化步骤之前或之后。
术语“核酸序列[...]整合到微生物或细胞的基因组中”意指所述核酸序列整体地、单独地或包含在核酸构建体中,优选可操作地连接到一个或更多个被宿主细胞识别的控制序列,被插入到所述微生物或细胞的基因组(遗传基因座)的某个位点。
术语“编码具有β1,3-N-乙酰氨基葡萄糖转移酶活性的多肽的核酸序列”或“编码具有β1,3-半乳糖基转移酶活性的多肽的核酸序列”意指分别表达具有β1,3-N-乙酰氨基葡萄糖转移酶活性或β1,3-半乳糖基转移酶活性的多肽的基因、其功能片段或其密码子优化版本。
在本文中,术语“基因”涉及编码核酸序列。“功能片段”或“基因的功能变体”优选地意指编码序列或修饰的编码序列的片段,修饰的编码序列例如包含一个或更多个不同于原始编码序列相同位置的核苷酸的序列,其表达具有与从原始编码序列表达的多肽相同或相似的功能特征(一种或多种)的多肽。
术语“核酸构建体”意指人工构建的核酸片段,特别是旨在移植到靶细胞(例如细菌细胞)中的DNA序列。在本发明的上下文中,核酸构建体含有重组DNA序列,该重组DNA序列包含本发明的编码DNA序列。在一个优选的实施方式中,核酸构建体基本上包含四个可操作地连接在一起的分离的DNA序列:编码DNA序列、连接到编码DNA序列上从而能够启动所述编码DNA序列转录的启动子DNA序列、位于基因上游的5'非翻译区(5'-UTR)的DNA片段,即直接位于起始密码子上游和启动子序列下游的基因前导DNA序列。可将本发明的DNA构建体插入质粒DNA/载体中,移植到靶/宿主细胞中,并且以质粒或染色体携带的形式表达。DNA构建体可为线性或环状的。整合到宿主细菌基因组或表达质粒中的线性或环状DNA构建体在本文中可互换地称为“表达组件(“expression cassette)”、“表达盒(expression cartridge)”或“盒(cartridge)”。优选地,该盒是线性DNA构建体,其基本上包含启动子、启动子下游的5'-UTR DNA(包括核糖体结合位点)的序列,并且可操作地连接到编码目的生物学分子的编码DNA序列。该构建体还可包含其他序列,诸如转录终止子序列,以及两个末端侧翼区域,其与基因组区域同源且能够进行同源重组。另外,盒可含有如下所述的其他顺序。该盒可通过本领域公知的方法来制造,例如使用《生物化学和分子生物学的原理和技术》(Wilson和Walker编辑),剑桥大学出版社(2010)中描述的标准方法。线性表达盒的使用可提供以下优点:基因组的整合位点可通过盒的侧翼同源区域的相应设计自由选择。因此,线性表达盒的整合允许在基因组区域方面有更大的可变性。由于线性盒也更容易构建,因此此类盒是本发明的构建体的优选的实施方式。
术语“启动子”意指参与RNA聚合酶结合以启动可操作地连接的基因转录的核酸序列,其中该基因包括编码DNA序列和其他(非编码)序列,例如位于编码序列上游的5'非翻译区(5'-UTR),其包含核糖体结合位点。本发明中的启动子是分离的DNA序列,即不是基因组DNA的整合DNA片段。本发明的启动子的核苷酸序列对应于被视为基因的启动子区(例如大肠杆菌的glp操纵子或lac操纵子的启动子区)的细菌基因组DNA片段的核苷酸序列,或者与其具有至少80%的同一性,优选90-99.9%的同一性。“操纵子”意指基因组DNA的功能单元,其含有在单个启动子控制下的基因簇。“glp操纵子”意指参与细菌甘油的呼吸代谢的基因簇。“lac操纵子”意指参与乳糖的转运和代谢的基因簇。在优选的实施方式中,本发明涉及大肠杆菌的四个glp操纵子,特别是glpFKX、glpABC、glpTQ和glpD。在其他优选的实施方式中,本发明涉及包含基因Z、Y和A的大肠杆菌的lac操纵子。优选地,包含在本发明的DNA构建体中的glp操纵子启动子序列对应于被视为大肠杆菌的相应glp操纵子的启动子区的基因组DNA片段的核苷酸序列,或者与其具有至少80%的同一性,优选90-99.9%的同一性;特别地,本发明的glp操纵子的启动子的分离序列对应于基因组序列上游具有GenBank ID:EG10396(glpFKX)、EG10391(glpABC)、EG10394(glpD)、EG10401(glpTQ)的序列的片段,或者与该片段具有所述的同一性百分比;并且操纵子lacZYA的启动子的分离序列对应于基因组序列上游具有GenBank ID:EG10527(lacZ)的序列的片段,或者与该片段具有所述的同一性百分比。大肠杆菌基因组在本文中指大肠杆菌K-12MG1655的完整基因组DNA序列(GenBankID:U00096.3)。
本发明中的启动子序列可包含几个结构特征/元件,诸如能够结合细胞中的RNA聚合酶并启动下游(3'-方向)编码序列的转录的调控区、转录起始位点及其特异性转录调节蛋白的结合位点。调控区包括负责RNA聚合酶结合的蛋白质结合域(共有序列),诸如-35框和-10框(Pribnow框)。
本发明中的启动子序列优选地包含至少90个核苷酸,更优选地100至150个核苷酸,例如110-120、120-130、130-140、140-150,或甚至更优选超过150个核苷酸,诸如155-165、165-175、175-185、185-195、195-205、205-215、215-225、225-235、235-245、245-255、255-265。在一些实施方式中,启动子序列可甚至更长,诸如长达500-1000个核苷酸。在一些优选的实施方式中,启动子的分离的序列是glp操纵子的序列。
本发明还涉及包括在本发明的构建体中的启动子DNA序列的变体。本内容中的“变体”意指与所关注的启动子DNA序列的核苷酸序列具有70-99.9%的相似性的人工核酸序列。比较的核酸序列的相似性百分比指示具有相同结构即相同核苷酸组成的序列部分。为了本发明的目的,序列相似性的百分比可通过使用本领域公知的任何方法(例如BLAST)来确定。术语“变体”的范围包括与本文所述DNA序列互补的核苷酸序列、mRNA序列和合成核苷酸序列(例如PCR引物)以及与本发明构建体的核酸序列相关的其他寡核苷酸。
在一个优选的实施方式中,如上所述的glp操纵子的启动子或其变体与异源β1,3-N-乙酰氨基葡萄糖转移酶、异源β1,3-半乳糖基转移酶和/或异源α1,3/4-岩藻糖基转移酶可操作地连接。更优选地,glp操纵子的启动子是glpF启动子或其变体。
同样,优选地,对于合成LNFP-V所必需的异源β1,3-N-乙酰氨基葡萄糖转移酶、异源β1,3-半乳糖基转移酶和异源α1,3/4-岩藻糖基转移酶在glpF启动子变体下表达。在这方面,构建表达盒,每个表达盒分别包含可操作地连接到glpF启动子变体并插入宿主细胞的基因组中的异源β1,3-N-乙酰氨基葡萄糖转移酶、异源β1,3-半乳糖基转移酶或异源α1,3/4-岩藻糖基转移酶。优选地,glpF启动子变体是由SEQ ID No.5表征的核酸构建体。
术语“微生物或细胞包含功能性GDP-岩藻糖代谢途径”意指所述细胞或微生物能够原位生产GDP-岩藻糖,其在岩藻糖基化步骤中用作岩藻糖供体,以在微生物或细胞内制备LNFP-V。GDP-岩藻糖代谢途径是从头合成或根据补救途径而发生。在从头合成途径中,GDP-L-岩藻糖由果糖-6-磷酸和GTP通过以下五种酶的连续作用生物合成:甘露糖6-磷酸异构酶、磷酸甘露糖变位酶、甘露糖-1-磷酸鸟苷酰基转移酶、GDP-甘露糖-4,6-脱水酶和GDP-岩藻糖合酶。在大肠杆菌中,这五种酶分别由manA、manB、manC、gmd和wcaG编码,它们是可拉酸基因簇的一部分。其他细菌或酵母菌株可能缺少一种或更多种上述酶;从头的GDP-岩藻糖合成途径中固有缺失的任何酶均可作为基因或重组DNA构建体提供,既可在质粒表达载体中提供,也可作为整合到宿主细胞染色体中的外源基因提供。另外,编码UDP-葡萄糖脂质载体转移酶的可拉酸簇的wcaJ基因应被删除或失活,以抑制可拉酸的产生,从而GDP-岩藻糖生物合成通量将从它转移到LNFP-V的合成。优选地,以上公开的同源可拉酸簇在lac启动子(Plac)的控制下。另外,为了进一步增加GDP-岩藻糖库,编码可拉酸操纵子的正调控子的基因rscA可能被过表达(参见例如Dumon等人,Glycoconj.J.18,465(2001))。在另一个实施方式中,遗传修饰的细胞可利用补救的岩藻糖来生产GDP-岩藻糖。在补救途径中,在岩藻糖通透酶的帮助下在细胞内内在化的外源添加的岩藻糖被岩藻糖激酶磷酸化,并且通过岩藻糖-1-磷酸鸟苷酰基转移酶转化为GDP-岩藻糖。参与该过程的酶可为异源的或同源的。在一个实施方式中,岩藻糖激酶和岩藻糖-1-磷酸鸟苷酰基转移酶可组合成双功能酶(参见例如WO 2010/070104)。
术语“包含由乳糖通透酶介导的主动转运机制的乳糖导入系统”意指在包含对乳糖具有特异性的转运蛋白(称为乳糖通透酶)的主动转运的帮助下,将制造LNFP-V所必需的和外源添加到培养物中的乳糖内在化,从而遗传修饰的细胞或微生物在其细胞质中允许并浓缩外源乳糖。内在化不能影响细胞的基本和重要功能,也不能破坏细胞的完整性。一种公认的广泛用于将乳糖导入细胞的通透酶是LacY(参见例如WO 01/04341),但是也可考虑对乳糖具有特异性的其他通透酶。
在一个优选的实施方式中,本文公开的能够从乳糖生产LNFP-V的遗传修饰的微生物或细胞包含编码具有α1,3/4-岩藻糖基转移酶活性的多肽的异源核酸序列,所述多肽选自:SEQ ID No.1的蛋白质(Ma等人,J.Biol.Chem.281,6385(2006))、SEQ ID No.2的蛋白质(Gen Bank ID:AAB81031.1,Ge等人,J.Biol.Chem.272,21357(1997))、SEQ ID No.3的蛋白质(Gen Bank ID:NP_207177.1)、SEQ ID No.4的蛋白质(Choi等人,Biotechnol.Bioeng.113,1666(2016))或SEQ ID No.7的蛋白质。
优选地,编码包含与SEQ ID No.1或SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成的多肽的异源核酸序列,有利地,编码SEQ ID No.1的蛋白质(称为“截短的”fucT)、SEQ ID No.2的蛋白质(称为fucT)、SEQ ID No.3的蛋白质(称为futA)、SEQ ID No.4的蛋白质(称为futA_mut)或SEQ ID No.7的蛋白质(称为futA_mut2)的异源核酸序列对于本发明的表达系统是密码子优化的。
优选地,以上公开的遗传修饰的微生物或细胞不能够水解或降解LNFP-V或其在从乳糖开始的生物合成途径中的中间体(例如乳-N-三糖II或LNT)。同样,在一个实施方式中,细胞缺乏会降解受体(乳糖)的任何酶活性,诸如LacZ(β-半乳糖苷酶)活性。这可通过缺失或灭活编码β-半乳糖苷酶的LacZ来实现。在其他实施方式中,以上公开的遗传修饰的微生物或细胞,尽管其天然lacZ被缺失或失活,但仍可能具有低水平的β-半乳糖苷酶活性,例如由于掺入了编码β-半乳糖苷酶的异源基因。就这一点而言,发酵后可将外源添加的过量乳糖完全水解,从而有利于所产生的目的寡糖的分离和纯化。例如在WO2012/112777中公开了这种解决方案。在其他实施方式中,可附加地改变以上公开的遗传修饰的微生物或细胞,以包含可操作地连接到诱导型启动子例如温度诱导型启动子的β-半乳糖苷酶基因。在这方面,β-半乳糖苷酶在较低的温度下,例如在培养微生物以生产LNFP-V的温度下不表达,而在发酵结束时升高温度时诱导其表达,因此过量的乳糖可被水解。此类解决方案公开在例如WO 2015/036138中。
同样,优选地,编码具有β1,3-N-乙酰氨基葡萄糖转移酶活性的多肽的整合到遗传修饰的微生物或细胞的基因组中的核酸序列是脑膜炎奈瑟氏球菌053442(GenBank ID:CP000381)的IgtA基因或其密码子优化版本。优选地,将IgtA基因或其密码子优化版本的编码序列可操作地连接到由SEQ ID No.5表征的glpF启动子变体,从而在该变体下表达。
同样,优选地,编码具有β1,3-半乳糖基转移酶活性的多肽的整合到遗传修饰的微生物或细胞的基因组中的核酸序列是称为galTK的基因、其功能片段或密码子优化版本。galTK与幽门螺杆菌43504的编码β1,3-半乳糖基转移酶的基因(GenBank ID:BD182026、US6974687)同源,并且编码由SEQ ID No.6表征的蛋白质,称为GalTK。US 6974687公开的β1,3-半乳糖基转移酶与本申请中使用的GalTKβ1,3-半乳糖基转移酶(由galTK编码)的结构比较如图1所示。
根据本发明,本文所述的遗传修饰的微生物或细胞,包括优选的和更优选的实施方式,提供足够量的GDP-岩藻糖,用于通过从头或补救途径,优选通过从头途径(参见上文)生物合成LNFP-V。然而,为了通过提供必要和足够的GDP-岩藻糖水平来进一步优化LNFP-V生物合成,可将可拉酸基因簇的额外拷贝引入细胞中,优选地并入细胞的基因组中。
本文公开的遗传修饰的微生物或细胞,包括优选的和更优选的实施方式,包含整合到细胞基因组中的异源β1,3-N-乙酰氨基葡萄糖转移酶、异源β1,3-半乳糖基转移酶和异源α1,3/4-岩藻糖基转移酶。后一种异源基因可整合到宿主细胞的任何遗传基因座中,从而不会干扰细胞代谢,并且细胞能够产生所需的寡糖。在本发明中使用的或合适的表达系统允许广泛的可变性。原则上,可选择具有已知序列的任何基因座,条件是该序列的功能是可有可无的,或者如果必要的话可被补充(例如在营养缺陷型的情况下)。现有技术中描述了许多适合于本发明目的的整合基因座(参见例如Francia等人,J.Bacteriol.178,894(1996);Juhas等人(2014)PLoS ONE 9,e111451(2014);Juhas等人(2015)MicrobialBiothechnol.8,617(2015);Sabi等人Microbial.Cell Factories 12:60(2013))。
优选地,在一个实施方式中,整合的基因组位点是糖代谢基因(诸如半乳糖、木糖、核糖、麦芽糖或岩藻糖的那些)的操纵子中的基因座。
根据本发明,在一个实施方式中,包括以上公开的任何优选的实施方式的遗传修饰的微生物或细胞,仅包含β1,3-半乳糖基转移酶基因的一个(单个)拷贝,优选galTK或其密码子优化版本,更优选在glp启动子(Pglp)或其变体,例如PglpF,特别是根据SEQ IDNo.5的PglpF变体的控制下。
根据本发明,在一个实施方式中,包括以上公开的任何优选的实施方式的遗传修饰的微生物或细胞,仅包含β1,3-N-乙酰氨基葡萄糖转移酶基因的一个(单个)拷贝,优选IgtA基因或其密码子优化版本的编码序列,更优选在glp启动子(Pglp)或其变体,例如PglpF,特别是根据SEQ ID No.5的PglpF变体的控制下。
在一个实施方式中,包括以上公开的任何优选的实施方式的遗传修饰的微生物或细胞,仅包含β1,3-半乳糖基转移酶基因(优选galTK或其密码子优化版本)、β1,3-N-乙酰氨基葡萄糖转移酶基因(优选IgtA基因或其密码子优化版本的编码序列)以及编码与SEQ IDNo.1或SEQ ID No.3具有至少90%的氨基酸序列同一性的多肽的α1,3/4-岩藻糖基转移酶基因(优选“截短的”fucT、fucT、futA、futA_mut或futA_mut2)中的每一个的一个(单个)拷贝。更优选地,每个此类糖基转移酶均在根据SEQ ID No.5的glpF启动子变体的控制下。不同糖基转移酶基因的每个拷贝均整合到不同的基因组位点中,优选整合到与替代碳源利用相关的基因座中。
在一个实施方式中,包括以上公开的优选的实施方式中的任一个的遗传修饰的微生物或细胞,包含β1,3-半乳糖基转移酶基因(优选galTK或其密码子优化版本)的两个拷贝,其中的每一个均整合到两个不同的基因组位点中,以及编码与SEQ ID No.1或SEQ IDNo.3具有至少90%的氨基酸序列同一性的多肽的α1,3/4-岩藻糖基转移酶基因(优选“截短的”fucT、fucT、futA、futA_mut或futA_mut2)的两个拷贝,其中的每一个均整合到两个不同的基因组位点中,更优选地,每个此类糖基转移酶编码序列均在PglpF或其他glp启动子或其变体(例如PglpA或PglpT)的控制下表达,优选在根据SEQ ID No.5的glpF启动子变体的控制下表达。
生产LNFP-V必需的上述三种不同种类的异源糖基转移酶基因作为表达盒的一部分并入宿主细胞的基因组中,表达盒是以DNA构建体的形式存在的,所述DNA构建体包含可操作地连接到启动子序列的糖基转移酶编码序列。该启动子可为能够在一定水平上起始并维持可操作地连接的基因的转录并被宿主细胞识别的任何合适的启动子。优选地,启动子是碳源诱导型启动子。优选地,启动子是天然调控大肠杆菌的四个glp操纵子(glpFKX、glpABC、glpTQ和glpD)中的一个基因转录的启动子或其变体。
在一个实施方式中,包括上面公开的优选和更优选的实施方式的遗传修饰的微生物或细胞,仅包含选自fucT、futA、futA_mut和futA_mut2的α1,3/4-岩藻糖基转移酶的一个(单个)拷贝,优选在glp启动子的控制下,更优选在glpF启动子或其变体的控制下,甚至更优选在根据SEQ ID No.5的glpF启动子变体的控制下。
如上所述,在一个实施方式中,根据本发明的适于从乳糖制备LNFP-V的遗传修饰的微生物或细胞可包含GDP-岩藻糖从头生物合成途径,以在细胞内提供GDP-岩藻糖。GDP-岩藻糖的从头途径利用宿主细胞(优选大肠杆菌)的天然可拉酸基因簇,其包含manA、manB、manC、gmd和wcaG,其中wcaJ被删除或失活。天然可拉酸基因簇优选在Plac启动子的控制下。在另一个实施方式中,本发明的遗传修饰的微生物或细胞,除了天然可拉酸基因簇以外,还可包含额外的可拉酸基因拷贝,以增强GDP-岩藻糖的生物合成,从而提供更高水平的GDP-岩藻糖。可拉酸基因簇的此类第二拷贝优选整合到基因组中,并且优选在glp启动子的控制下表达,更优选在glpF启动子或其变体下表达,甚至更优选在根据SEQ ID No.5的glpF启动子变体的控制下表达。至于其中掺入了可拉酸基因簇的第二拷贝的基因组位点,它可优选地是如上所述的细胞糖代谢基因的基因座。在另一个实施方式中,当细胞包含可拉酸基因簇的额外拷贝时,仅存在α1,3/4-岩藻糖基转移酶基因的一个(单个)基因组拷贝,优选为futA_mut或futA_mut2,更优选为futA_mut2。
本发明的第二方面涉及一种生产LNFP-V的方法,该方法包括:
a)提供本发明的第一方面中公开的遗传修饰的微生物或细胞,
b)在乳糖存在下培养所述微生物或细胞,和
c)从所述微生物或细胞、从培养基或从两者分离LNFP-V。
五糖LNFP-V可容易地通过以下方法获得,该方法涉及在含有乳糖和一种或更多种碳基底物的水性培养基或发酵培养基中培养或发酵根据本发明第一方面的遗传修饰的细胞或微生物,随后将它们从培养基中分离。术语“培养基”意指在遗传修饰的细胞外的发酵罐中发酵过程的水环境。
在进行该过程中,遗传修饰的细胞在碳基底物诸如甘油、葡萄糖、蔗糖、糖原、果糖、麦芽糖、淀粉、纤维素、果胶、壳多糖等的存在下培养。优选地,细胞用甘油、葡萄糖、蔗糖和/或果糖培养。
该过程还涉及最初将外源乳糖从培养基转运到遗传修饰的细胞中。乳糖以常规方式外源地添加到培养基中,然后从培养基中转运到细胞中。乳糖在主动转运机制的帮助下被内在化,通过该机制乳糖在细胞的转运蛋白或乳糖通透酶(LacY)的影响下扩散穿过细胞的质膜,该转运蛋白或乳糖通透酶在lac启动子的控制下表达。
在一些实施方式中,用于该过程的遗传修饰的细胞缺乏酶活性,该酶活性会显著降解细胞内乳糖、LNFP-V和LNFP-V生物合成途径中的代谢中间体,例如乳-N-三糖II或LNT。在这方面,培养细胞的天然β-半乳糖苷酶(由大肠杆菌中的lacZ基因编码,其将乳糖水解为半乳糖和葡萄糖)优选被缺失或失活(LacZ-基因型)。在本发明第二方面的一个实施方式中,在步骤b)中加入的过量乳糖在发酵后不被除去或降解,并且乳糖和LNFP-V的混合物,任选地伴有一种或更多种寡糖副产物,例如乳-N-三糖II、LNT、3-FL和/或LNDFH-II,从培养基中分隔和分离。在另一个实施方式中,乳糖和LNFP-V的混合物,任选地伴有一种或更多种寡糖副产物,例如乳-N-三糖II、LNT、3-FL和/或LNDFH-II,通过如上所述的发酵生产,并且LNFP-V,任选地伴有一种或更多种寡糖副产物,例如乳-N-三糖II、LNT、3-FL和/或LNDFH-II,从培养环境和任选过量的乳糖中分隔和分离。在另一个实施方式中,乳糖和LNFP-V的混合物,任选地伴有一种或更多种寡糖副产物,例如乳-N-三糖II、LNT、3-FL和/或LNDFH-II,通过如上所述的发酵生产,随后
i)添加乳糖降解酶,例如半乳糖苷酶,其外源性地将乳糖水解为单糖,或
ii)让发酵继续进行,直到发酵步骤中添加的所有乳糖均被消耗掉,
提供基本上不含乳糖的肉汤。就这一点而言,在选项ii)中,以上公开的LacZ-基因型的遗传修饰细胞还可包含功能性重组β-半乳糖苷酶。这种功能性半乳糖苷酶可由为热诱导的外源lacZ基因编码(参见例如WO 2015/036138)。在发酵温度下,这种功能性β-半乳糖苷酶不被细胞表达,因此当生产HMO时,细胞中的内在化乳糖不会降解。当肉汤中达到所需的LNFP-V浓度或量时,在升高的温度下继续培养,从而表达功能性β-半乳糖苷酶并降解过量的乳糖。另选地,上述公开的LacZ-基因型的遗传修饰的细胞可包含低但可检测活性水平的重组β-半乳糖苷酶(参见例如WO 2012/112777),以便在发酵结束时除去任选的残留乳糖。
通常,该方法涉及在培养基中提供碳基底物和每升培养基初始体积中至少30至多约100克的乳糖。优选地,该方法还在28℃至35℃的温度下进行,优选连续搅拌和连续通气2至5天。优选培养基的最终体积不超过向培养基中提供乳糖和碳基底物之前培养基初始体积的三倍。
根据实施本发明方法的一个实施方式,以下列方式培养遗传修饰的LacZ-Y+大肠杆菌菌株:
(1)指数细胞生长的第一阶段,该阶段由培养基中提供的碳基底物(诸如葡萄糖或蔗糖)确保,并且优选持续到葡萄糖全部消耗掉,该阶段优选至少12小时,诸如约18小时或20-25小时;和
(2)细胞生长的第二阶段,该阶段受在第一阶段之后,优选连续地在培养基中提供的碳基底物(诸如葡萄糖、蔗糖或甘油和乳糖)的限制,并且该第二阶段持续到碳基底物和优选大部分(例如至少60%)乳糖被消耗完,该第二阶段优选至少35小时,诸如至少45小时、50至70小时或至多约130小时。
在遗传修饰的细胞的培养过程中,LNFP-V和任选的一种或更多种寡糖副产物,例如乳-N-三糖II、LNT、3-FL和/或LNDFH-II均在细胞的细胞内和细胞外基质中积累。产生的寡糖可通过使用标准技术从肉汤中分离和/或彼此分隔。
本发明的第三方面涉及一种蛋白质(多肽),其包含由SEQ ID No.7表征的氨基酸序列或由其组成。包含由SEQ ID No.7表征的氨基酸序列或由其组成的蛋白质(多肽)具有α1,3/4-岩藻糖基转移酶活性,并且可有利地用于LNFP-V的发酵生产中,如实施例中所公开的。
本发明的第四方面涉及具有α1,3/4-岩藻糖基转移酶活性的多肽在LNFP-V的生产中的用途,该多肽选自:
-多肽,其包含与SEQ ID No.1的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成,和
-多肽,其包含与SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
在某些实施方式中,α1,3/4-岩藻糖基转移酶包含与SEQ ID No.1或SEQ ID No.3(视情况而定)具有至少92%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%同一性的多肽,优选由其组成。
在一个实施方式中,α1,3/4-岩藻糖基转移酶包含SEQ ID No.1或SEQ ID No.2的氨基酸序列,优选由其组成。
在一个实施方式中,α1,3/4-岩藻糖基转移酶包含SEQ ID No.3、SEQ ID No.4或SEQ ID No.7的氨基酸序列,优选由其组成。
在一个优选的实施方式中,α1,3/4-岩藻糖基转移酶包含与SEQ ID No.7相同的多肽,或优选由其组成。
在一个实施方式中,编码具有α1,3/4-岩藻糖基转移酶活性的多肽的核酸序列包含在能够从乳糖生产LNFP-V的微生物或细胞中。可通过使用适当的表达质粒或通过基因组(染色体)整合将核酸序列引入微生物或细胞中。
实施例
在实施例中,所有利用的菌株均来源于大肠杆菌平台菌株,该菌株是通过破坏(缺失)基因lacZ、nanKETA、lacA、melA、wcaJ、mdoH并在gmd基因上游插入Plac启动子而从大肠杆菌K12 DH1(基因型:F-、λ-、gyrA96、recA1、relA1、endA1、thi-1、hsdR17、supE44,得自Deutsche Sammlung von Mikroorganismen und Zellkulturen(DSMZ),www.dsmz.de,参考DSM 4235)构建的。
染色体DNA中的基因靶向是使用标准的DNA操作技术完成的,例如,如Warming等人,Nucleic Acids Res,33,e36(2005)中所公开的。通过如Herring等人,Gene,311,153(2003)所描述的基因Gorging完成遗传盒在染色体DNA中的插入。
使用4天方案在24个深孔板中筛选实施例中公开的菌株。在最初的24小时内,细胞生长至高密度,而在接下来的72小时内,将细胞转移到允许诱导基因表达和产物形成的培养基中。具体而言,在第1天期间,使用补充有硫酸镁、硫胺素和葡萄糖的基础基本培养基制备新鲜接种物。将制备好的培养物在34℃下以700rpm振摇孵育24小时后,将细胞转移到补充有硫酸镁和硫胺素的新基础基本培养基(2ml)中,向该培养基中注入20%葡萄糖溶液(1μl)和10%的乳糖溶液(0.1ml),然后将50%的蔗糖溶液作为碳源提供给细胞,同时加入蔗糖水解酶(转化酶,4μl的0.1g/l溶液),从而通过转化酶对蔗糖的切割以缓慢的速度提供葡萄糖用于生长。接种新培养基后,将细胞在28℃下以700rpm的速度振摇72小时。变性并随后离心后,通过HPLC分析上清液。
实施例1
如下进一步修饰大肠杆菌平台菌株(见上文):将用于LgtA的密码子优化的IgtA编码序列的单个拷贝整合到大肠杆菌平台菌株的基因组(染色体)中与糖代谢相关的基因座中并在glpF启动子的控制下表达;将密码子优化的galTK的单个拷贝整合到大肠杆菌平台菌株基因组中的另一个参与糖代谢的基因座中并在glpF启动子的控制下表达;将可拉酸簇的额外拷贝整合到第三个基因座中,该基因座与替代碳源的利用有关并在glpF启动子的控制下表达;并且将lacl从lac操纵子中删除(Δlacl)。基于上述菌株,菌株1-5通过将编码α1,3/4-岩藻糖基转移酶的基因的单个拷贝整合到能够进行糖代谢的大肠杆菌平台菌株的基因座中的一个中并在glpF启动子的控制下而构建:
-菌株1:密码子优化的futA序列,其编码SEQ ID No.3的蛋白质
-菌株2:密码子优化的futA_mut2序列,其编码SEQ ID No.7的蛋白质
-菌株3:密码子优化的截短的fucT序列,其编码SEQ ID No.1的蛋白质
-菌株4:密码子优化的fucTIII,其来自幽门螺杆菌DSM 6709,GenBank ID:AY450598.1(Rabbani等人,Glycobiolog,15,1076(2005))
-菌株5:密码子优化的fucTa,其来自幽门螺杆菌UA948,GenBank ID:AF194963.2。
培养后,测量以下LNFP-V浓度(细胞内和细胞外浓度合计):
如上表所示,分别表达FutA、FutA_mut2和截短的FucTα1,3/4-岩藻糖基转移酶的菌株1-3,比在此类构建体中表达从现有技术已知的FucTIII酶的参考菌株4产生高得多的LNFP-V滴度(分别高300%、150%和210%)。表达FucTaα1,3/4-岩藻糖基转移酶的参考菌株5未产生LNFP-V。
实施例2
基于实施例1中公开的菌株1,产生了菌株6,使得它包含整合在糖利用基因座中并在glpF启动子控制下表达的密码子优化的futA基因的额外(第二)拷贝。
类似地,基于实施例1中公开的菌株3,产生了菌株7,使得它包含整合在另一个糖利用基因座中并在glpF启动子控制下表达的密码子优化的截短fucT基因的额外(第二)拷贝。
如下进一步修饰大肠杆菌平台菌株(参见上文)以制备菌株8:将密码子优化的IgtA编码序列的单个基因组拷贝整合到参与糖消耗的基因座中,并且在glpF启动子的控制下表达;将密码子优化的galTK的单个基因组拷贝整合到另一个糖代谢基因座中,并且在glpF启动子的控制下表达;将密码子优化的futA_mut2的单个基因组拷贝整合到一个基因座中,从而能够利用另一种替代碳源,并且在glpF启动子的控制下表达;将可拉酸簇的额外拷贝整合到第四个糖代谢基因座中,并且在glpF启动子的控制下表达;并且将lacl从lac操纵子中删除(Δlacl)。基于菌株8,产生菌株9,使其含有整合在参与糖消耗的基因座中的密码子优化的futA_mut2基因的额外(第二)拷贝,并且在glpF启动子的控制下表达。
培养后,测量以下LNFP-V的相对浓度(细胞内和细胞外浓度合计):
如上表所示,并入编码α1,3/4-岩藻糖基转移酶的futA或截短的fucT的第二拷贝不能显著提高LNFP-V滴度,而futA_mut2的第二拷贝则对LNFP-V滴度具有负面影响。总之,带有单个基因组拷贝的α1,3/4-岩藻糖基转移酶基因的菌株是优选的。
实施例3
如下进一步修饰大肠杆菌平台菌株(参见上文)以制备菌株10:将密码子优化的IgtA编码序列的单个基因组拷贝整合到糖代谢基因座中,并且在glpF启动子的控制下表达;将密码子优化的galTK的单基因组拷贝整合到另一个参与替代碳源利用的基因座中,并且在glpF启动子的控制下表达;将密码子优化的futA_mut2的单个基因组拷贝整合到与糖消耗相关的第三个基因座中,并且在glpF启动子的控制下表达;并且lacl由galK替换而删除(lacl::galK)。
基于菌株10,菌株11-13的构建如下:
-菌株11:将可拉酸簇的额外拷贝整合到糖利用基因座中,并且在glpF启动子的控制下表达;
-菌株12:将密码子优化的futA_mut2基因的额外(第二)拷贝整合到另一个糖代谢基因座中,并且在glpF启动子的控制下表达;
-菌株13:将可拉酸簇的额外拷贝整合到参与利用替代碳源的基因座中,并且在glpF启动子的控制下表达,并且将密码子优化的futA_mut2基因的额外(第二)拷贝整合到也能够消耗特定糖的基因座中,并且在glpF启动子的控制下表达。
培养后,测量以下LNFP-V的相对浓度(细胞内和细胞外浓度合计):
表达CA基因簇的额外拷贝和来自单个拷贝的α1,3/4-岩藻糖基转移酶的细胞(菌株11)比没有这种额外PglpF-驱动的CA基因拷贝的类似细胞(菌株10)产生更高的LNFP-V浓度(约17%)。值得注意的是,添加futA_mut2基因的第二基因组拷贝并不能提高所观察到的LNFP-V滴度,而与CA基因拷贝数无关。
实施例4
基于实施例2中公开的菌株8,产生了菌株14,使得它包含整合到参与给定碳源的代谢的基因座中并在glpF启动子的控制下表达的密码子优化的galTK基因的额外(第二)拷贝。
类似地,基于实施例2中公开的菌株9,产生了菌株15,使得它包含整合到大肠杆菌平台菌株的基因座中并在glpF启动子的控制下表达的密码子优化的galTK基因的额外(第二)拷贝。
培养后,测量以下LNFP-V的相对浓度(细胞内和细胞外浓度合计):
向具有α1,3/4-岩藻糖基转移酶基因的单个拷贝的菌株8中添加第二β1,3-半乳糖基转移酶基因拷贝对最终的LNFP-V没有影响。然而,当向包含α1,3/4-岩藻糖基转移酶基因的2个拷贝的菌株9中添加第二β1,3-半乳糖基转移酶基因拷贝时,LNFP-V滴度显著增加。
序列表
<110> 格礼卡姆股份公司
<120> 岩藻糖基化寡糖LNFP-V的合成
<130> 134WO00
<160> 7
<150> DK201800952
<151> 2018-12-04
<170> BiSSAP 1.3.6
<210> 1
<211> 441
<212> PRT
<213> 人工序列
<220>
<223> Ma等人. J. Biol. Chem. 281, 6385 (2006)
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Phe Ile Leu Ser Gln Arg Tyr Thr Ile Thr Leu His Gln Asn Pro Asn
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Glu Phe Ser Asp Leu Val Phe Gly Asn Pro Leu Gly Ser Ala Arg Lys
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Ile Leu Ser Tyr Gln Asn Ala Lys Arg Val Phe Tyr Thr Gly Glu Asn
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Glu Ser Pro Asn Phe Asn Leu Phe Asp Tyr Ala Ile Gly Phe Asp Glu
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Leu Asp Phe Asn Asp Arg Tyr Leu Arg Met Pro Leu Tyr Tyr Asp Arg
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Leu His His Lys Ala Glu Ser Val Asn Asp Thr Thr Ala Pro Tyr Lys
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Leu Lys Asp Asn Ser Leu Tyr Ala Leu Lys Lys Pro Ser His Cys Phe
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Lys Glu Lys His Pro Asn Leu Cys Ala Val Val Asn Asp Glu Ser Asp
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Pro Leu Lys Arg Gly Phe Ala Ser Phe Val Ala Ser Asn Pro Asn Ala
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Pro Ile Arg Asn Ala Phe Tyr Asp Ala Leu Asn Ser Ile Glu Pro Val
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Thr Gly Gly Gly Ser Val Arg Asn Thr Leu Gly Tyr Asn Val Lys Asn
210 215 220
Lys Asn Glu Phe Leu Ser Gln Tyr Lys Phe Asn Leu Cys Phe Glu Asn
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Thr Gln Gly Tyr Gly Tyr Val Thr Glu Lys Ile Ile Asp Ala Tyr Phe
245 250 255
Ser His Thr Ile Pro Ile Tyr Trp Gly Ser Pro Ser Val Ala Lys Asp
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Phe Asn Pro Lys Ser Phe Val Asn Val His Asp Phe Lys Asn Phe Asp
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Glu Ala Ile Asp Tyr Ile Lys Tyr Leu His Thr His Lys Asn Ala Tyr
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Leu Asp Met Leu Tyr Glu Asn Pro Leu Asn Thr Leu Asp Gly Lys Ala
305 310 315 320
Tyr Phe Tyr Gln Asn Leu Ser Phe Lys Lys Ile Leu Ala Phe Phe Lys
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Thr Ile Leu Glu Asn Asp Thr Ile Tyr His Asp Asn Pro Phe Ile Phe
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Cys Arg Asp Leu Asn Glu Pro Leu Val Thr Ile Asp Asp Leu Arg Val
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Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg Ile Asn Tyr
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Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg
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Ile Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn
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Tyr Glu Arg Leu Leu Ser Lys Ala Thr
<210> 2
<211> 478
<212> PRT
<213> α1,3-岩藻糖基转移酶 [幽门螺杆菌 NCTC 11639]
<220>
<223> GenBank ID: AAB81031.1
<400> 2
Met Phe Gln Pro Leu Leu Asp Ala Tyr Val Glu Ser Ala Ser Ile Glu
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Trp Trp Gly Asp Glu Glu Ile Lys Glu Phe Lys Asn Ser Val Leu Tyr
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Phe Ile Leu Ser Gln Arg Tyr Thr Ile Thr Leu His Gln Asn Pro Asn
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Glu Phe Ser Asp Leu Val Phe Gly Asn Pro Leu Gly Ser Ala Arg Lys
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Ile Leu Ser Tyr Gln Asn Ala Lys Arg Val Phe Tyr Thr Gly Glu Asn
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Glu Ser Pro Asn Phe Asn Leu Phe Asp Tyr Ala Ile Gly Phe Asp Glu
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Leu Asp Phe Asn Asp Arg Tyr Leu Arg Met Pro Leu Tyr Tyr Asp Arg
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Leu His His Lys Ala Glu Ser Val Asn Asp Thr Thr Ala Pro Tyr Lys
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Leu Lys Asp Asn Ser Leu Tyr Ala Leu Lys Lys Pro Ser His Cys Phe
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Lys Glu Lys His Pro Asn Leu Cys Ala Val Val Asn Asp Glu Ser Asp
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Pro Leu Lys Arg Gly Phe Ala Ser Phe Val Ala Ser Asn Pro Asn Ala
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Pro Ile Arg Asn Ala Phe Tyr Asp Ala Leu Asn Ser Ile Glu Pro Val
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Lys Asn Glu Phe Leu Ser Gln Tyr Lys Phe Asn Leu Cys Phe Glu Asn
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Thr Gln Gly Tyr Gly Tyr Val Thr Glu Lys Ile Ile Asp Ala Tyr Phe
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Ser His Thr Ile Pro Ile Tyr Trp Gly Ser Pro Ser Val Ala Lys Asp
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Phe Asn Pro Lys Ser Phe Val Asn Val His Asp Phe Lys Asn Phe Asp
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Glu Ala Ile Asp Tyr Ile Lys Tyr Leu His Thr His Lys Asn Ala Tyr
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Leu Asp Met Leu Tyr Glu Asn Pro Leu Asn Thr Leu Asp Gly Lys Ala
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Tyr Phe Tyr Gln Asn Leu Ser Phe Lys Lys Ile Leu Ala Phe Phe Lys
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Thr Ile Leu Glu Asn Asp Thr Ile Tyr His Asp Asn Pro Phe Ile Phe
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Cys Arg Asp Leu Asn Glu Pro Leu Val Thr Ile Asp Asp Leu Arg Val
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Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg Ile Asn Tyr
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Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg Ile Asn Tyr Asp Asp
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Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg
405 410 415
Ile Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn
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Tyr Glu Arg Leu Leu Ser Lys Ala Thr Pro Leu Leu Glu Leu Ser Gln
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Asn Thr Thr Ser Lys Ile Tyr Arg Lys Ala Tyr Gln Lys Ser Leu Pro
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Leu Leu Arg Ala Ile Arg Arg Trp Val Lys Lys Leu Gly Leu
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<210> 3
<211> 425
<212> PRT
<213> 岩藻糖基转移酶 [幽门螺杆菌 26695]
<220>
<223> GenBank ID: NP_207177.1
<400> 3
Met Phe Gln Pro Leu Leu Asp Ala Phe Ile Glu Ser Ala Ser Ile Glu
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Lys Met Ala Ser Lys Ser Pro Pro Pro Pro Leu Lys Ile Ala Val Ala
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Asn Trp Trp Gly Asp Glu Glu Ile Lys Glu Phe Lys Lys Ser Val Leu
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Tyr Phe Ile Leu Ser Gln Arg Tyr Ala Ile Thr Leu His Gln Asn Pro
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Asn Glu Phe Ser Asp Leu Val Phe Ser Asn Pro Leu Gly Ala Ala Arg
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Lys Ile Leu Ser Tyr Gln Asn Thr Lys Arg Val Phe Tyr Thr Gly Glu
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Asn Glu Ser Pro Asn Phe Asn Leu Phe Asp Tyr Ala Ile Gly Phe Asp
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Glu Leu Asp Phe Asn Asp Arg Tyr Leu Arg Met Pro Leu Tyr Tyr Ala
115 120 125
His Leu His Tyr Lys Ala Glu Leu Val Asn Asp Thr Thr Ala Pro Tyr
130 135 140
Lys Leu Lys Asp Asn Ser Leu Tyr Ala Leu Lys Lys Pro Ser His His
145 150 155 160
Phe Lys Glu Asn His Pro Asn Leu Cys Ala Val Val Asn Asp Glu Ser
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Asp Leu Leu Lys Arg Gly Phe Ala Ser Phe Val Ala Ser Asn Ala Asn
180 185 190
Ala Pro Met Arg Asn Ala Phe Tyr Asp Ala Leu Asn Ser Ile Glu Pro
195 200 205
Val Thr Gly Gly Gly Ser Val Arg Asn Thr Leu Gly Tyr Lys Val Gly
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Asn Lys Ser Glu Phe Leu Ser Gln Tyr Lys Phe Asn Leu Cys Phe Glu
225 230 235 240
Asn Ser Gln Gly Tyr Gly Tyr Val Thr Glu Lys Ile Leu Asp Ala Tyr
245 250 255
Phe Ser His Thr Ile Pro Ile Tyr Trp Gly Ser Pro Ser Val Ala Lys
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Asp Phe Asn Pro Lys Ser Phe Val Asn Val His Asp Phe Asn Asn Phe
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Asp Glu Ala Ile Asp Tyr Ile Lys Tyr Leu His Thr His Pro Asn Ala
290 295 300
Tyr Leu Asp Met Leu Tyr Glu Asn Pro Leu Asn Thr Leu Asp Gly Lys
305 310 315 320
Ala Tyr Phe Tyr Gln Asp Leu Ser Phe Lys Lys Ile Leu Asp Phe Phe
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Lys Thr Ile Leu Glu Asn Asp Thr Ile Tyr His Lys Phe Ser Thr Ser
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Phe Met Trp Glu Tyr Asp Leu His Lys Pro Leu Val Ser Ile Asp Asp
355 360 365
Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Arg Leu Leu
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Gln Asn Ala Ser Pro Leu Leu Glu Leu Ser Gln Asn Thr Thr Phe Lys
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Ile Tyr Arg Lys Ala Tyr Gln Lys Ser Leu Pro Leu Leu Arg Ala Val
405 410 415
Arg Lys Leu Val Lys Lys Leu Gly Leu
420 425
<210> 4
<211> 425
<212> PRT
<213> 人工序列
<220>
<223> Choi et al. Biotechnol. Bioengin. 113, 1666 (2016)
<400> 4
Met Phe Gln Pro Leu Leu Asp Ala Phe Ile Glu Ser Ala Ser Ile Glu
1 5 10 15
Lys Met Ala Ser Lys Ser Pro Pro Pro Pro Leu Lys Ile Ala Val Ala
20 25 30
Asn Trp Trp Gly Asp Glu Glu Ile Lys Glu Phe Lys Lys Ser Val Leu
35 40 45
Tyr Phe Ile Leu Ser Gln Arg Tyr Ala Ile Thr Leu His Gln Asn Pro
50 55 60
Asn Glu Phe Ser Asp Leu Val Phe Ser Asn Pro Leu Gly Ala Ala Arg
65 70 75 80
Lys Ile Leu Ser Tyr Gln Asn Thr Lys Arg Val Phe Tyr Thr Gly Glu
85 90 95
Asn Glu Ser Pro Asn Phe Asn Leu Phe Asp Tyr Ala Ile Gly Phe Asp
100 105 110
Glu Leu Asp Phe Asn Asp Arg Tyr Leu Arg Met Pro Leu Tyr Tyr Asn
115 120 125
Glu Leu His Tyr Lys Ala Glu Leu Val Asn Asp Thr Thr Ala Pro Tyr
130 135 140
Lys Leu Lys Asp Asn Ser Leu Tyr Ala Leu Lys Lys Pro Ser His His
145 150 155 160
Phe Lys Glu Asn His Pro Asn Leu Cys Ala Val Val Asn Asp Glu Ser
165 170 175
Asp Leu Leu Lys Arg Gly Phe Ala Ser Phe Val Ala Ser Asn Ala Asn
180 185 190
Ala Pro Met Arg Asn Ala Phe Tyr Asp Ala Leu Asn Ser Ile Glu Pro
195 200 205
Val Thr Gly Gly Gly Ser Val Arg Asn Thr Leu Gly Tyr Lys Val Gly
210 215 220
Asn Lys Ser Glu Phe Leu Ser Gln Tyr Lys Phe Asn Leu Cys Phe Glu
225 230 235 240
Asn Ser Gln Gly Tyr Gly Tyr Val Thr Glu Lys Ile Leu Asp Ala Tyr
245 250 255
Phe Ser His Thr Ile Pro Ile Tyr Trp Gly Ser Pro Ser Val Ala Lys
260 265 270
Asp Phe Asn Pro Lys Ser Phe Val Asn Val His Asp Phe Asn Asn Phe
275 280 285
Asp Glu Ala Ile Asp Tyr Ile Lys Tyr Leu His Thr His Pro Asn Ala
290 295 300
Tyr Leu Asp Met Leu Tyr Glu Asn Pro Leu Asn Thr Leu Asp Gly Lys
305 310 315 320
Ala Tyr Phe Tyr Gln Asp Leu Ser Phe Lys Lys Ile Leu Asp Phe Phe
325 330 335
Lys Thr Ile Leu Glu Asn Asp Thr Ile Tyr His Lys Phe Ser Thr Ser
340 345 350
Phe Met Trp Glu Tyr Asp Leu His Lys Pro Leu Val Ser Ile Asp Asp
355 360 365
Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Arg Leu Leu
370 375 380
Gln Asn Ala Ser Pro Leu Leu Glu Leu Ser Gln Asn Thr Thr Phe Lys
385 390 395 400
Ile Tyr Arg Lys Ala Tyr Gln Lys Ser Leu Pro Leu Leu Arg Ala Val
405 410 415
Arg Lys Leu Val Lys Lys Leu Gly Leu
420 425
<210> 5
<211> 300
<212> DNA
<213> 人工序列
<220>
<223> PglpF变体
<400> 5
gcggcacgcc ttgcagatta cggtttgcca cacttttcat ccttctcctg gtgacataat 60
ccacatcaat cgaaaatgtt aataaatttg ttgcgcgaat gatctaacaa acatgcatca 120
tgtacaatca gatggaataa atggcgcgat aacgctcatt ttatgacgag gcacacacat 180
tttaagttcg atatttctcg tttttgctcg ttaacgataa gtttacagca tgcctacaag 240
catcgtggag gtccgtgact ttcacgcata caacaaacat taaccaagga ggaaacagct 300
<210> 6
<211> 439
<212> PRT
<213> 人工序列
<220>
<223> GalTK
<400> 6
Met Ile Ser Val Tyr Ile Ile Ser Leu Lys Glu Ser Gln Arg Arg Leu
1 5 10 15
Asp Thr Glu Lys Leu Val Leu Glu Ser Asn Glu Lys Phe Lys Gly Arg
20 25 30
Cys Val Phe Gln Ile Phe Asp Ala Ile Ser Pro Lys His Glu Asp Phe
35 40 45
Glu Lys Phe Val Gln Glu Leu Tyr Asp Ser Ser Ser Leu Leu Lys Ser
50 55 60
Asp Trp Phe His Ser Asp Tyr Cys Tyr Gln Glu Leu Leu Pro Gln Glu
65 70 75 80
Phe Gly Cys Tyr Leu Ser His Tyr Leu Leu Trp Lys Glu Cys Val Lys
85 90 95
Leu Asn Gln Pro Val Val Ile Leu Glu Asp Asp Val Ala Leu Glu Ser
100 105 110
Asn Phe Met Gln Ala Leu Glu Asp Cys Leu Lys Ser Pro Phe Asp Phe
115 120 125
Val Arg Leu Tyr Gly His Tyr Trp Gly Gly His Lys Thr Asn Leu Cys
130 135 140
Ala Leu Pro Val Tyr Thr Glu Thr Glu Glu Ala Glu Ala Ser Ile Glu
145 150 155 160
Lys Thr Pro Ile Glu Asn Tyr Glu Val Thr Ser Pro Pro Pro Pro Asn
165 170 175
Pro Thr Arg Asp Thr Gln Gln Asp Phe Ile Thr Glu Thr Gln Gln Asp
180 185 190
Pro Lys Glu Leu Ser Glu Pro Cys Lys Ile Ala Pro Gln Lys Ile Ser
195 200 205
Phe Asn Gln Val Val Phe Lys Lys Ile Lys Arg Lys Leu Asn Arg Phe
210 215 220
Ile Gly Ser Ile Leu Ala Arg Thr Glu Val Tyr Lys Asn Ile Val Ala
225 230 235 240
Lys Tyr Asp Asp Leu Thr Thr Lys Tyr Asp Asp Leu Thr Thr Lys Tyr
245 250 255
Asp Asp Leu Thr Thr Lys Tyr Asp Asp Leu Thr Thr Lys Tyr Asp Asp
260 265 270
Leu Asn Lys Asn Ile Ala Glu Lys Tyr Asp Glu Leu Met Gly Lys Tyr
275 280 285
Glu Ser Leu Leu Ala Lys Glu Val Asn Ile Lys Glu Thr Phe Trp Glu
290 295 300
Ser Arg Ala Asp Ser Glu Lys Glu Ala Leu Phe Leu Asp His Phe Tyr
305 310 315 320
Leu Thr Ser Val Tyr Val Ala Thr Thr Ala Gly Tyr Tyr Leu Thr Pro
325 330 335
Lys Gly Ala Lys Thr Phe Ile Glu Ala Thr Glu Arg Phe Lys Ile Ile
340 345 350
Glu Pro Val Asp Met Phe Ile Asn Asn Pro Thr Tyr His Asp Ile Ala
355 360 365
Asn Phe Thr Tyr Val Pro Cys Pro Val Ser Leu Asn Lys His Ala Phe
370 375 380
Asn Ser Thr Ile Gln Asn Ala Lys Lys Pro Asp Ile Ser Leu Lys Pro
385 390 395 400
Pro Lys Lys Ser Tyr Phe Asp Asn Leu Phe Tyr His Lys Phe Asn Ala
405 410 415
Arg Lys Cys Leu Lys Ala Phe Asn Lys Tyr Ser Lys Gln Tyr Ala Pro
420 425 430
Leu Lys Thr Pro Lys Glu Val
435
<210> 7
<211> 425
<212> PRT
<213> 人工序列
<220>
<223>
<400> 7
Met Phe Gln Pro Leu Leu Asp Ala Phe Ile Glu Ser Ala Ser Ile Glu
1 5 10 15
Lys Met Ala Ser Lys Ser Pro Pro Pro Pro Leu Lys Ile Ala Val Ala
20 25 30
Asn Trp Trp Gly Asp Glu Glu Ile Lys Glu Phe Lys Lys Ser Val Leu
35 40 45
Tyr Phe Ile Leu Ser Gln Arg Tyr Ala Ile Thr Leu His Gln Asn Pro
50 55 60
Asn Glu Phe Ser Asp Leu Val Phe Ser Asn Pro Leu Gly Ala Ala Arg
65 70 75 80
Lys Ile Leu Ser Tyr Gln Asn Thr Lys Arg Val Phe Tyr Thr Gly Glu
85 90 95
Asn Glu Ser Pro Asn Phe Asn Leu Phe Asp Tyr Ala Ile Gly Phe Asp
100 105 110
Glu Leu Asp Phe Asn Asp Arg Tyr Leu Arg Met Pro Leu Tyr Tyr Asn
115 120 125
Glu Leu His Tyr Lys Ala Glu Leu Val Asn Asp Thr Thr Ala Pro Tyr
130 135 140
Lys Leu Lys Gly Asn Ser Leu Tyr Ala Leu Lys Lys Pro Ser His His
145 150 155 160
Phe Lys Glu Asn His Pro Asn Leu Cys Ala Val Val Asn Asp Glu Ser
165 170 175
Asp Leu Leu Lys Arg Gly Phe Ala Ser Phe Val Ala Ser Asn Ala Asn
180 185 190
Ala Pro Met Arg Asn Ala Phe Tyr Asp Ala Leu Asn Ser Ile Glu Pro
195 200 205
Val Thr Gly Gly Gly Ser Val Arg Asn Thr Leu Gly Cys Lys Val Gly
210 215 220
Asn Lys Ser Glu Phe Leu Ser Gln Tyr Lys Phe Asn Leu Cys Phe Glu
225 230 235 240
Asn Ser Gln Gly Tyr Gly Tyr Val Thr Glu Lys Ile Leu Asp Ala Tyr
245 250 255
Phe Ser His Thr Ile Pro Ile Tyr Trp Gly Ser Pro Ser Val Ala Lys
260 265 270
Asp Phe Asn Pro Lys Ser Phe Val Asn Val His Asp Phe Asn Asn Phe
275 280 285
Asp Glu Ala Ile Asp Tyr Ile Lys Tyr Leu His Thr His Pro Asn Ala
290 295 300
Tyr Leu Asp Met Leu Tyr Glu Asn Pro Leu Asn Thr Leu Asp Gly Lys
305 310 315 320
Ala Tyr Phe Tyr Gln Asp Leu Ser Phe Lys Lys Ile Leu Asp Phe Phe
325 330 335
Lys Thr Ile Leu Glu Asn Asp Thr Ile Tyr His Lys Phe Ser Thr Ser
340 345 350
Phe Met Trp Glu Tyr Asp Leu His Lys Pro Leu Val Ser Ile Asp Asp
355 360 365
Leu Arg Val Asn Tyr Asp Asp Leu Arg Val Asn Tyr Asp Arg Leu Leu
370 375 380
Gln Asn Ala Ser Pro Leu Leu Glu Leu Ser Gln Asn Thr Thr Phe Lys
385 390 395 400
Ile Tyr Arg Lys Ala Tyr Gln Lys Ser Leu Pro Leu Leu Arg Ala Val
405 410 415
Arg Lys Leu Val Lys Lys Leu Gly Leu
420 425
Claims (20)
1.一种能够从乳糖产生LNFP-V的重组微生物,优选细菌细胞,更优选大肠杆菌,其包含:
-基因组整合的异源核酸序列,其编码具有β1,3-N-乙酰氨基葡萄糖转移酶活性的多肽,
-基因组整合的异源核酸序列,其编码具有β1,3-半乳糖基转移酶活性的多肽,和
-基因组整合的异源核酸序列,其编码具有α1,3/4-岩藻糖基转移酶活性的多肽,
其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽选自:
-多肽,其包含与SEQ ID No.1的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成,和
-多肽,其包含与SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
2.根据权利要求1所述的微生物,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽选自:
-蛋白质,其包含由SEQ ID No.1表征的氨基酸序列,优选由其组成,
-蛋白质,其包含由SEQ ID No.3表征的氨基酸序列,优选由其组成,
-蛋白质,其包含由SEQ ID No.4表征的氨基酸序列,优选由其组成,和
-蛋白质,其包含由SEQ ID No.7表征的氨基酸序列,优选由其组成。
3.根据权利要求1所述的微生物,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽是一种蛋白质,其包含由SEQ ID No.7表征的氨基酸序列,优选由其组成。
4.根据权利要求1-3中任一项所述的微生物,其包含功能性GDP-岩藻糖生物合成途径。
5.根据权利要求1-4中任一项所述的微生物,其中所述β1,3-N-乙酰氨基葡萄糖转移酶由脑膜炎奈瑟氏球菌053442的IgtA基因或其密码子优化版本编码,和/或所述β1,3-半乳糖基转移酶是由SEQ ID No.6表征的蛋白质。
6.根据权利要求1-5中任一项所述的微生物,其中所述异源核酸序列在根据SEQ IDNo.5的glp启动子变体的控制下表达。
7.根据权利要求6所述的微生物,其中所述glp启动子是glpF或其根据SEQ ID No.5的变体。
8.根据权利要求1-7中任一项所述的微生物,其中每个异源核酸序列以单个拷贝整合到所述微生物的基因组中。
9.根据权利要求1-7中任一项所述的微生物,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽是一种蛋白质,所述蛋白质包含由SEQ ID No.7表征的氨基酸序列,优选由其组成,并且其编码核酸序列以至少两个拷贝整合到所述微生物的基因组中,以及其中所述β1,3-半乳糖基转移酶是由SEQ ID No.6表征的蛋白质,并且其编码核酸序列以至少两个拷贝整合到所述微生物的基因组中。
10.根据权利要求1-9中任一项所述的微生物,其中至少一个、优选每个异源核酸序列整合到与糖代谢有关的操纵子的位点中。
11.根据权利要求1-10中任一项所述的微生物,其中所述GDP-岩藻糖生物合成途径包含在lac启动子的控制下表达的重组manA、manB、manC、gmd和wcaG基因。
12.根据权利要求11所述的微生物,其中在glp启动子,优选glpF或其根据SEQ ID No.5的变体的控制下,参与所述GDP-岩藻糖生物合成途径的基因的额外拷贝整合到所述微生物的基因组中。
13.根据权利要求12所述的微生物,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽是一种蛋白质,所述蛋白质包含由SEQ ID No.7表征的氨基酸序列,优选由其组成,并且其编码核酸序列以单个拷贝整合到所述微生物的基因组中。
14.一种在重组微生物中生产LNFP-V的方法,所述方法包括:
a)提供根据权利要求1-13中任一项所述的遗传修饰的微生物,
b)在乳糖存在下培养所述微生物,和
c)从所述微生物、从培养基或从两者分离LNFP-V。
15.一种蛋白质,其包含由SEQ ID No.7表征的氨基酸序列或由其组成。
16.具有α1,3/4-岩藻糖基转移酶活性的多肽在生产LNFP-V中的用途,所述多肽选自:
-多肽,其包含与SEQ ID No.1的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成,和
-多肽,其包含与SEQ ID No.3的氨基酸序列具有至少90%的序列同一性的氨基酸序列或由其组成。
17.根据权利要求16所述的用途,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽选自:
-蛋白质,其包含由SEQ ID No.1表征的氨基酸序列,优选由其组成,
-蛋白质,其包含由SEQ ID No.3表征的氨基酸序列,优选由其组成,
-蛋白质,其包含由SEQ ID No.4表征的氨基酸序列,优选由其组成,和
-蛋白质,其包含由SEQ ID No.7表征的氨基酸序列,优选由其组成。
18.根据权利要求16所述的用途,其中所述具有α1,3/4-岩藻糖基转移酶活性的多肽是一种蛋白质,所述蛋白质包含由SEQ ID No.7表征的氨基酸序列,优选由其组成。
19.根据权利要求16-18中任一项所述的用途,其中编码所述具有α1,3/4-岩藻糖基转移酶活性的多肽的核酸序列包含在能够从乳糖生产LNFP-V的微生物,优选细菌细胞,更优选大肠杆菌中。
20.根据权利要求19所述的用途,其中所述微生物在权利要求1-13的任一项中定义。
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CN113832092A (zh) * | 2021-10-20 | 2021-12-24 | 江南大学 | 一种提高乳酰-n-岩藻五糖产量的基因工程菌及其生产方法 |
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WO2023097604A1 (zh) * | 2021-12-02 | 2023-06-08 | 岩唐生物科技(杭州)有限责任公司 | 分离的多肽及其应用 |
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US11926858B2 (en) | 2014-06-27 | 2024-03-12 | Glycom A/S | Oligosaccharide production |
US20220267782A1 (en) * | 2019-06-21 | 2022-08-25 | Glycom A/S | Nucleic acid construct comprising 5' utr stem-loop for in vitro and in vivo gene expression |
WO2022013143A1 (en) | 2020-07-13 | 2022-01-20 | Glycom A/S | Oligosaccharide production |
DK180952B1 (en) | 2020-12-22 | 2022-08-10 | Glycom As | A dfl-producing strain |
WO2023099680A1 (en) | 2021-12-01 | 2023-06-08 | Dsm Ip Assets B.V. | Cells with tri-, tetra- or pentasaccharide importers useful in oligosaccharide production |
DK202200588A1 (en) | 2022-06-20 | 2024-02-23 | Dsm Ip Assets Bv | Mixture of fucosylated HMOs |
WO2024003223A1 (en) | 2022-06-29 | 2024-01-04 | Inbiose N.V. | Fucosylated saccharide for use in the prevention or treatment of parasitic disease |
WO2024003222A1 (en) | 2022-06-29 | 2024-01-04 | Inbiose N.V. | Fucosylated saccharide for use in the prevention or treatment of bacterial disease |
WO2024013348A1 (en) | 2022-07-15 | 2024-01-18 | Dsm Ip Assets B.V. | New fucosyltransferases for in vivo synthesis of complex fucosylated human milk oligosaccharides |
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