CN116855462A - 一种生产棘白霉素类药物的基因工程菌及其应用 - Google Patents
一种生产棘白霉素类药物的基因工程菌及其应用 Download PDFInfo
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Abstract
本发明公开了一种生产棘白霉素类药物的基因工程菌及其应用。所述基因工程菌包括一种基因组合,所述基因组合包括来源于丝状真菌Coleophoma empetri中编码P450单加氧酶CEP450‑3的基因和编码磺酰基转移酶CESUL的基因。本发明还公开了一种棘白霉素类化合物,其组成环脂肽的高酪氨酸处具有磺酰氧基的修饰。本发明还公开了通过培养所述基因工程菌来制备所述棘白霉素类化合物的方法,以及所述基因组合、重组表达载体和基因工程菌在生产所述棘白霉素类化合物中的应用。本发明的基因工程菌能生产具有磺酰氧基修饰的新化合物PBS和EcBS,新化合物的水溶性和抗菌活性均分别优于原未经磺酰氧基修饰的化合物PB0和EcB。
Description
技术领域
本发明属于基因工程技术领域,具体涉及一种生产棘白霉素类药物的基因工程菌及其应用,所述基因工程菌包括基因组合CEp450-3和CEsul。本发明还涉及利用所述基因工程菌生产的具有磺酰氧基修饰的新棘白霉素类化合物PBS和EcBS。
背景技术
米卡芬净是一种棘白霉素类抗生素,于2006年FDA批准上市,主要用于深部真菌感染的治疗。棘白霉素类药物还包括卡泊芬净和阿尼芬净,该类药物通过非竞争性抑制细胞壁1,3-β葡聚糖合酶的活性来抑制真菌细胞壁的合成,具有良好的抗真菌活性。
FR901379是合成米卡芬净的关键前体,由丝状真菌Coleophoma empetri F-11899产生,其结构式为:
其生物合成机制尚无报道。
纽莫康定B0(Pneumocandin B0,PB0)是合成卡泊芬净的关键前体,由丝状真菌Glarea lozoyensis产生,其结构式为:
其生物合成途径已报道。
EcB(Echinocandin B)是合成阿尼芬净的关键前体,由丝状真菌Aspergilluspachycristatus NRRL11440产生,其结构式为:
其生物合成途径也已报道。
然而,PB0和EcB都存在水溶性差的问题,因此,需要提高PB0和EcB的水溶性。
发明内容
为解决现有技术中棘白霉素类药物水溶性不高的问题,提供了一种生产棘白霉素类药物的基因工程菌及其应用。
发明人推测FR901379比PB0和EcB水溶性更好的原因可能在于其化学结构中组成环脂肽的高酪氨酸处具有磺酰氧基的修饰,但负责该修饰的基因尚不明确。因PB0和EcB不存在该修饰,所以无法通过基因比对的方法分析得到。故本发明在丝状真菌Coleophomaempetri F-11899中敲除负责合成FR901379的基因,并最终从中筛选到了与FR901379的磺酰氧基修饰相关的基因:CEp450-3和CEsul,并将该基因分别在PB0产生菌株Glarealozoyensis和EcB产生菌株A.pachycristatus中进行异源表达,获得的基因改造菌株经发酵产生一系列新的棘白霉素类化合物,且抗菌活性优于原未经磺酰氧基修饰的化合物。
为解决上述技术问题,本发明提供的技术方案之一为:一种基因组合,所述基因组合包括来源于丝状真菌Coleophoma empetri中编码P450单加氧酶CEP450-3的基因和编码磺酰基转移酶CESUL的基因。
在本发明一些优选实施方案中,所述丝状真菌Coleophoma empetri为Coleophomaempetri F-11899;和/或,所述CEP450-3的氨基酸序列如SEQ ID NO:28所示;和/或,所述CESUL的氨基酸序列如SEQ ID NO:30所示。
在本发明一些优选实施方案中,编码所述CEP450-3的核苷酸序列如SEQ ID NO:29所示,和/或,编码所述CESUL的核苷酸序列如SEQ ID NO:31所示。
为解决上述技术问题,本发明提供的技术方案之二为:一种重组表达载体,所述重组表达载体包括如技术方案之一所述的基因组合。
在本发明一些较佳实施方案中,所述CEP450-3和CESUL在同一个重组表达载体上。
在本发明一些更佳实施方案中,所述重组表达载体的骨架质粒为pAg1-H3。
为解决上述技术问题,本发明提供的技术方案之三为:一种基因工程菌,所述基因工程菌包括如技术方案之一所述的基因组合,或如技术方案之二所述的重组表达载体。
在本发明一些较佳实施方案中,所述基因工程菌以棘白霉素类化合物生产菌为出发菌。
在本发明一些更佳实施方案中,所述棘白霉素类化合物生产菌为Glarealozoyensis或Aspergillus pachycristatus。
为解决上述技术问题,本发明提供的技术方案之四为:一种棘白霉素类化合物,所述棘白霉素类化合物的结构如式I所示:
其中,R1为C1-20烷基或C2-20烯基;
R2为H或C1-6烷基;
R3为C1-6烷基或被取代的C1-6烷基;
X+为一价阳离子;
带“*”的碳原子为手性碳原子或非手性碳原子,当为手性碳原子时,为R构型和/或S构型。
在某一方案中,式I中所述X+为Na+、K+或NH4 +,例如为Na+。
在某一方案中,R1中,所述C1-20烷基为C10-20烷基,例如为
在某一方案中,R1中,所述C2-20烯基为C10-20烯基,例如为
在某一方案中,R2中,所述C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;优选为甲基。
在某一方案中,R3中,所述C1-6烷基和被取代的C1-6烷基中的C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;优选为甲基。
在某一方案中,所述棘白霉素类化合物为:
为解决上述技术问题,本发明提供的技术方案之五为:一种制备如技术方案之四所述棘白霉素类化合物的方法,所述方法包括在发酵培养基中培养如技术方案之三所述的基因工程菌,使其表达产生所述棘白霉素类化合物。
在本发明一些具体实施方案中,所述发酵培养基的pH值为6.0~7.0,和/或,所述发酵培养基包含80~120g/L甘露醇,4~6g/L棉籽饼粉,8~12g/L黄豆饼粉,3~5g/L K2HPO4和0.8~1.2g/L CaCO3;和/或,所述培养的温度为23~27℃,和/或,所述培养的转速为200~240rpm,和/或,所述培养的时间为8~12天。
在本发明一些优选实施方案中,所述发酵培养基的pH值为6.5;所述甘露醇浓度为100g/L,所述棉籽饼粉浓度为5g/L,所述黄豆饼粉浓度为10g/L,所述K2HPO4浓度为4g/L,所述CaCO3浓度为1g/L;所述温度为25℃;所述转速为220rpm;所述时间为10天。
为解决上述技术问题,本发明提供的技术方案之六为:如技术方案之一所述的基因组合,或如技术方案之二所述重组表达载体,或如技术方案之三所述的基因工程菌在生产如技术方案之四所述的棘白霉素类化合物中的应用。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
通过敲除实验,获得可能与FR901379合成过程中负责磺酰氧基的修饰相关的基因。并将该基因在PB0和EcB生产菌株中进行异源表达,获得了具有磺酰氧基修饰的新化合物PBS和EcBS。新化合物PBS和EcBS的水溶性和抗菌活性均分别优于原未经磺酰氧基修饰的化合物PB0和EcB。
附图说明
图1为对照菌株Ce-PC和敲除菌株C.e(ΔCEp450-3)的发酵产物的HPLC图谱。
图2为对照菌株Ce-PC和敲除菌株C.e(ΔCEsul)的发酵产物的HPLC图谱。
图3为PB0和PBS发酵HPLC图。
图4为EcB和EcBS发酵HPLC图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明敲除菌株的构建:
首先将含有cas9基因的质粒pDHt/sk-PC通过农杆菌介导(Agrobacteriumtumefaciens-mediated transformation,AMT)的方法导入出发菌株Coleophoma empetriF-11899,获得工程菌株Ce-PC。在质粒pAgG的基础上利用分子克隆方法构建用于基因敲除的sgRNA表达盒子,该表达盒子由5s rRNA作为启动子,引导N20和sgRNA的转录,N20为用于敲除目的基因的20bp的靶基因序列。对于不同的目的基因,设计的N20如下表1:
表1
基因 | SEQ ID NO: | N20 |
CEp450-3 | 1 | AAGTTCTGCGCAAGACTAGA |
CEsul | 2 | tgcctaggactatgtcgaac |
e20_02930 | 3 | TCCCAAGTCTCACAGAGCAA |
将构建好的敲除质粒导入工程菌株Ce-PC中,挑取转化子,对转化子进行PCR验证筛选,对得到的敲除菌株进行发酵培养,HPLC检测发酵产物,LC-MS分析产物的分子量。
最后,将本专利中的所有化合物进行抗真菌活性检测。
本发明所用的菌株、质粒、试剂、仪器及HPLC检测方法:
菌株Aspergillus pachycristatus NRRL11440和Glarea lozoyensis ATCC20868分别购自于NRRL和ATCC菌种保藏中心。用于AMT的Agrobacterium tumefaciensLBA4404感受态购自唯地生物公司。质粒pAg1-H3来自于中国科学院微生物研究所。pDHt/sk-PC来自于中国科学院上海生命科学研究院植物生理生态研究所合成生物学元件与数据库研究组。
本发明中使用的DNA胶回收纯化试剂盒和质粒提取试剂盒购自上海生工,反转录试剂盒、PCR酶及所有限制性内切酶都购自Takara公司,同源重组试剂盒(ClonExpress IIOne Step Cloning Kit)购自Vazyme公司,色谱纯的乙腈购自Amethyst Chemicals公司,其他常规试剂均为国产分析纯或进口分装。
本发明中使用的恒温发酵摇床购自上海世平实验设备有限公司,1200型高效液相色谱仪购自Agilent Technologies公司。
本发明所用的培养基
1、液体LB培养基(1L)
蛋白胨10g,酵母提取物5g,NaCl 10g,蒸馏水1L;121℃灭菌20分钟。
2、固体LB培养基(1L)
蛋白胨10g,酵母提取物5g,NaCl 10g,琼脂粉20g;121℃灭菌20分钟。
3、PPY培养基(1L):高聚蛋白胨20g,酵母提取物20g,马铃薯肉汤培养基20g。
4、诱导液体培养基(IM):0.8mL K buffer,20mL MN buffer,1mL 1%CaCl2·2H2O,10mL 0.01%FeSO4·7H2O,5mL微量元素,2.5mL 20%硝酸铵,10mL 50%甘油,40mL 1M MES,10mL 20%葡萄糖,加905.7mL无菌水。
培养基中所用溶液:
1%CaCl2·2H2O:称取1g CaCl2·2H2O,加水定容至100mL,使用前需灭菌。
0.01%FeSO4·7H2O:称取0.01g FeSO4·7H2O,加水定容至100mL,使用前需过滤除菌。
20%葡萄糖:称取20g葡萄糖,加水定容至100mL,使用前需灭菌。
50%甘油:量取50mL的甘油,与50mL的水混匀,使用前需灭菌。
20%硝酸铵:称取20g硝酸铵,加水定容至100mL,使用前需灭菌。
K buffer:将1.25M K2HPO4·3H2O加入1.25M K2HPO4至PH为4.8,使用前需灭菌。
MN buffer:称取3g MgSO4·7H2O和1.5g NaCl,加水定容至100mL,使用前需灭菌。
微量元素:称取10mg ZnSO4·7H2O,10mg CuSO4·5H2O,10mg H3BO3,10mg MnSO4·H2O,10mg NaMoO4·2H2O,加水定容至100mL,使用前需灭菌。
1M MES:称取10.66g MES,溶解于水中,调节pH至5.3,定容至50mL。保存于-20℃冰箱中,使用前需过滤除菌。
0.2M AS:称取785mg的AS,溶解于DMSO中,定容至20mL,避光保存于20℃冰箱中,使用前需过滤除菌。
5、诱导固体培养基:向以灭菌的含2%琼脂粉的无菌水中加0.8mL K buffer,20mLMN buffer,1mL 1%CaCl2·2H2O,10mL 0.01%FeSO4·7H2O,5mL微量元素,2.5mL 20%硝酸铵,10mL 50%甘油,40mL 1M MES,10mL 20%葡萄糖。
6、种子培养基配方(1L):
葡萄糖20g,黄豆饼粉10g,KH2PO4 2g,pH值为6.5;121℃灭菌20分钟。
7、发酵培养基配方(1L):
甘露醇100g,棉籽饼粉5g,黄豆饼粉10g,K2HPO4 4g,CaCO3 1g,pH值为6.5;121℃灭菌20分钟。
本发明中的HPLC检测方法为:
HPLC液相检测方法:
流动相:50%乙腈和50%水(含0.5%NaH2PO4);
色谱柱:C18 4.6×250nm;
流速:1mL/min;
检测波长:210nm;
柱温:30℃;
进样量:20μL。
本发明所用引物的碱基序列见下表2,其中-F表示上游引物,-R表示下游引物。
表2
实施例1 CEp450-3的基因敲除及产物分析
本实施例敲除的CEp450-3的基因的氨基酸序列如SEQ ID NO:28所示,其核苷酸序列如SEQ ID NO:29所示。
1、质粒构建:
(1)pAgG及pAgG-sgRNA-CEp450-3的构建
以pAg1-H3为模板,用引物Ptrpc-F/R(本实施例使用的引物的碱基序列见表2)进行PCR得到trpC启动子片段(片段1)。以质粒pEGFP-N2为模板,用引物NeoR-F/R进行PCR得到G418抗性基因Neo片段(片段2)。以pAg1-H3为模板,用引物Ttrpc-F/R进行PCR,得到trpC终止子片段(片段3)。以PCR片段1,片段2,片段3为模板,用引物Ptrpc-F和Ttrpc-R进行重叠PCR,得到G418抗性基因表达盒,将该表达盒连接至HindIII/SpeI线性化的pAg1-H3载体上,最终得到质粒pAg1-HG。pAg1-HG利用EcoRI单切后自连得到pAgG。
以Coleophoma empetri F-11899基因组为模板,5S-F/R为引物,PCR得到5s rRNA片段。用N20-CEp450-3-F和sgRNA-R为引物,PCR得到可特异性识别CEp450-3的sgRNA片段。以5s rRNA片段和sgRNA片段作为模板,用5S-F和sgRNA-R为引物进行重叠PCR,得到sgRNA表达盒。将该表达盒利用同源重组试剂盒(ClonExpress II One Step Cloning Kit)连接至BglII/EcoRI酶切处理的pAgG线性载体,得到敲除质粒pAgG-sgRNA-CEp450-3。
2、敲除菌株的构建
利用AMT,将质粒pAgG-sgRNA-CEp450-3导入Ce-PC菌株中,筛选得到工程菌株C.e(ΔCEp450-3)。
3、工程菌株C.e(ΔCEp450-3)的发酵
为了检测工程菌株C.e(ΔCEp450-3)的发酵产物,将其接种于20mL种子培养基中,25℃,220rpm,培养4天,按10%接种量接种到30mL发酵培养基中,25℃,220rpm,培养10天。
4、HPLC检测
利用反向HPLC(安捷伦)检测发酵产物:取2mL发酵液,加8ml丙酮充分混匀,超声震荡30min,过滤后得滤液进行检测,结果如图1所示。
结果显示:工程菌株C.e(ΔCEp450-3)的发酵产物化合物6的分子量为1126,经分析化合物6的结构为:
推测该基因编码的酶参与FR901379磺酰氧基的合成。
5、抗真菌活性:化合物6的抗菌活性结果见表3,由结果可知,化合物6有抗真菌活性。
实施例2 CEsul的基因敲除及产物分析
本实施例敲除的CEsul的基因的氨基酸序列如SEQ ID NO:30所示,其核苷酸序列如SEQ ID NO:31所示。
1、质粒构建:
(1)pAgG-sgRNA-CEsul的构建
以Coleophoma empetri F-11899基因组为模板,5S-F/R为引物,PCR得到5s rRNA片段。用N20-CEsul-F和sgRNA-R为引物,PCR得到可特异性识别CEsul的sgRNA片段。以5srRNA片段和sgRNA片段作为模板,用5S-F和sgRNA-R为引物进行重叠PCR,得到sgRNA表达盒。将该表达盒利用同源重组试剂盒(ClonExpress II One Step Cloning Kit)连接至BglII/EcoRI酶切处理的pAgG线性载体,得到敲除质粒pAgG-sgRNA-CEsul。
2、敲除菌株的构建
利用AMT,将质粒pAgG-sgRNA-CEsul导入Ce-PC菌株中,筛选得到工程菌株C.e(ΔCEsul)。
3、工程菌株C.e(ΔCEsul)的发酵
为了检测工程菌株C.e(ΔCEsul)的发酵产物,将其接种于20mL种子培养基中,25℃,220rpm,培养2天,按10%接种量接种到30mL发酵培养基中,25℃,220rpm,培养10天。
4、HPLC检测
利用反向HPLC(安捷伦)检测发酵产物:取2mL发酵液,加8ml丙酮充分混匀,超声震荡30min,过滤后得滤液进行检测。
结果显示:工程菌株C.e(ΔCEsul)的发酵产物不产生FR901379,推测该基因所编码的酶为参与FR901379磺酰氧基合成的磺酰基转移酶,如图2所示。
对比例1磺酰基转移酶基因e20_02930敲除及产物分析
本实施例敲除的e20_02930的基因的氨基酸序列如SEQ ID NO:32所示,其核苷酸序列如SEQ ID NO:33所示。
1、质粒构建:
(1)pAgG-sgRNA-02930的构建
以Coleophoma empetri F-11899基因组为模板,5S-F/R为引物,PCR得到5s rRNA片段。用N20-02930-F和sgRNA-R为引物,PCR得到可特异性识别e20_02930的sgRNA片段。以5s rRNA片段和sgRNA片段作为模板,用5S-F和sgRNA-R为引物进行重叠PCR,得到sgRNA表达盒。将该表达盒利用同源重组试剂盒(ClonExpress II One Step Cloning Kit)连接至BglII/EcoRI酶切处理的pAgG线性载体,得到敲除质粒pAgG-sgRNA-02930。
2、敲除菌株的构建
利用AMT,将质粒pAgG-sgRNA-02930导入Ce-PC菌株中,筛选得到工程菌株C.e(Δ02930)。
3、工程菌株C.e(Δ02930)的发酵
为了检测工程菌株C.e(Δ02930)的发酵产物,将其接种于20mL种子培养基中,25℃,220rpm,培养4d,按10%接种量接种到30mL发酵培养基中,25℃,220rpm,培养10天。
4、HPLC检测
利用反向HPLC(安捷伦)检测发酵产物:取2mL发酵液,加8ml丙酮充分混匀,超声震荡30min,过滤后得滤液进行检测。
结果显示:工程菌株C.e(Δ02930)的发酵产物与出发菌株无差别,仍产生FR901379,推测该基因所编码的磺酰基转移酶未参与FR901379的磺酰氧基合成。
实施例3 CEP450-3和CESUL在PB0产生菌株Glarea lozoyensis中的异源表达及应用
1、表达质粒的构建:
以G.lozoyensis基因组为模板,分别利用引物Pgpd-F/R和Tgpd-F/R进行PCR,得到glgpd启动子和终止子片段。以C.empetri cDNA为模板,利用CEP450-3-F/R进行PCR,获得片段CEP450-3。利用获得的三个片段为模板,Pgpd-F和Tgpd-R为引物进行重叠PCR,得到Pglgpd-CEP450-3-Tglgpd。将该片段利用同源重组试剂盒连接至PvuII/EcoRI线性化的pAg1-H3载体上,得到pAg1-H3-Pglgpd-CEp450-3。
以Coleophoma empetri基因组为模板,分别利用引物Pcegpd-F/R和Tcegpd-F/R进行PCR,得到cegpd启动子和终止子片段。以C.empetri cDNA为模板,利用CESUL-F/R进行PCR,获得片段CESUL。利用获得的两个片段为模板,Pcegpd-F和Tcegpd-R为引物进行重叠PCR,得到Pcegpd-CESUL-Tcegpd。将该片段利用同源重组试剂盒连接至SalI/SpeI线性化的pAg1-H3载体上,得到pAg1-H3-Pcegpd-CESUL。
将构建好的pAg1-H3-Pcegpd-CESUL用SalI/SpeI双切,回收大小为3438bp的片段。将构建好的pAg1-H3-Pglgpd-CEp450-3用SalI/SpeI双切,回收大小为10459bp的片段。将回收的两个片段利用T4连接酶连接,获得pAg1-H3-CEP450-3+CESUL。
2、工程菌株的构建
将三个质粒pAg1-H3-Pcegpd-CESUL、pAg1-H3-Pglgpd-CEp450-3、pAg1-H3-CEP450-3+CESUL利用AMT分别导入G.lozoyensis菌株中,得到工程菌株Gl-CEP450-3、Gl-CESUL、Gl-CEP450-3+CESUL。
3、工程菌株产物的分析:
将菌株其接种于20mL种子培养基中,25℃,220rpm,培养4天,按10%接种量接种到30mL发酵培养基中,25℃,220rpm,培养10天。取2mL发酵液,加8ml无水乙醇充分混匀,超声震荡30min,过滤后得滤液进行检测。
从菌株Gl-CEP450-3+CESUL中检测到新化合物PBS,其发酵产量见表4,其结构为:
原始菌株G.lozoyensis和工程菌株Gl-CEP450-3+CESUL发酵分别产生PB0和PBS的HPLC图谱如图3所示。
4、抗真菌活性:
卡泊芬净、PB0和新化合物PBS的抗菌活性结果见表3,由表3可以看出,PBS的抗菌活性优于PB0。
5、溶解性:PB0和新化合物PBS的溶解性见表4,由表4可以看出,PBS的溶解性优于PB0。
实施例4 CEP450-3和CESUL在EcB产生菌株A.pachycristatus NRRL11440中的异源表达及应用
1、工程菌株的构建
将三个质粒pAg1-H3-Pcegpd-CESUL、pAg1-H3-Pglgpd-CEp450-3、pAg1-H3-CEP450-3+CESUL利用AMT分别导入A.pachycristatus菌株中,得到工程菌株Ap-CEP450-3、Ap-CESUL、Ap-CEP450-3+CESUL。
3、工程菌株产物的分析:
将菌株其接种于20mL种子培养基中,25℃,220rpm,培养2天,按10%接种量接种到30mL发酵培养基中,25℃,220rpm,培养10天。取2mL发酵液,加6ml丙酮充分混匀,超声震荡30min,过滤后得滤液进行检测。
从菌株Ap-CEP450-3+CESUL中检测到新化合物EcBS,其发酵产量见表4,其结构为:
原始菌株A.pachycristatus和工程菌株Ap-CEP450-3+CESUL发酵分别产生EcB和EcBS的HPLC图谱如图4所示。
4、抗真菌活性:
阿尼芬净、EcB和新化合物EcBS的抗菌活性结果见表3,由表3可以看出,EcBS的抗菌活性优于EcB。
5、溶解性:EcB和新化合物EcBS的溶解性见表4,由表4可以看出,EcBS的溶解性优于EcB。
表3抑菌活性检测结果
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表4化合物的发酵产量及溶解性
化合物 | 发酵产量 | 水溶性 |
EcB | 1g/L | 0.5g/L |
EcBS | 0.6g/L | 10g/L |
PB0 | 2g/L | 1g/L |
PBS | 1.8g/L | 20g/L |
SEQUENCE LISTING
<110> 上海医药工业研究院有限公司
中国医药工业研究总院有限公司
<120> 一种生产棘白霉素类药物的基因工程菌及其应用
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aagttctgcg caagactaga gttttagagc tagaaatagc 40
<210> 21
<211> 59
<212> DNA
<213> Artificial Sequence
<220>
<223> N20-02930-F
<400> 21
tatgaaagga cgaaacacct cccaagtctc acagagcaag ttttagagct agaaatagc 59
<210> 22
<211> 47
<212> DNA
<213> Artificial Sequence
<220>
<223> CESUL-F
<400> 22
tactaacaag caatcagaat catggcttta gaccgccaga atgcgaa 47
<210> 23
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> CESUL-R
<400> 23
tcggtaagga agagaagacc ctacttccta gctagccaaa 40
<210> 24
<211> 52
<212> DNA
<213> Artificial Sequence
<220>
<223> Pcegpd-F
<400> 24
ggagaattaa gggagtcacg aagcttgtcg acgcacttgt ggtatgaata ga 52
<210> 25
<211> 46
<212> DNA
<213> Artificial Sequence
<220>
<223> Pcegpd-R
<400> 25
actaacaagc aatcagaatc atggctttag accgccagaa tgcgaa 46
<210> 26
<211> 46
<212> DNA
<213> Artificial Sequence
<220>
<223> Tcegpd-F
<400> 26
gtttagaggt aatccttctt actagtaagg gggggtttat gttggt 46
<210> 27
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> Tcegpd-R
<400> 27
tttggctagc taggaagtag ggtcttctct tccttaccga 40
<210> 28
<211> 500
<212> PRT
<213> Artificial Sequence
<220>
<223> CEP450-3氨基酸序列
<400> 28
Met Ile Asn Leu Ala Ser Pro Leu Phe Ala Thr Thr Ala Val Leu Val
1 5 10 15
Trp Leu Ser Ser Leu Ile Ile Tyr Arg Leu Tyr Leu Ser Pro Leu Ser
20 25 30
Arg Phe Pro Gly Pro Lys Leu Ala Ala Leu Thr Gly Trp Tyr Glu Thr
35 40 45
Tyr Phe Asp Leu Phe Lys Arg Gly Arg Tyr Trp Ile Glu Ile Glu Arg
50 55 60
Met His Glu Val Tyr Gly Pro Ile Ile Arg Ile Asn Pro Asn Glu Leu
65 70 75 80
His Val Asn Asp Pro Glu Trp Asn Glu Pro Tyr Lys Ile Ser Gly Arg
85 90 95
Val Asp Lys Tyr Asp Trp Tyr Tyr Thr Phe Val Gly Ser Ser Gly Ser
100 105 110
Ser Ser Ala Phe Gly Thr Ile Asp His Asp Val His Arg Gly Arg Arg
115 120 125
Lys Ala Gln Gln Gly Tyr Phe Thr Thr Asp Ala Ile Thr Arg Phe Glu
130 135 140
Pro His Leu Glu Thr Leu Thr Ala Lys Phe Cys Ala Arg Leu Asp Gly
145 150 155 160
Phe Lys Gly Thr Gly Lys His Val Asn Leu Ser Asp Ala Phe Arg Ser
165 170 175
Ile Ala Val Asp Val Ala Ala Met Phe Thr Leu Asn Gln Ser Tyr Gly
180 185 190
Phe Ile Asp Asp Pro Asp Phe Lys Ala Glu Val His Gln Gly Ile Arg
195 200 205
Ala Phe Pro Asp Ile Gly Val Leu Asn Arg His Phe Thr Gly Leu Phe
210 215 220
Val Val Leu Glu Ser Ile His Arg Trp Val Leu Ser Val Ile Asn Pro
225 230 235 240
Ser Glu Glu Asp Asn Gly Leu Leu Thr Ser Arg Ile Asn Leu His Cys
245 250 255
Lys Ala Ile Ile Ala Asp Tyr Ala Ser Lys Lys Gly Asp Val Lys Pro
260 265 270
Asn Ile Ile His Arg Met Leu Asp Ala Pro Glu Leu Ser Met Lys Asp
275 280 285
Lys Thr Ala Trp Arg Leu Gln Leu Glu Ala Arg Thr Leu Ile Gly Ala
290 295 300
Gly Thr Glu Thr Thr Gly His Thr Leu Ala Val Ile Ala Phe His Leu
305 310 315 320
Leu Ala Asn Pro Glu Lys Ala Lys Arg Leu Lys Glu Glu Ile Leu Ala
325 330 335
Thr Lys Glu Gly Arg Glu Lys Pro Leu Thr Tyr Gln Glu Leu Gln Met
340 345 350
Leu Pro Tyr Leu Ser Ser Val Val Leu Glu Gly His Arg Ile Ser Ser
355 360 365
Val Val Ser Gly Arg Leu Pro Arg Val Asn Thr Lys Glu Pro Leu Arg
370 375 380
Tyr Gly Asp Tyr Ser Ile Pro Ile Gly Thr Pro Val Ser Thr Thr Gln
385 390 395 400
Arg Leu Thr His Tyr Asn Ala Thr Ile Phe Pro Ser Pro Asn Thr Phe
405 410 415
Leu Pro Glu Arg Trp Leu Gln Pro Ser Glu Arg Lys Arg Leu Glu Lys
420 425 430
Tyr Ile Gln Pro Phe Gly Arg Gly Ser Arg Ser Cys Ile Gly Met His
435 440 445
Leu Ala Asn Ala Glu Ile Tyr Lys Thr Leu Ala Glu Met Phe Ala Arg
450 455 460
Phe Asp Met Lys Leu Tyr Asp Thr Glu Phe Glu Asp Ile Met Gln Val
465 470 475 480
His Asp Phe Phe Thr Ser Phe Pro Ser Ser Glu Arg Gly Leu Arg Ile
485 490 495
Leu Val Glu Ala
500
<210> 29
<211> 1802
<212> DNA
<213> Artificial Sequence
<220>
<223> CEp450-3的DNA序列(含内含子)
<400> 29
atgataaatc ttgcaagtcc cctcttcgca acaacagcag ttctagtctg gctcagcagt 60
ctcataatct atcgcctata tctctctcca ctatctcgat ttcccggccc aaaactcgct 120
gctctaacag gatggtacga gacatacttc gacctcttta aacggggtcg ctactggatc 180
gagattgaac gcatgcacga agtctatggt aagtttgtat tttcttcaat aaaaagcgga 240
tatattttga caccagccag gccctatcat ccgcatcaat cccaatgagc tacatgttaa 300
tgacccagaa tggaatgagc cctacaagat cagcggccgc gttgacaagt atgactggta 360
ctacaccttt gttggtagtt ccggatcctc atctgcattc ggaaccatag accacgacgt 420
tcatcgtggc cgccggaaag ctcaacaggg ctatttcacc accgacgcca tcacgcgctt 480
tgaaccacat ttagaaaccc tgacagcaaa gttctgcgca agactagacg gcttcaaggg 540
gacgggaaag catgttaatc tctccgatgc gttccgatca atcgcggtgg atgtggccgc 600
gatgtttaca ttgaatcaat cgtatggttt catcgatgac ccggatttca aggccgaggt 660
ccatcaaggg atccgggcat ttccggatat tggagtgctg aatcgccatt ttacgggttt 720
gttcgtggtt ttggagtcaa tccatagatg ggtgttgagt gttatcaacc cgtcagaaga 780
agataatggg ttactcacaa gtgtacgtat ctttccacta atactgcttt ccccgagatc 840
ctaatgcgtg atagagaata aacctgcatt gtaaagctat tattgccgac tacgccagta 900
agaaaggcga cgtcaagccc aatatcattc acagaatgct agacgcacca gaactatcga 960
tgaaagataa gacagcgtgg cgccttcaat tggaggcgcg cacccttata ggagctggaa 1020
ctgaaacgac aggacacaca ttagccgtca tagcattcca tctgctagca aatccggaga 1080
aggcaaagag gttgaaggag gagatcttag ctacgaaaga agggcgggaa aagcctttaa 1140
cttatcagga gttacaaatg cttccgtatt tagtgagtgt attgttatgg tctgcagagc 1200
atggctaatg aaagcagtct tctgtggtcc ttgaaggtca tcggtaggga gttgattttt 1260
acttttcaga agatgaggct aataacctgt agcatttcta gtgttgtatc aggtcgtctg 1320
ccacgggtca atacaaaaga gccgctcaga tatggtgact atagtatccc tattggcgca 1380
agttttcctc tcctttcgct ctctttctat aactgacgga ttagacagac acccgtcagc 1440
accacccaac ggttaacaca ctacaatgcc accatattcc cctccccaaa cacattcctc 1500
cccgaacgtt ggcttcagcc ctcggaacga aagcgcctgg agaaatacat ccagccgttc 1560
gggcgtggct caagatcttg tataggcatg cagtaagtct cgtcccctat tcgagtgtga 1620
ctaaaatgac taatgagaga agtcttgcaa atgcagagat ttacaaaaca ttggcggaga 1680
tgtttgcaag gtttgacatg aagttatatg atacggagtt cgaggatatt atgcaagtgc 1740
atgacttttt tacttcgttt ccatcgagcg agaggggttt aagaatactt gtggaagcat 1800
aa 1802
<210> 30
<211> 282
<212> PRT
<213> Artificial Sequence
<220>
<223> CESUL 氨基酸序列
<400> 30
Met Ala Leu Asp Arg Gln Asn Ala Lys Val Thr Thr Phe Gly Leu Ser
1 5 10 15
Lys Pro Lys Thr Asn Ile Asp Arg Arg Ser Cys Gln Arg Thr Val Pro
20 25 30
Met Lys Val Leu Cys Leu Gly Leu Cys Arg Thr Gly Thr Ser Ser Leu
35 40 45
Arg Ala Ala Leu Phe Glu Leu Gly Leu Asp Asp Val Tyr His Met Cys
50 55 60
Ser Val Thr Glu Glu Asn Pro Leu Asp Ser Lys Leu Trp Lys Glu Ala
65 70 75 80
Phe Asp Ala Lys Tyr Glu Gly Ile Gly Lys Pro Tyr Gly Arg Ala Glu
85 90 95
Phe Asp Ala Leu Leu Gly His Cys Met Ala Thr Ser Asp Phe Pro Ser
100 105 110
Val Ala Phe Ala Pro Glu Leu Ile Ala Ala Tyr Pro Glu Ala Lys Ile
115 120 125
Ile Leu Thr Val Arg Asp Asn Ala Asp Val Trp Tyr Asp Ser Val Leu
130 135 140
Asn Thr Ile Trp Arg Val Ser Asn Phe Leu Arg Ala Pro Pro Arg Thr
145 150 155 160
Leu Thr Gln Arg Val Val Gln Ala Ile Leu Pro Lys Pro Asp Phe Asn
165 170 175
Ile Phe Lys Tyr Ser Pro Leu Gly Asn Phe Pro Glu Glu Gly Cys Gln
180 185 190
Trp Tyr Ser Asp Trp Asn Glu Glu Ile Arg Thr Leu Ala Lys Gly Arg
195 200 205
Asp Phe Leu Glu Phe Asn Val Lys Glu Gly Trp Gly Pro Leu Cys Arg
210 215 220
Phe Leu Glu Val Glu Gln Pro Glu Thr Pro Phe Pro Arg Val Asn Asp
225 230 235 240
Ser Asn Thr Phe Lys Glu Phe His Asp Lys Gly Leu Glu Gln Asp Ile
245 250 255
Gln Arg Leu Val Gly Ile Ser Thr Lys Leu Val Ala Ala Val Gly Val
260 265 270
Leu Gly Leu Ala Val Trp Leu Ala Arg Lys
275 280
<210> 31
<211> 965
<212> DNA
<213> Artificial Sequence
<220>
<223> CEsul的DNA序列(含内含子)
<400> 31
atggctttag accgccagaa tgcgaaagtt acaactttcg gtctgtcaaa gccgaaaacc 60
aatatagatc gccgatcatg tcagagaact gtccccatga aggttctctg cctaggacta 120
tgtcgaaccg gcacttcctg ttcgtatcaa accatatctc tcacattgct actctcgcta 180
accattcaac agcattgcgt gcggctctct ttgagcttgg ccttgatgat gtctatcaca 240
tgtgtagtgt gacggaagag aatcccctcg actccaagtt gtggaaagag gccttcgacg 300
cgaaatatga agggatcggc aagccctacg gaagagctga atttgacgca ctcttgggtc 360
attgcatggt aagaatcacc tgatcccaac tcttaacgtc caaagtatct gtattactaa 420
caatgcacta ggcaacctcg gatttcccca gcgttgcctt cgctccagaa ctcatcgccg 480
cttaccccga ggcaaagata attctcactg tacgagataa cgccgatgtc tggtatgact 540
ccgttctcaa cacgatctgg agagtctcca acttccttcg cgctcctccg agaactttaa 600
cccaacgagt cgttcaagcg attcttccca agccggattt caacatattc aagtacagcc 660
cccttggcaa ctttcctgag gaaggctgtc agtggtatag tgactggaat gaagagatta 720
gaactctagc caaagggagg gacttcttgg aattcaatgt aaaggaggga tggggtccac 780
tctgtagatt cttggaggtg gagcagccgg agacgccatt tccaagagtc aatgattcaa 840
atacattcaa ggaatttcat gataagggtt tggagcagga tattcaaaga ctggtaggca 900
taagtactaa gcttgtcgcc gctgttggtg tattgggttt ggctgtttgg ctagctagga 960
agtag 965
<210> 32
<211> 455
<212> PRT
<213> Artificial Sequence
<220>
<223> e20_02930氨基酸序列
<400> 32
Met Phe Arg Ser Glu Asn Ser Gln Val Ser Gln Ser Lys Gly Ala Phe
1 5 10 15
Lys Pro Arg Thr Phe Ser Phe Ser Pro Gln Thr Pro Ser Leu Ser Ser
20 25 30
Cys Asn Ser Phe Tyr Leu Tyr Ile His Gly Val Ser Lys Arg Val Pro
35 40 45
Ala Gly Glu Glu Ser Glu Ser Arg Leu Thr Ala Gln Asn Leu Val Trp
50 55 60
Ser Gly Tyr Asn Ala Ala Phe Gly Asn Asp Val Ala Trp Asp Phe Lys
65 70 75 80
Val Val Gln Leu Asn Thr Thr Ala Gln Gly Leu Ala Phe Phe Arg Gly
85 90 95
Ser Met Ala Arg Gly His Gly Ser Gly Gln Ile Ile Leu Leu Asp Glu
100 105 110
Ser Tyr Lys Leu His Arg Thr Ile Ser Ala Glu Ile Glu Gly Ala Ser
115 120 125
Leu Asp Ala His Asp Phe Gln Leu Leu Asp Asn Gly Arg Val Ala Ile
130 135 140
Val Val Met Tyr Thr Ala Val Gln Arg Asp Leu Ser Ser Arg Asp Tyr
145 150 155 160
Thr Ala Gly Leu Gly Trp Leu Ile Ser His Glu Asp Ser Ser Ile Ile
165 170 175
Trp Arg Leu Gly Gly Pro Arg Ser Asp Phe Glu Leu Glu Asp Phe Thr
180 185 190
Phe Ser Ala Gln His Asp Val Arg Ile Val Gln Glu Ser Asp Asp Lys
195 200 205
Glu Gln Ile Ser Leu Phe Asn Asn Gly Trp Asn Gly Ala Thr Gln Thr
210 215 220
Arg Phe Asp Ser Val Ala Met Val Leu Glu Leu Asp Ile Gln Glu Lys
225 230 235 240
Lys Ala Arg Val Leu Lys Glu Trp Ser Pro Leu Asn Gly Gly Leu Ala
245 250 255
Leu His Glu Gly Ser Ile Arg Phe Leu Glu Asn Gly Asn Thr Leu Val
260 265 270
Ser Trp Gly Gly Leu Pro Gln Phe Ser Glu Phe Ala Pro Asp Gly Glu
275 280 285
Arg Val Leu Asp Val Lys Phe Glu Arg His Thr Val Ala Thr Tyr Arg
290 295 300
Thr Ile Lys His Gly Trp Val Gly Arg Pro Asp Thr Leu Pro Asp Leu
305 310 315 320
Tyr Ile Tyr Ser Arg Ser Glu Val Asp Pro Ser Tyr Val Tyr Met Ser
325 330 335
Trp Asn Gly Ala Thr Glu Val Val Ser Trp Lys Val Tyr Gly Val Gly
340 345 350
Asn Asp Ala Ser Thr Ala Pro Glu Phe Leu Gly Ser Ile Asp Arg Gln
355 360 365
Gly Phe Glu Thr Gln Tyr Ile Ala Pro Gln Thr Ile Val Ser Gly Tyr
370 375 380
Val Glu Ala Ile Asp Lys His Gly Glu Ile Leu Ala Thr Ser Val Val
385 390 395 400
Thr Thr Thr Thr Ile Pro Pro Glu Asn Leu Arg Pro Gln Cys Glu Ile
405 410 415
Trp His Cys Ser Ala Gln Ala Asp Glu Asn Ala Pro Asp Ser Asp Phe
420 425 430
Asn Asp Gly Gln Lys Pro Pro Gln Phe Met Asn Val Lys Glu Pro Val
435 440 445
Leu Gln Ala Thr Lys Glu Asp
450 455
<210> 33
<211> 2055
<212> DNA
<213> Artificial Sequence
<220>
<223> e20_02930 DNA序列
<400> 33
atgtttcgtt ccgagaactc ccaagtctca cagagcaagg gcgcctttaa acctcgtaca 60
ttctcattct ctccgcaaac cccctcgctt agctcctgta attcattcta cctatacata 120
cagtagaact ttctatgtcg aaaggttctt cacggtcgta atgctatctt gaacctaact 180
taatgctatc atgagagttg ttctgctcct aaaactgtcc atcctgaatt ggatgtcaag 240
accatatgct tctgctctgt cttttttatc agtacgtgcc tctgagatcg gtacttaacc 300
tgcagaagtg actcttttcc agagacccga cttgaatata cctactttca ttattcgtat 360
acacgaagaa caacgatgtg ctcccggata ctggtttgtg gcaccatgga cgggcccaca 420
ccaacacgca ccatacatct acgataacag tggtgtaagt aaaagagtcc ctgcgggaga 480
ggaaagtgaa agtcggttaa cagcacagaa tcttgtctgg tctggttaca atgctgcctt 540
tggcaatgac gtggcgtggg acttcaaggt tgtccagctc aacacgactg cccagggact 600
cgctttcttt cgcggatcga tggcgcgtgg acacggctcg ggtcagatca ttcttctcga 660
cgagtcgtac aaattgcacc ggacgattag tgcggagata gaaggagctt cacttgatgc 720
acatgacttt caactgcttg ataatggacg cgtcgccatt gtagttatgt atactgcggt 780
tcaaagagac ctctcatcga gagattatac agctgggttg ggttggttgt acgattgtag 840
cttcaaggaa tacgagcttg agacggggaa tgtactgttc gagtggaatt cgctagatca 900
tgtacctatc gacgaatcag ttttggagat aaatctcatt caaggagttg gaagttcaac 960
tctgaagccg tgggattatt tgtaaggata tgtcattatc cgctattgga cattgctaac 1020
ttctctcagc cacatcaact cagtcgagaa gtacaaaaat ggagattatc ttatctctgc 1080
aagacacacc gatacaatct ataggatctc tcacgaggat tcatcaatca tatggagact 1140
gggaggacct cgttcagact ttgagcttga agacttcacg ttctcggcac agcacgacgt 1200
acgaatcgtc caagaaagtg acgacaagga gcaaatttca ctgtttaaca acggctggaa 1260
tggagcaaca caaacccgct ttgattcggt agcaatggtt ctcgagctag atatccaaga 1320
gaagaaagcg agggtactga aagagtggtc accgctgaac ggcgggttgg ctctgcatga 1380
gggaagcata agattcctcg agaacggtaa tactttggtg agctggggag gacttccaca 1440
gttcagcgag ttcgcaccag atggcgagcg ggttctggac gtgaaattcg aacgtcacac 1500
ggtagcgacg tatcgaacca tcaaacatgg ttgggttggc agaccagaca cactcccaga 1560
tctttacatt tattcgcgct cggaagtcga ccccagctat gtctacatga gttggaacgg 1620
agccaccgag gtagtgagtt ggaaagtgta cggggtaggg aatgacgcct cgacggcacc 1680
cgaatttctg ggaagtatcg acaggcaagg attcgagacg caatatattg cgccgcagac 1740
tatcgtctcc ggatacgtcg aggccattga taagcatggc gaaattctcg caacttccgt 1800
tgtgacgacg acgaccatcc cacctgaaaa tctacggcca cagtgtgaga tctggcactg 1860
ttcagcccaa gctgatgaaa acgcaccaga ttctgacttt aacgatggcc agaaaccacc 1920
ccagtttatg aatgtgaagg aaccggtcct gcaagccacg aaggaagtat caaaatgtca 1980
aatgaatagg aggcttttat tgataattgc tggtgtcgtg ttattgggta tcggctttta 2040
cgctggtagg attag 2055
Claims (10)
1.一种基因组合,其特征在于,所述基因组合包括来源于丝状真菌Coleophomaempetri中编码P450单加氧酶CEP450-3的基因和编码磺酰基转移酶CESUL的基因。
2.如权利要求1所述的基因组合,其特征在于,所述丝状真菌Coleophoma empetri为Coleophoma empetri F-11899;和/或,所述CEP450-3的氨基酸序列如SEQ ID NO:28所示;和/或,所述CESUL的氨基酸序列如SEQ ID NO:30所示;
优选地,编码所述CEP450-3的核苷酸序列如SEQ ID NO:29所示,和/或,编码所述CESUL的核苷酸序列如SEQ ID NO:31所示。
3.一种重组表达载体,其特征在于,所述重组表达载体包括如权利要求1或2所述的基因组合;
较佳地,所述CEP450-3和CESUL在同一个重组表达载体上;
更佳地,所述重组表达载体的骨架质粒为pAg1-H3。
4.一种基因工程菌,其特征在于,所述基因工程菌包括如权利要求1或2所述的基因组合,或权利要求3所述的重组表达载体;
较佳地,所述基因工程菌以棘白霉素类化合物生产菌为出发菌;
更佳地,所述棘白霉素类化合物生产菌为Glarea lozoyensis或Aspergilluspachycristatus。
5.一种棘白霉素类化合物,其特征在于,所述棘白霉素类化合物的结构如式I所示:
其中,R1为C1-20烷基或C2-20烯基;
R2为H或C1-6烷基;
R3为C1-6烷基或被取代的C1-6烷基;
X+为一价阳离子;
带“*”的碳原子为手性碳原子或非手性碳原子,当为手性碳原子时,为R构型和/或S构型。
6.如权利要求5所述棘白霉素类化合物,其特征在于,在式I中,所述X+为Na+、K+或NH4 +,例如为Na+;和/或,
R1中,所述C1-20烷基为C10-20烷基,例如为或,
R1中,所述C2-20烯基为C10-20烯基,例如为和/或,
R2中,所述C1-6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基;和/或,
R3中,所述C1-6烷基和被取代的C1-6烷基中的C1-6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基,优选为甲基。
7.如权利要求5所述棘白霉素类化合物,其特征在于,所述棘白霉素类化合物为:
8.一种制备如权利要求5~7任一项所述棘白霉素类化合物的方法,其特征在于,所述方法包括在发酵培养基中培养如权利要求4所述的基因工程菌,使其表达产生所述棘白霉素类化合物。
9.如权利要求8所述的方法,其特征在于,所述发酵培养基的pH值为6.0~7.0,和/或,所述发酵培养基包含80~120g/L甘露醇,4~6g/L棉籽饼粉,8~12g/L黄豆饼粉,3~5g/LK2HPO4和0.8~1.2g/L CaCO3;和/或,
所述培养的温度为23~27℃,和/或,所述培养的转速为200~240rpm,和/或,所述培养的时间为8~12天;
所述发酵培养基的pH值优选6.5;
所述甘露醇优选100g/L,所述棉籽饼粉优选5g/L,所述黄豆饼粉优选10g/L,所述K2HPO4优选4g/L,所述CaCO3优选1g/L;
所述温度优选25℃;所述转速优选220rpm;所述时间优选10天。
10.如权利要求1或2所述的基因组合,或如权利要求3所述重组表达载体,或如权利要求4所述的基因工程菌在生产棘白霉素类化合物中的应用;优选地,所述棘白霉素类化合物如权利要求5~7任一项所定义。
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