CN115197172B - 二倍半萜化合物、其合成基因簇与合成方法 - Google Patents
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Abstract
本发明涉及二倍半萜化合物、其生物合成基因簇与合成方法,通过基因组挖掘,从一株真菌链格孢Alternaria alternata中获得了sesteralterin二倍半萜生物合成基因簇aas,该基因簇包含一个萜环化酶基因aasA和两个细胞色素P450酶基因aasB与aasC,通过米曲霉异源表达系统对基因簇中各基因进行表达,共获得了9个结构新颖且具有抗菌活性的sesteralterin二倍半萜化合物,首次报道了该类化合物生物合成途径,为实现其绿色高效合成奠定了重要的基础,同时,丰富二倍半萜化合物库,为发现新的抗生素等药用原料提供了先导化合物资源。
Description
本申请享有专利申请号为“202111166526.3”,申请日为“2021年9月30日”,发明名称为“二倍半萜化合物、其合成基因簇与合成方法”的优先权。
技术领域
本发明属于基因工程技术领域领域,具体涉及二倍半萜化合物、其合成基因簇与合成方法,从真菌链格孢Alternaria alternata得到的该类化合物基因簇,并利用该基因簇通过异源表达合成该类化合物的方法。
技术背景
萜类化合物是一类碳氢骨架以异戊二烯(C5)为基本结构单元组成的天然产物,在自然界中分布广泛,也是小分子天然产物中最大的一类化合物,目前为止已经发现超过8万种,具有重要的生理活性和药用价值。二倍半萜化合物作为萜类化合物中的一个重要亚类,相比于其它萜类化合物其数量相对稀少,约占萜类总数的不到2%,二倍半萜化合物主要来源于海绵和丝状真菌,少部分来源于植物。截止到目前,人们从真菌中发现的二倍半萜化合物大约有170多个,虽然二倍半萜化合物在数量上相对稀少,但是却具有复杂多样的化学结构和广泛的药理活性,如从Talaromyces wortmannii ATCC 26942中发现的asperterpenoid A具有显著的MptpB抑制活性以;从Bipolaris oryza中分离获得ophiobolin A表现出突出的抗癌作用;从我国台湾的海洋真菌Halorosellinia oceanica的研究中发现其二倍半萜代谢产物halorosellinic acid有一定抗疟活性。由于目前从真菌中发现的二倍半萜化合物还相对稀少,只占二倍半萜总数的不到9%,因此,对于真菌来源的二倍半萜化合物仍有较大的开发空间。
近年来,随着基因测序技术的迅速发展,越来越多的真菌基因组相继被发现。生物信息学分析显示真菌基因组中的基因簇数量远远超过了从中发现的天然产物的数目,这暗示真菌基因组中蕴藏着丰富的天然产物资源,亟待人们发掘利用。
目前,基因挖掘结合异源表达策略已成为发掘新型活性天然产物的一种重要手段,通过强制激活基因簇中的“沉默”基因,进一步获得传统分离手段难以发现的新颖结构的天然产物。因此,利用基因挖掘技术从真菌中获取相应的酶并结合异源表达方法得到结构新颖的化合物,对于从真菌中开发稀有的二倍半萜化合物有重要的意义。
发明内容
针对现有的技术问题,本发明提供了二倍半萜类化合物、其生物合成基因簇,并提供了该类二倍半萜类化合物的生物合成方法以及抗菌活性;
所述二倍半萜类化合物均含有5/8/6/5四环骨架,其结构式如1~9所示:
所述的合成上述1~9化合物的基因簇为sesteralterin二倍半萜类基因簇aas,其来源于真菌链格孢Alternaria alternata,该基因簇aas中包含一个萜环化酶基因aasA和两个P450酶基因aasB与aasC,其相应的基因序列如SEQ ID NO.1-3所示;所述合成上述1~9化合物的生物酶为aasA、aasB和aasC基因表达的蛋白,其氨基酸序列如SEQ ID NO.4-6所示;所述的真菌链格孢Alternaria alternata菌株保藏于暨南大学-中药及天然药物研究所,保藏编号为JNU18-J13211Y-01。
上述化合物的合成方法如下:
1)基因异源表达载体的构建
首先,利用PCR技术,以Alternaria alternata基因组DNA为模板扩增出目的基因aasA、aasB、aasC;然后,将目的基因分别连接到米曲霉表达质粒pTAex3或pUSA质粒中,构建重组表达质粒pTAex3-aasA、pTAex3-aasB、pUSA-aasC;
最后,以重组质粒pTAex3-aasB为模板,通过相应的引物扩增含有淀粉酶amyB启动子和终止子的DNA表达框,分别将含有aasB的DNA表达框连接到pAdeA质粒中,构建重组表达质粒pAdeA-aasB
所述引物包括Inf-aasA-F/Inf-aasA-R、Inf-aasB-F/Inf-aasB-R、Inf-aasC-F/Inf-aasC-R、Inf-pAdeA-Parm-F/Inf-pAdeA-Tamy-R,所述引物的序列如SEQ ID NO.7-14所示;
2)米曲霉异源表达菌株的构建
采用PEG介导的方法,将表达载体pTAex3-aasA转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasA;将表达载体pTAex3-aasA与pUSA-aasC共同转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasAC;将表达载体pTAex3-aasA与pAdeA-aasB共同转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasAB;将表达载体pAdeA-aasB转化至米曲霉AO-aasAC的原生质体中,得到转化子AO-aasABC;
3)米曲霉异源表达菌株培养与发酵
将转化子AO-aasA、AO-aasAC、AO-aasAB、AO-aasABC的菌丝体分别接种于种子液培养基中进行种子液的培养,进一步将种子液转移到诱导培养基中进行培养,诱导外源基因表达,获得代谢产物;
所述种子液培养基为DPY培养基,其组成包括:2%dextrin,1%polypeptone,0.5%yeast extract,0.05%MgSO4·7H2O,0.5%KH2PO4;
所述诱导培养基为CD-starch培养基,其组成包括:0.3%NaNO3,0.2%KCl,0.05%MgSO4·7H2O,0.1%KH2PO4,0.002%FeSO4·7H2O,1%polypeptone,2%starch,pH为5.5;
收集步骤3)中菌株培养发酵5天后的菌体与菌液,菌体用适量丙酮浸没过夜,超声,减压浓缩得到浸膏提取物,菌液用乙酸乙酯萃取,减压浓缩得到浸膏提取物,获得的菌体提取物经硅胶柱层析分离富集目标组分,菌液提取物经中低压ODS柱层析分离富集;然后通过半制备柱YMC-Pack ODS-A column,5μm,10×250mm,进一步纯化,获得单体化合物。
本发明的有益效果如下:
本发明中以米曲霉作为优势表达宿主,采用基因逐步导入的方式,在其体内完整地异源重构了sesteralterin二倍半萜生物合成基因簇,并分离鉴定到9个新的二倍半萜化合物,且具有一定的抗菌活性,可应用在生物医药领域中;另外,本发明为获取该类sesteralterin二倍半萜产物的途径及进一步的深入探究奠定了坚实的基础,为丰富二倍半萜化合物库、以期发现新抗生素等药用原料提供了先导化合物资源。
附图说明
图1是基因簇aas示意图。
图2为本发明米曲霉异源表达所用的质粒pTAex3-aasA、pAdeA-aasB、pUSA-aasC、结构示意图。
图3为本发明AO-aasA、AO-wild type菌株代谢产物的GC-MS检测图谱。
图4本发明化合物1转变为化合物2的HPLC-ELSD分析图谱。
图5-10为本发明化合物1的核磁图谱。
图11-16为本发明化合物2的核磁图谱。
图17为本发明AO-aasAC、AO-aasAB、AO-aasA、AO-wild type菌株代谢产物的HPLC检测图谱。
图18-23为本发明化合物3的核磁图谱。
图24-29为本发明化合物4的核磁图谱。
图30-35为本发明化合物5的核磁图谱。
图36-41为本发明化合物6的核磁图谱。
图42为本发明AO-aasABC、AO-aasAC菌株代谢产物的HPLC检测图谱。
图43-48为本发明化合物7的核磁图谱。
图49-54为本发明化合物8的核磁图谱。
图55-60为本发明化合物9的核磁图谱。
图61为本发明的化合物2-9的HRESIMS图谱。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明了,下面结合具体实施方式,对本发明进一步详细说明。应该理解,这些描述只是示例性的,而并非要限制本发明的范围。此外,在以下说明中,省略了对公知结构和技术的描述,以避免不必要地混淆本发明的概念。
实施例1sesteralterin二倍半萜化合物生物合成基因簇生物信息学分析
基于Local Blast同源搜索,本发明从链格孢真菌Alternaria alternata基因组中找到了sesteralterin二倍半萜化合物生物合成基因簇aas,通过NCBI数据库对该基因簇aas中的基因进行了功能预测,其包含一个萜环化酶基因aasA和两个P450酶基因aasB与aasC如附图1所示。
实施例2基因异源表达载体的构建
pTAex3-aasA质粒构建:以Alternaria alternata基因组为模板,利用引物Inf-aasA-F/Inf-aasA-R对萜环化酶基因aasA进行PCR扩增,将PCR反应体系进行琼脂糖凝胶电泳,经胶回收试剂盒纯化后回收aasA目的片段,接下来,利用In-fusion试剂盒将aasA片段整合到SmaI酶切后的线性载体pTAex3中,并转化到大肠杆菌E.coli DH5α中,通过氨苄青霉素筛选出阳性克隆,挑选阳性克隆子进行液体发酵,提取质粒并进行测序验证,得终得到正确的表达载体pTAex3-aasA;
pTAex3-aasB质粒构建:以Alternaria alternata基因组为模板,利用引物Inf-aasB-F/Inf-aasB-R对萜环化酶基因aasB进行PCR扩增,利用上述相同的方法,获得表达载体pTAex3-aasB;
pAdeA-aasB质粒构建:以重组质粒pTAex3-aasB为模板,利用引物Inf-pAdeA-Parm-F/Inf-pAdeA-Parm-R对基因aasB进行PCR扩增,获得含有淀粉酶amyB启动子和终止子的aasB基因表达框,利用上述相同的方法,将aasB基因表达框整合到XbaI切割的pAdeA质粒中,最终获得表达载体pAdeA-aasB;
pUSA-aasC质粒构建:以Alternaria alternata基因组为模板,利用引物Inf-aasC-F/Inf-aasC-R对萜环化酶基因aasC进行PCR扩增,利用上述相同的方法,将aasC片段整合到SmaI酶切后的线性载体pUSA中,最终获得表达载体pUSA-aasC;
所述的引物见表1;
表1:引物列表
实施例3米曲霉转染菌株的构建
在米曲霉转染菌株构建中,均是采用PEG介导的原生质体转化的方法将含有不同基因的表达质粒转染至米曲霉中,具体操作方法如下:
1)将含有目的表达质粒的大肠杆菌宿主细胞接种至20-30mL含Amp+抗生素的LB液体培养基中过夜培养,然后提取高浓度(>1g/L)重组质粒,用于接下来的转染实验;
2)从A.oryzae NSAR1平板上挑取适量菌丝于10mL DPY培养基(2%dextrin,1%polypeptone,0.5%yeast extract,0.05%MgSO4·7H2O,0.5%KH2PO4,定容至1L)中,28℃,200rpm震荡培养1-2天;
3)将10mL上述培养液加入到100mL DPY培养基中,混匀后于28℃,180rpm震荡培养1天;
4)制备10mL TF solution 1:称取0.79g(NH4)2SO4和0.1g Yatalase裂解酶于15mL的离心管中,加入TF solution 0~10mL,上下颠倒溶解后,用0.22μm微孔滤膜过滤到50mL离心管中;
5)根据菌液浓度,取适量菌液至已灭菌的注射筒中,过滤菌液,压干收集菌体,用已灭菌的长竹签取出菌体,将其放入装有10mL TF solution 1的离心管中,于30℃,70rpm下,在恒温箱中震荡培养3h,破除细胞壁;待上清液明显浑浊且呈淡红色时,将原生质体化的菌液通过注射筒过滤器过滤到50mL离心管中;
6)加入等量的TF solution 2,上下颠倒混匀,4℃,1500rpm离心10min,弃掉上清,向沉淀中加入5mL的TF solution 2,上下颠倒混匀,吸取10μL,用血球计板在显微镜下数原生质体的数目,4℃,1500rpm离心10min,弃掉上清,再加入适量体积的TF solution 2(根据上述计数的原生质体数目,适当稀释或浓缩,使原生质体浓度在1~5×107个/mL),上下颠倒混匀;
7)取200μL的原生质体溶液至15mL离心管中,加入10μL浓度为1μg/μL的重组质粒,混匀,在冰上静置30min,向混悬液中分三次分别加入250μL,250μL以及850μL的TFsolution 3,每次加入后,都用1mL枪头轻轻混匀,室温下静置20min;
8)静置结束后,向15ml离心管中加入5mL TF solution 2,上下颠倒混匀,4℃,1500rpm离心10min,弃掉上清,加入200μL TF solution 2,轻轻混悬后加入到下层培养基中央,并在四周迅速加入上层培养基,快速摇匀;
9)上述培养基平板吹干后,用parafilm缠好,倒置于28℃培养箱中培养3-7天,挑取转化株,并接种到M稳定培养基上进行稳定传代1-3次,待转化株稳定后,提取转化株基因组,对目的基因进行PCR验证,将PCR结果为阳性的菌株,进行后续的发酵实验。
为了鉴定sesteralterin二倍半萜基因簇中的萜环化酶aasA功能,按照上述的转染方法,本发明将表达质粒pTAex3-aasA转染至米曲霉中,得到含有aasA基因的转染菌株AO-aasA;
为了鉴定二倍半萜基因簇中的两个P450酶aasB和aasC的功能,本发明将表达质粒pAdeA-aasB与pTAex3-aasA一起转染至米曲霉中,得到转染菌株AO-aasAB;将表达质粒pUSA-aasC与pTAex3-aasA一起转染至米曲霉中,得到转染菌株AO-aasAC;将表达质粒pAdeA-aasB转染到AO-aasAC菌株中,得到转染菌株AO-aasABC;
实施例4米曲霉转染菌株AO-aasA培养、发酵以及代谢产物分析
将实施例3得到的AO-aasA米曲霉转染株接种于CD-starch液体培养基(0.3%NaNO3,0.2%KCl,0.05%MgSO4·7H2O,0.1%KH2PO4,0.002%FeSO4·7H2O,1%polypeptone,2%starch,定容至1L,培养基的pH为5.5)中,28℃,220rpm培养发酵5天,通过布什漏斗分别收集菌体和菌液,菌体使用适量丙酮浸泡12h,超声30min后,减压浓缩,菌液使用乙酸乙酯萃取,减压浓缩,浓缩样品溶于色谱甲醇中,高速离心,取上清进行GC-MS检测,得到的GC-MS结果见图3;
所述气质分析分析方法如下:
分析仪器:Agilent 7890B GC,配备HP-5MS色谱柱(0.32mm i.d.,0.25μm filmthickness)和5977B单四极杆电子电离质谱仪(70eV)模式,系统采用氦气作为载体,速率为1mL/min。
分析条件:柱箱温度50℃,持续3min,再从20℃/min的速率升至70℃,持续1min,最后从15℃/min的速率升至300℃,持续3min。
由图3的GC-MS结果显示,与空白对照组(米曲霉野生株AO-Wild type)相比,AO-aasA菌株在20.6min处产生了明显的差异峰(化合物1),且分子离子峰为358。
实施例5米曲霉转染菌株AO-aasA代谢产物分离及结构鉴定
将AO-aasA米曲霉转染菌株发酵3L,在CD-starch培养基(同实施例4)中培养5天后,收集菌体,用丙酮浸泡过夜,超声提取,减压浓缩蒸馏得到2.6g菌体浸膏,通过硅胶柱层析进行分离,流动相依次用环己烷、乙酸乙酯洗脱,经TLC分析发现化合物1在子馏分纯环己烷层,然后通过半制备柱YMC-Pack ODS-A column(5μm,10×250mm)进一步纯化,用100%的乙腈进行等度洗脱,纯化得到该化合物1(tR:16.0min,10mg);
随后,对上述化合物1进行液质分析发现,化合物1在CDCl3溶液中能够自发地转变为化合物2(见附图4)。高分辨质谱数据显示化合物2(C25H42O2)的分子量比化合物1(C25H42O)的分子量大16Da,这暗示着化合物2是在化合物1的基础上氧化形成的;
所述液质分析方法采用HPLC-DAD-ELSD-MS;
分析仪器:采用DionexUltimate 3000,配备有UltiMate3000 Diode ArrayDetector以及amaZon SL离子阱电喷雾质谱;
色谱柱:液相分析柱YMC C18(5μm,4.6×250mm),Phenomenex Gemini C18(5μm,4.6×250mm);
流动相:乙腈-水(含0.1%甲酸)作为流动相,以1mL/min的流速进行梯度洗脱;
梯度洗脱程序:50%-100%乙腈(0-20min),100%-100%乙腈(20-60min)。
本发明通过NMR确定了化合物2的结构;
将化合物2与化合物1的核磁数据进行比对,本发明发现化合物2少了两个双键碳信号(δC 143.0,133.0),而多了两个连氧季碳信号(δC 79.1,67.6),这表明化合物2是由化合物1的C10-C11位的双键发生环氧化形成的;
由于化合物1的部分碳信号缺失,而无法获得其完整核磁信号,因此,根据上述推断并结合化合物1的部分二维核磁数据,并确定了化合物1的平面结构;
化合物1的绝对构型是通过其后续的氧化产物4(通过单晶确定结构)的绝对构型确定的,基于以上结果,本发明阐明了萜环化酶aasA可以催化GFPP形成sesteralterin二倍半萜骨架化合物1。
化合物1,2理化性质如下:
化合物1:白色粉末。;UV(MeOH)λmax(logε)206(3.48)nm;IR(KBr)νmax 3510,2933,2864,1738,1455,1374,720cm-1;GC-MS(positive)m/z 358.4(calcd.for C25H42O,358.6070),从而确定化合物分子式为C25H42O,不饱和度为5。核磁数据见表3,附图5-10。
化合物2:白色粉末。;UV(MeOH)λmax(logε)205(3.72)nm;IR(KBr)νmax 3674,3281,2952,2930,2867,1738,1458,1374,1014,954,895,727cm-1;HRESIMS(positive)m/z 375.3257[M+H]+(calcd.for C25H43O2,375.3263),从而确定化合物分子式为C25H42O2,不饱和度为5。HRESIMS见图61。核磁数据见表4,附图11-16。
实施例6米曲霉转染菌株AO-aasAC与AO-aasAB培养、发酵以及代谢产物分析
将本发明将转染菌株AO-aasAC与AO-aasAB分别接种于CD-starch液体培养基(同实施例4)中,28℃,220rpm培养发酵5天,通过布什漏斗收集菌体和菌液,菌体使用适量丙酮浸泡过夜,超声30min后,减压浓缩,菌液使用乙酸乙酯萃取,减压浓缩,浓缩样品加入色谱甲醇溶解,高速离心,取上清进行HPLC-MS检测,得到的结果见附图17;
对上述样品进行液质分析:
分析方法同实施例5;
由图17结果显示,转染菌株AO-aasAC产生了4个新的色谱峰,分别为化合物3、4、5、6,而转染菌株AO-aasAB未产生新的色谱峰。
实施例7米曲霉转染菌株AO-aasAC代谢产物分离及结构鉴定
化合物3、4、5、6的分离纯化:将AO-aasAC米曲霉转染菌株,发酵12L,在CD-starch培养基(同实施例4)中培养5天后,过滤收集菌液,用乙酸乙酯萃取三次,减压浓缩蒸馏得到3.8g提取物,经中低压ODS柱层析,用甲醇-水(5:5,8:2和10:0,v/v)洗脱,得到3个子馏分,经分析发现四个目标化合物在子馏分3(220mg)中,然后通过半制备柱YMC-Pack ODS-Acolumn(5μm,10×250mm)进一步纯化,用86%乙腈-水(含0.1%甲酸)进行等度洗脱,得到化合物5(tR:23.5min,14mg)、化合物6(tR:27.7min,9.8mg)、化合物3(tR:47.4min,9.6mg)和化合物4(tR:50.1min,5mg)。
通过1D和2D核磁,X-ray单晶衍射以及计算碳谱的方法,本发明确定了化合物3、4、5、6的结构。其中,化合物3和4都是在骨架化合物1的基础上,在C9位和C22位发生了氧化并形成五元内酯环的结构,但两者C9位的手性不同,化合物3的C9位为S构型,而化合物4的C9位为R构型,两者互为差向异构体。化合物5是在骨架化合物1的基础上,在C9位与C22位分别氧化形成α-羟基与羧基的结构。化合物6是在五元内酯环的基础上,在C9位继续氧化形成α-羟基的结构。
化合物3、4、5、6理化性质如下:
化合物3:白色针状晶体。m.p.253.0–254.0℃;;UV(MeOH)λmax(logε)226(3.78)nm;IR(KBr)νmax 3533,3423,2975,2873,2839,1643,1463,1388,1356,1028,944cm-1;HRESIMS(positive)m/z 387.2881[M+H]+(calcd.for C25H39O3,387.2899),从而确定化合物分子式为C25H38O3,不饱和度为7。HRESIMS见图61。核磁数据见表5,附图18-23。
化合物4:棕黄色块状晶体。m.p.258.0–259.0℃;;UV(MeOH)λmax(logε)220(4.00)nm;IR(KBr)νmax 3530,3420,2958,2876,1651,1460,1385,1206,1078,960cm-1;HRESIMS(positive)m/z 369.2799[M+H-H2O]+(calcd.for C25H37O2,369.2794),从而确定化合物分子式为C25H38O3,不饱和度为7。核磁数据见表6,附图24-29。
化合物5:白色块状晶体。m.p.283.0–284.0℃;;UV(MeOH)λmax(logε)210(3.75)nm;IR(KBr)νmax 3443,2930,2870,1698,1687,1650,1457,1379,1235,1017,954cm-1;HRESIMS(positive)m/z 405.3027[M+H]+(calcd.for C25H41O4,405.3005),从而确定化合物分子式为C25H40O4,不饱和度为6。HRESIMS见图61。核磁数据见表7,附图30-35。
化合物6:黄色粉末。;UV(MeOH)λmax(logε)223(3.63),265(3.67)nm;IR(KBr)νmax 3431,2952,2927,2870,1719,1614,1457,1382,1141,942cm-1;ECDλmax(Δε)(c 1.1×10-4mol/L,MeOH)236(–7.35),278(–4.30)nm;HRESIMS(positive)m/z403.2840[M+H]+(calcd.for C25H39O4,403.2848),从而确定化合物分子式为C25H38O4,不饱和度为7。HRESIMS见图61。核磁数据见表8,附图36-41。
实施例8米曲霉转染菌株AO-aasABC培养、发酵以及代谢产物分析
本发明将转染菌株AO-aasABC接种于CD-starch液体培养基(同实施例4)中,28℃,220rpm培养发酵5天,通过布什漏斗收集菌体和菌液,菌体使用适量丙酮浸泡过夜,超声30min后,减压浓缩,菌液使用乙酸乙酯萃取,减压浓缩,浓缩样品溶于色谱甲醇中,高速离心,取上清进行HPLC-MS检测,得到的结果见图42;
对上述样品进行液质分析:
分析方法:HPLC-DAD-ELSD-MS;
分析仪器:采用DionexUltimate 3000,配备有UltiMate3000 Diode ArrayDetector以及amaZon SL离子阱电喷雾质谱;
色谱柱:液相分析柱YMC C18(5μm,4.6×250mm),Phenomenex Gemini C18(5μm,4.6×250mm);
流动相:乙腈-水(含0.1%甲酸)作为流动相,以1mL/min的流速进行梯度洗脱;
梯度洗脱程序:50%-100%乙腈(0-20min),100%-100%乙腈(20-60min)。
由图12结果显示,转染菌株AO-aasABC产生了3个新的色谱峰,分别为化合物7、8、9。
实施例9米曲霉转染菌株AO-aasABC代谢产物分离及结构鉴定
化合物7、8、9的分离纯化:将AO-aasABC米曲霉转染菌株,发酵6L,在CD-starch培养基(同实施例4)中培养5天后,过滤收集菌液,用乙酸乙酯萃取三次,减压浓缩蒸馏得到0.55g提取物,经中低压ODS柱层析,用甲醇-水(4:6,6:4,8:2和10:0,v/v)洗脱,得到4个子馏分。经分析发现三个目标化合物在子馏分2(120mg)中。然后通过半制备柱YMC-Pack ODS-A column(5μm,10×250mm)进一步纯化,用55%乙腈-水(含0.1%甲酸)进行等度洗脱,得到化合物7(tR:9.6min,21mg)、化合物8(tR:11.3min,11.4mg)和化合物9(tR:19.8min,6mg)。
通过1D和2D核磁分析,本发明确定了化合物7,8、9的结构。其中,化合物7是在骨架C9位和C22位分别被氧化成α-羟基和羧基的基础上,在C16位继续氧化成β-羟基的结构。化合物8是在骨架C22位甲基单独被氧化成羧基的基础上,在C16位和C17位分别氧化形成羰基和α-羟基的结构。化合物9是在化合物4的基础上,在C16位引入了β-羟基的结构。
化合物7,8、9理化性质如下:
化合物7:白色粉末。;UV(MeOH)λmax(logε)206(3.74)nm;IR(KBr)νmax 3431,2952,2930,2870,1698,1681,1452,1382,1232,1138,1028,956cm-1;HRESIMS(positive)m/z 841.5804[2M+H]+(calcd.for C50H81O10,841.5830),从而确定化合物分子式为C25H40O5,不饱和度为6。HRESIMS见图61。核磁数据见表9,图43-48。
化合物8:白色粉末。;UV(MeOH)λmax(logε)206(3.64);IR(KBr)νmax 3466,2955,2873,1751,1684,1637,1455,1385,1124,1028cm-1;HRESIMS(positive)m/z 401.2689[M+H-H2O]+(calcd.for C25H37O4,401.2692),从而确定化合物分子式为C25H38O5,不饱和度为7。HRESIMS见图61。核磁数据见表10,图49-54。
化合物9:白色粉末。;UV(MeOH)λmax(logε)218(3.90)nm;IR(KBr)νmax 3414,2958,2904,2873,1735,1647,1461,1384,1348,1305,1251,1039,957,793cm-1;HRESIMS(positive)m/z 403.2853[M+H]+(calcd.for C25H39O4,403.2848),从而确定化合物分子式为C25H38O4,不饱和度为7。HRESIMS见图61。核磁数据见表11,图55-60。
实例10抗菌活性测试
本发明采用二倍稀释法测试了化合物1~9的抗真菌及抗细菌活性;测定方法如下:
1)将两种细菌Staphylococcus aureus 209P和Escherichia coli ATCC0111接种至牛肉膏培养基,两种真菌Candida albicans FIM709和Aspergillus.niger R330接种至沙氏培养基,细菌37℃培养1-2天,真菌32℃培养4-7天;
2)用生理盐水收集平板表面的菌体,用血球计数板计数,使菌液浓度在107-109个/mL范围内,取200μL菌液加入到200mL培养基中,充分摇匀;
3)用DMSO分别溶解阳性药和样品,配制浓度为12.5mg/mL的细菌阳性药妥布霉素(Tobramycin)和真菌阳性药伊曲康唑(Itraconzaole),配制浓度为50mg/mL的样品溶液;
4)往96孔板第一孔中加入200μL培养基与菌液混匀液,第一孔中加入1μL样品,依次对半稀释,每孔浓度分别为256,128,64,32,16,8,4,2,1μg/mL,其中,第一排为阴性对照(DMSO),第二排为阳性对照(阳性药),其余9排为实验组;
5)放入保温箱培养,细菌(37℃)约1天后可观测结果,真菌(32℃)约1-3天后可观测结果,若溶液澄清则表示有抗菌活性;
结果如表2所示:化合物1~9均具有一定的抗真菌活性,可用于生物医药领域。
表2:化合物抗菌活性实验结果
SEQUENCE LISTING
1.aasA基因序列
ATGGAGGACCAGATCTTTATTCAGTCTCGCCTTATTGATCCGGATGAGGCCCGCAAGAATGGTGCCTTCACCACCCTCCCTATTCGCATCCACAAGCGAAATGACATTGCCGATGAGACCGCTCGTAGGGTCCTTCGTGATTGGGGTCACCATGTGGGTGATGGCATGGAGAAGAAGGCACTCACATCATTCAGTCACCTAGGCAATCTCAATGCCTTCACATACACTGAGGCATTGCCGGAGAGACTGGGTGTATTGTCCTACTTACTCGACCTTGGACTGATCCATGATGGTACGTGCTCCACTTATAATCTTGTTTCGAAACGAGTAAAGCTGATATTACTTGTTCCACAGATGCCACCGAAGGGATGGGCTTAGAAGATGCCATAGCCGAGCACCATGACTTTGAGCGATCCCTGGACGTTGAAGCGACGGAGGAGGTTGCTCAAGGCTCGAGAGCGGACAAGCTCAAGAAGCTTGGCGCTCAAATTCTTTTAGAAGCAGTTCAAATCGACCGAGAGATGGGAATGCATATGTTGGAGATGTACCAGAAAGAATGGTTGGCCATCGTTGAGAAGAACGACGACAAGGAATTCGACGACTTGGAAGCTTACTACGCTTATCGAAAGTGTAATTTTGGAATGAGGTAAGCGTCTCCACTCACTCCATGGGAGGTTTCGTGGCTTACTGAAACTAGAGCATTCTGGCCCATGGTCGAATATGGAATGGGCTACCGATTAACCGCAAAGCAACACGAACTTATTAAGGATGTGATGGAGCCCATTGAAGAAGCACTCATGCTTACCAACGATTACTGGAGCTGGGATCGCGAATACGAGGATTGGAAAACAAATGGCAACCGGCTTGTCAACGTTGTTGACGTCGTACGGCGAACACGGTCGATACCTACCGACGCAGCTCGAGATATCGTGAAGCAAATGATTATCGAGACTGAGCAAACTTACGTCAAGAGGAAGACCGCTTTCTACAAAGAACATCCCGATGTCTCGATGGAGGTGAGGCGTTGGATCGAAGCCGCCGGCTGTGTTGTGTCTGGAAGTCATTACTGGGCAACAAGCGCACCTCGTCACCATGTCCGGTTCCGCGAATCGTTTGCACAGGAGAATTCTCCTTTGAACGTTACCAGCGACAGCTCTTCCCCAGGAGCTTCCAGCGTGACGAGTGCTTTAAGTGATGCCTGCTCTAGTAACACCTCATTTGCTACGCTCGTATACGAGAACCCTGAAGCCAGGGATGTACAGGTAGCGACGAACACGGAGAATGGCAAACGAGGGCAGAAGAGGAATATCGAGGATGGGTCTCGTCAAGACAGCCCAAGCAAGAAGGTCCATACAGAACTCGGTTGGGAGATGCCCAATGACATGGCGGTTCAATCTCCATGCCATTATATCAGATCCTTGCCTTCGAAAGGGGTCAGATCGATGCTCATCAATGCTTTGAACGTGTGGATACAAGCTCCAAAGAAGTCTGTCAAGGCTGTAGAGGAGCTGATCCGCTTACTGCACAACGCGTCGCTAATCCTCGACGACATCGAAGATGATTCGCCCCTTCGTAGGGGTAGAGCGGCTACGCACCTGGTTTTTGGGCATTCTCAAGCAATTAACAGTGCAAACTTCATGTTTGTCCAAGCCGTTCAGCACGCACGCAAGCTTTCGAACCCGACGGCGGTGGACATCGTACTGTATGAGCTGGAGCGATTGCATCTTGGACAAAGTTGGGATTTGTTCTGGAAGCACAATCTACTCAGTCCGAAAGAGGAGGAATATATGAAAATGGTGGATAGCAAGACTGGCGGGTTATTCCGTATGCTGTTGCAGCTTATCGTCGGCGAAAGCGCACAGGAGCCCAAATGCGATGTGGAAAGGCTGATCCGGCTGATGGCGCTGCTGGGGCGGTTTTTCCAAGTGCGTGACGATTACGTTAACCTGAAGTCAGACACATACGCCGAGCAGAAAGGGTTCTGTGAAGACTTGGATGAGGGCAAGTTCTCTTATCCAATTGTACATTTCCTGCAACATGCACCGGAAATGCTACGAGCTCACGTCATCAGCATATTCCGGCAGCGACCGAGTGGTGGTACAGGACGAGAGACCACGCCGATGGCGAGAGAGGTTAAGCAGCATGTGTTGGATCTTCTCGAGTCAGAGGGAACGTTCGAGGCTGTGCTAAAATTGCTGCGTCAAATGGAAGCTGAGATCATCGCGGAAATTGGGCAGTTGGAAGAGATCACTGGCGAAAGGAATCCTATGCTGCGGCTTGTGATCGAGGGCATCAGCGTGCGAGGGCTGGCGTAA
2.aasB基因序列
ATGGAGTTCAGTGCGACTGTCTCTGAACCTGTCTCATATCTTGCTTACCCATTTTCTCTCCCTTCGATTGCAACCGCGGTGTTCAGTTGCTTTTTGTGTTTTTTCTACTTATACTTCTTTGGTAGAGGGCTTAGTACAAACGCGACTTGGTATGCGCTTACTGAAGATGCACTGTCGAATCACTCAAAGGCGAGGGAACAATGGATGACAGATGCTCAGGAGCTGTTGTACGGAGGACTCAAAAAGGTATCGAAAAATTCAGATGCGGGCAAACGTCCTGTACTAACATGTCCTCGAGATCAAGGGCGCTATCATAGTCACTTCCCCCATTGGGCCGACAATCTTCTTGCCAAATTCGTTTGCAGGTGAGATTCGCAACATGAAAGAACTCAGCTTTAGTCGATCTATTGTGAAAGTACGTTACGCTACTCAGCTTATGAACATCACTGACTTCGTCTTGTGTAGAATGCTTTGGCTCGCGAACCAGGATTGAACCCGATTCTGGCGATTGACTATCATGGAGTCATGCAAGAGGTTGCCCGGCTCGACCTTACTCGCTCTCTGGGTATGAGATACAAGTTCCAGACTGCTTACTTGACTGCTCACATCAATAGATTCCGTCACTGAAGTCATGAATACCGAAGTTGAAGCCGCCCTCCTGGAGATGCTAGGAGACATCTCCGATTGGAAGACTGTGGATCTGAAGCCTCTTATTCACCGCCTTGTTGCCCGCATCTCCAGCCGCGTCTTCCTCGGTCCTGAACTCTCCAACAACGAAGAATGGTTGAACATTGCCTTGTCGTACGTTACCCAAGCAAGCATGGTGACGCGGAAGCTTCGTGGCTTGCATCCACTATTACGACCCCTAGCGCGGTGGTGGTTTCCCGAACTAGGCGTATGTAGAGAGCAGGTTGACAAAGCGCGGAAAATTATCACTCCACTCGTGCAGGATCGTCTACAGAGAAAGGCCAACGGGCAAATCACCGAGAAGACTGCTGATATGTTAAGTTGGCTGGACGACAAGGCAAAGGCGAAGGGTGTGAAGATTGATTTCGCAGAGTTTCAACTCTTGCTCGTGGTGGCGGCAGTACACACGACTACGGAGACAATCGCAATGTTCATGGCTGATCTGATTGAGAACAAAGAGGCAATTTCACAGCTCAGGAAGGAGATTATTTCGACGTTCTCGACTTCTGGTTGGAAAAAGACATCGTTGGCTTCAATGACGTTGCTTGACAGCGCGATGAAGGAATCACAGCGGTTGAATCCTATCACGGATCGTAAGTGACATGTCCAACTTCATTGATGATTCTTCTCTCACGCTCATAGTCTCGATGCAACGGATCGCTTTGACCGATGTCACTCTTTCTGACGGTACAATCATTCCTAAAGGTTACAGACTGGCTGTGGAGCACCGCCTTCGAGATCCAACCCTGTGGTCCGATGTCAACAAATTCCAACCGGACCGTTTCCTCAAGTTACGCGATACTGATCGAAGCAAGTGGAACTTCGTCACTGGTTCGCCCGAGCACCTCGGATTTGGCTACGGGAAACAATCATGCCCGGGACGGTTCTTTGCTAGTAACGAGATCAAAGTCATCGTCATACACATGCTTCTCAAGTATGATTGGGAGTTTACGGATCAAGGAAGATTACCAAACGGGTTATCTGGGACAGACCGCTACATGGACCCGAGGCAAAAAGTCATGCTAAAGAGTAGGAAAGAGGAAATCAACCTGGGTTTACCTTAA
3.aasC基因序列
ATGGCAACCATCCAGGGCGCTCTTTCTGCCCAGAACATTAAAGCTATCCCGGCTTTTGCAAGTCCTTACACACGGGGAAACACCGCACCACGTTTCAGTGATGTTGACATCCTTAAGATAAGGTACCGCACTGACGGCGCATCTGCCCGAGAGTTGATCCCAGAGCAGCTGTCTTTTGAAAGACAACCCATCGTCACAACGTGGGTGCTGGATTATGGCTTCACAAACATCGGACCATACAAAGAACTTATCCATCAGATCGAAGTAACATTTCAAGGAAGGAAATACGATTACGCGATCCTGCTGGTTTTGGACAATGAAGATGCTGTCTATGGTGGGCGTGAGAATTTCGGCCACCCCAAAGTTATGGGCGAGATAGACTTCAATGTTACCAAGAGAACCGGAGTAGCGAGTTTCGTCACTGCTACTGTCTCGCGACCGCCTGGTAATCCGATCATCGAATACCTGTTTAAACCCTCTAACTTCATTGGAACGGGCCCAATACCGCCACGGGGGAACGAGGGTCTTAACCTTCGAGTCATCCCCAATATTATTCCTGGAGCGAAGCCCAATATTCGCCAGTTCATTCCTATCACGTTCAAGCCAGACGTCGGAGAGAGATGGGAGGGTATCGGCAGCCTGAAGTTCCCATCAACAAGCGAGTTTGATCCTTTGCACAAAACGCCTGTTGTCGAATATCTGGGCTCAGAGTTGCTACGGAACTGCCAGGCTTCGTTTGGAGGTTTTTCTACTGAGGCTTTCGATTTCTGGTCTTTGATTGACTTATACTCGCGGAAATGCTCGTATCCTTGA
4.aasA氨基酸序列
MEDQIFIQSRLIDPDEARKNGAFTTLPIRIHKRNDIADETARRVLRDWGHHVGDGMEKKALTSFSHLGNLNAFTYTEALPERLGVLSYLLDLGLIHDDATEGMGLEDAIAEHHDFERSLDVEATEEVAQGSRADKLKKLGAQILLEAVQIDREMGMHMLEMYQKEWLAIVEKNDDKEFDDLEAYYAYRKCNFGMRAFWPMVEYGMGYRLTAKQHELIKDVMEPIEEALMLTNDYWSWDREYEDWKTNGNRLVNVVDVVRRTRSIPTDAARDIVKQMIIETEQTYVKRKTAFYKEHPDVSMEVRRWIEAAGCVVSGSHYWATSAPRHHVRFRESFAQENSPLNVTSDSSSPGASSVTSALSDACSSNTSFATLVYENPEARDVQVATNTENGKRGQKRNIEDGSRQDSPSKKVHTELGWEMPNDMAVQSPCHYIRSLPSKGVRSMLINALNVWIQAPKKSVKAVEELIRLLHNASLILDDIEDDSPLRRGRAATHLVFGHSQAINSANFMFVQAVQHARKLSNPTAVDIVLYELERLHLGQSWDLFWKHNLLSPKEEEYMKMVDSKTGGLFRMLLQLIVGESAQEPKCDVERLIRLMALLGRFFQVRDDYVNLKSDTYAEQKGFCEDLDEGKFSYPIVHFLQHAPEMLRAHVISIFRQRPSGGTGRETTPMAREVKQHVLDLLESEGTFEAVLKLLRQMEAEIIAEIGQLEEITGERNPMLRLVIEGISVRGLA*
5.aasB氨基酸序列
MEFSATVSEPVSYLAYPFSLPSIATAVFSCFLCFFYLYFFGRGLSTNATWYALTEDALSNHSKAREQWMTDAQELLYGGLKKIKGAIIVTSPIGPTIFLPNSFAGEIRNMKELSFSRSIVKNALAREPGLNPILAIDYHGVMQEVARLDLTRSLDSVTEVMNTEVEAALLEMLGDISDWKTVDLKPLIHRLVARISSRVFLGPELSNNEEWLNIALSYVTQASMVTRKLRGLHPLLRPLARWWFPELGVCREQVDKARKIITPLVQDRLQRKANGQITEKTADMLSWLDDKAKAKGVKIDFAEFQLLLVVAAVHTTTETIAMFMADLIENKEAISQLRKEIISTFSTSGWKKTSLASMTLLDSAMKESQRLNPITDLSMQRIALTDVTLSDGTIIPKGYRLAVEHRLRDPTLWSDVNKFQPDRFLKLRDTDRSKWNFVTGSPEHLGFGYGKQSCPGRFFASNEIKVIVIHMLLKYDWEFTDQGRLPNGLSGTDRYMDPRQKVMLKSRKEEINLGLP*
6.aasC氨基酸序列
MATIQGALSAQNIKAIPAFASPYTRGNTAPRFSDVDILKIRYRTDGASARELIPEQLSFERQPIVTTWVLDYGFTNIGPYKELIHQIEVTFQGRKYDYAILLVLDNEDAVYGGRENFGHPKVMGEIDFNVTKRTGVASFVTATVSRPPGNPIIEYLFKPSNFIGTGPIPPRGNEGLNLRVIPNIIPGAKPNIRQFIPITFKPDVGERWEGIGSLKFPSTSEFDPLHKTPVVEYLGSELLRNCQASFGGFSTEAFDFWSLIDLYSRKCSYP*
表3化合物1的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
*The signals were not observed.
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
表4化合物2的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
/>
表5化合物3的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
表6化合物4的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity
/>
表7化合物5的核磁数据归属(1H for 600MHz and 13C for 150MHz in CD3OD)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
/>
表8化合物6的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
/>
表9化合物7的核磁数据归属(1H for 600MHz and 13C for 150MHz in CD3OD)
aindiscernible signals due to overlap or the complex multiplicity arereported without designating multiplicity.
表10化合物8的核磁数据归属(1H for 600MHz and 13C for 150MHz in CD3OD)
aThe indiscernible signals due to overlap or the complex multiplicityare reported without designating multiplicity.
表11化合物9的核磁数据归属(1H for 600MHz and 13C for 150MHz in CDCl3)
aThe indiscernible signals from overlap or the complex multiplicityare reported without designating multiplicity.
SEQUENCE LISTING
<110> 暨南大学
<120> 二倍半萜化合物、其合成基因簇与合成方法
<130> 2022.6.30
<160> 6
<170> PatentIn version 3.3
<210> 1
<211> 2315
<212> DNA
<213> aasA基因序列
<400> 1
atggaggacc agatctttat tcagtctcgc cttattgatc cggatgaggc ccgcaagaat 60
ggtgccttca ccaccctccc tattcgcatc cacaagcgaa atgacattgc cgatgagacc 120
gctcgtaggg tccttcgtga ttggggtcac catgtgggtg atggcatgga gaagaaggca 180
ctcacatcat tcagtcacct aggcaatctc aatgccttca catacactga ggcattgccg 240
gagagactgg gtgtattgtc ctacttactc gaccttggac tgatccatga tggtacgtgc 300
tccacttata atcttgtttc gaaacgagta aagctgatat tacttgttcc acagatgcca 360
ccgaagggat gggcttagaa gatgccatag ccgagcacca tgactttgag cgatccctgg 420
acgttgaagc gacggaggag gttgctcaag gctcgagagc ggacaagctc aagaagcttg 480
gcgctcaaat tcttttagaa gcagttcaaa tcgaccgaga gatgggaatg catatgttgg 540
agatgtacca gaaagaatgg ttggccatcg ttgagaagaa cgacgacaag gaattcgacg 600
acttggaagc ttactacgct tatcgaaagt gtaattttgg aatgaggtaa gcgtctccac 660
tcactccatg ggaggtttcg tggcttactg aaactagagc attctggccc atggtcgaat 720
atggaatggg ctaccgatta accgcaaagc aacacgaact tattaaggat gtgatggagc 780
ccattgaaga agcactcatg cttaccaacg attactggag ctgggatcgc gaatacgagg 840
attggaaaac aaatggcaac cggcttgtca acgttgttga cgtcgtacgg cgaacacggt 900
cgatacctac cgacgcagct cgagatatcg tgaagcaaat gattatcgag actgagcaaa 960
cttacgtcaa gaggaagacc gctttctaca aagaacatcc cgatgtctcg atggaggtga 1020
ggcgttggat cgaagccgcc ggctgtgttg tgtctggaag tcattactgg gcaacaagcg 1080
cacctcgtca ccatgtccgg ttccgcgaat cgtttgcaca ggagaattct cctttgaacg 1140
ttaccagcga cagctcttcc ccaggagctt ccagcgtgac gagtgcttta agtgatgcct 1200
gctctagtaa cacctcattt gctacgctcg tatacgagaa ccctgaagcc agggatgtac 1260
aggtagcgac gaacacggag aatggcaaac gagggcagaa gaggaatatc gaggatgggt 1320
ctcgtcaaga cagcccaagc aagaaggtcc atacagaact cggttgggag atgcccaatg 1380
acatggcggt tcaatctcca tgccattata tcagatcctt gccttcgaaa ggggtcagat 1440
cgatgctcat caatgctttg aacgtgtgga tacaagctcc aaagaagtct gtcaaggctg 1500
tagaggagct gatccgctta ctgcacaacg cgtcgctaat cctcgacgac atcgaagatg 1560
attcgcccct tcgtaggggt agagcggcta cgcacctggt ttttgggcat tctcaagcaa 1620
ttaacagtgc aaacttcatg tttgtccaag ccgttcagca cgcacgcaag ctttcgaacc 1680
cgacggcggt ggacatcgta ctgtatgagc tggagcgatt gcatcttgga caaagttggg 1740
atttgttctg gaagcacaat ctactcagtc cgaaagagga ggaatatatg aaaatggtgg 1800
atagcaagac tggcgggtta ttccgtatgc tgttgcagct tatcgtcggc gaaagcgcac 1860
aggagcccaa atgcgatgtg gaaaggctga tccggctgat ggcgctgctg gggcggtttt 1920
tccaagtgcg tgacgattac gttaacctga agtcagacac atacgccgag cagaaagggt 1980
tctgtgaaga cttggatgag ggcaagttct cttatccaat tgtacatttc ctgcaacatg 2040
caccggaaat gctacgagct cacgtcatca gcatattccg gcagcgaccg agtggtggta 2100
caggacgaga gaccacgccg atggcgagag aggttaagca gcatgtgttg gatcttctcg 2160
agtcagaggg aacgttcgag gctgtgctaa aattgctgcg tcaaatggaa gctgagatca 2220
tcgcggaaat tgggcagttg gaagagatca ctggcgaaag gaatcctatg ctgcggcttg 2280
tgatcgaggg catcagcgtg cgagggctgg cgtaa 2315
<210> 2
<211> 1751
<212> DNA
<213> aasB基因序列
<400> 2
atggagttca gtgcgactgt ctctgaacct gtctcatatc ttgcttaccc attttctctc 60
ccttcgattg caaccgcggt gttcagttgc tttttgtgtt ttttctactt atacttcttt 120
ggtagagggc ttagtacaaa cgcgacttgg tatgcgctta ctgaagatgc actgtcgaat 180
cactcaaagg cgagggaaca atggatgaca gatgctcagg agctgttgta cggaggactc 240
aaaaaggtat cgaaaaattc agatgcgggc aaacgtcctg tactaacatg tcctcgagat 300
caagggcgct atcatagtca cttcccccat tgggccgaca atcttcttgc caaattcgtt 360
tgcaggtgag attcgcaaca tgaaagaact cagctttagt cgatctattg tgaaagtacg 420
ttacgctact cagcttatga acatcactga cttcgtcttg tgtagaatgc tttggctcgc 480
gaaccaggat tgaacccgat tctggcgatt gactatcatg gagtcatgca agaggttgcc 540
cggctcgacc ttactcgctc tctgggtatg agatacaagt tccagactgc ttacttgact 600
gctcacatca atagattccg tcactgaagt catgaatacc gaagttgaag ccgccctcct 660
ggagatgcta ggagacatct ccgattggaa gactgtggat ctgaagcctc ttattcaccg 720
ccttgttgcc cgcatctcca gccgcgtctt cctcggtcct gaactctcca acaacgaaga 780
atggttgaac attgccttgt cgtacgttac ccaagcaagc atggtgacgc ggaagcttcg 840
tggcttgcat ccactattac gacccctagc gcggtggtgg tttcccgaac taggcgtatg 900
tagagagcag gttgacaaag cgcggaaaat tatcactcca ctcgtgcagg atcgtctaca 960
gagaaaggcc aacgggcaaa tcaccgagaa gactgctgat atgttaagtt ggctggacga 1020
caaggcaaag gcgaagggtg tgaagattga tttcgcagag tttcaactct tgctcgtggt 1080
ggcggcagta cacacgacta cggagacaat cgcaatgttc atggctgatc tgattgagaa 1140
caaagaggca atttcacagc tcaggaagga gattatttcg acgttctcga cttctggttg 1200
gaaaaagaca tcgttggctt caatgacgtt gcttgacagc gcgatgaagg aatcacagcg 1260
gttgaatcct atcacggatc gtaagtgaca tgtccaactt cattgatgat tcttctctca 1320
cgctcatagt ctcgatgcaa cggatcgctt tgaccgatgt cactctttct gacggtacaa 1380
tcattcctaa aggttacaga ctggctgtgg agcaccgcct tcgagatcca accctgtggt 1440
ccgatgtcaa caaattccaa ccggaccgtt tcctcaagtt acgcgatact gatcgaagca 1500
agtggaactt cgtcactggt tcgcccgagc acctcggatt tggctacggg aaacaatcat 1560
gcccgggacg gttctttgct agtaacgaga tcaaagtcat cgtcatacac atgcttctca 1620
agtatgattg ggagtttacg gatcaaggaa gattaccaaa cgggttatct gggacagacc 1680
gctacatgga cccgaggcaa aaagtcatgc taaagagtag gaaagaggaa atcaacctgg 1740
gtttacctta a 1751
<210> 3
<211> 813
<212> DNA
<213> aasC基因序列
<400> 3
atggcaacca tccagggcgc tctttctgcc cagaacatta aagctatccc ggcttttgca 60
agtccttaca cacggggaaa caccgcacca cgtttcagtg atgttgacat ccttaagata 120
aggtaccgca ctgacggcgc atctgcccga gagttgatcc cagagcagct gtcttttgaa 180
agacaaccca tcgtcacaac gtgggtgctg gattatggct tcacaaacat cggaccatac 240
aaagaactta tccatcagat cgaagtaaca tttcaaggaa ggaaatacga ttacgcgatc 300
ctgctggttt tggacaatga agatgctgtc tatggtgggc gtgagaattt cggccacccc 360
aaagttatgg gcgagataga cttcaatgtt accaagagaa ccggagtagc gagtttcgtc 420
actgctactg tctcgcgacc gcctggtaat ccgatcatcg aatacctgtt taaaccctct 480
aacttcattg gaacgggccc aataccgcca cgggggaacg agggtcttaa ccttcgagtc 540
atccccaata ttattcctgg agcgaagccc aatattcgcc agttcattcc tatcacgttc 600
aagccagacg tcggagagag atgggagggt atcggcagcc tgaagttccc atcaacaagc 660
gagtttgatc ctttgcacaa aacgcctgtt gtcgaatatc tgggctcaga gttgctacgg 720
aactgccagg cttcgtttgg aggtttttct actgaggctt tcgatttctg gtctttgatt 780
gacttatact cgcggaaatg ctcgtatcct tga 813
<210> 4
<211> 733
<212> PRT
<213> aasA氨基酸序列
<400> 4
Met Glu Asp Gln Ile Phe Ile Gln Ser Arg Leu Ile Asp Pro Asp Glu
1 5 10 15
Ala Arg Lys Asn Gly Ala Phe Thr Thr Leu Pro Ile Arg Ile His Lys
20 25 30
Arg Asn Asp Ile Ala Asp Glu Thr Ala Arg Arg Val Leu Arg Asp Trp
35 40 45
Gly His His Val Gly Asp Gly Met Glu Lys Lys Ala Leu Thr Ser Phe
50 55 60
Ser His Leu Gly Asn Leu Asn Ala Phe Thr Tyr Thr Glu Ala Leu Pro
65 70 75 80
Glu Arg Leu Gly Val Leu Ser Tyr Leu Leu Asp Leu Gly Leu Ile His
85 90 95
Asp Asp Ala Thr Glu Gly Met Gly Leu Glu Asp Ala Ile Ala Glu His
100 105 110
His Asp Phe Glu Arg Ser Leu Asp Val Glu Ala Thr Glu Glu Val Ala
115 120 125
Gln Gly Ser Arg Ala Asp Lys Leu Lys Lys Leu Gly Ala Gln Ile Leu
130 135 140
Leu Glu Ala Val Gln Ile Asp Arg Glu Met Gly Met His Met Leu Glu
145 150 155 160
Met Tyr Gln Lys Glu Trp Leu Ala Ile Val Glu Lys Asn Asp Asp Lys
165 170 175
Glu Phe Asp Asp Leu Glu Ala Tyr Tyr Ala Tyr Arg Lys Cys Asn Phe
180 185 190
Gly Met Arg Ala Phe Trp Pro Met Val Glu Tyr Gly Met Gly Tyr Arg
195 200 205
Leu Thr Ala Lys Gln His Glu Leu Ile Lys Asp Val Met Glu Pro Ile
210 215 220
Glu Glu Ala Leu Met Leu Thr Asn Asp Tyr Trp Ser Trp Asp Arg Glu
225 230 235 240
Tyr Glu Asp Trp Lys Thr Asn Gly Asn Arg Leu Val Asn Val Val Asp
245 250 255
Val Val Arg Arg Thr Arg Ser Ile Pro Thr Asp Ala Ala Arg Asp Ile
260 265 270
Val Lys Gln Met Ile Ile Glu Thr Glu Gln Thr Tyr Val Lys Arg Lys
275 280 285
Thr Ala Phe Tyr Lys Glu His Pro Asp Val Ser Met Glu Val Arg Arg
290 295 300
Trp Ile Glu Ala Ala Gly Cys Val Val Ser Gly Ser His Tyr Trp Ala
305 310 315 320
Thr Ser Ala Pro Arg His His Val Arg Phe Arg Glu Ser Phe Ala Gln
325 330 335
Glu Asn Ser Pro Leu Asn Val Thr Ser Asp Ser Ser Ser Pro Gly Ala
340 345 350
Ser Ser Val Thr Ser Ala Leu Ser Asp Ala Cys Ser Ser Asn Thr Ser
355 360 365
Phe Ala Thr Leu Val Tyr Glu Asn Pro Glu Ala Arg Asp Val Gln Val
370 375 380
Ala Thr Asn Thr Glu Asn Gly Lys Arg Gly Gln Lys Arg Asn Ile Glu
385 390 395 400
Asp Gly Ser Arg Gln Asp Ser Pro Ser Lys Lys Val His Thr Glu Leu
405 410 415
Gly Trp Glu Met Pro Asn Asp Met Ala Val Gln Ser Pro Cys His Tyr
420 425 430
Ile Arg Ser Leu Pro Ser Lys Gly Val Arg Ser Met Leu Ile Asn Ala
435 440 445
Leu Asn Val Trp Ile Gln Ala Pro Lys Lys Ser Val Lys Ala Val Glu
450 455 460
Glu Leu Ile Arg Leu Leu His Asn Ala Ser Leu Ile Leu Asp Asp Ile
465 470 475 480
Glu Asp Asp Ser Pro Leu Arg Arg Gly Arg Ala Ala Thr His Leu Val
485 490 495
Phe Gly His Ser Gln Ala Ile Asn Ser Ala Asn Phe Met Phe Val Gln
500 505 510
Ala Val Gln His Ala Arg Lys Leu Ser Asn Pro Thr Ala Val Asp Ile
515 520 525
Val Leu Tyr Glu Leu Glu Arg Leu His Leu Gly Gln Ser Trp Asp Leu
530 535 540
Phe Trp Lys His Asn Leu Leu Ser Pro Lys Glu Glu Glu Tyr Met Lys
545 550 555 560
Met Val Asp Ser Lys Thr Gly Gly Leu Phe Arg Met Leu Leu Gln Leu
565 570 575
Ile Val Gly Glu Ser Ala Gln Glu Pro Lys Cys Asp Val Glu Arg Leu
580 585 590
Ile Arg Leu Met Ala Leu Leu Gly Arg Phe Phe Gln Val Arg Asp Asp
595 600 605
Tyr Val Asn Leu Lys Ser Asp Thr Tyr Ala Glu Gln Lys Gly Phe Cys
610 615 620
Glu Asp Leu Asp Glu Gly Lys Phe Ser Tyr Pro Ile Val His Phe Leu
625 630 635 640
Gln His Ala Pro Glu Met Leu Arg Ala His Val Ile Ser Ile Phe Arg
645 650 655
Gln Arg Pro Ser Gly Gly Thr Gly Arg Glu Thr Thr Pro Met Ala Arg
660 665 670
Glu Val Lys Gln His Val Leu Asp Leu Leu Glu Ser Glu Gly Thr Phe
675 680 685
Glu Ala Val Leu Lys Leu Leu Arg Gln Met Glu Ala Glu Ile Ile Ala
690 695 700
Glu Ile Gly Gln Leu Glu Glu Ile Thr Gly Glu Arg Asn Pro Met Leu
705 710 715 720
Arg Leu Val Ile Glu Gly Ile Ser Val Arg Gly Leu Ala
725 730
<210> 5
<211> 516
<212> PRT
<213> aasB氨基酸序列
<400> 5
Met Glu Phe Ser Ala Thr Val Ser Glu Pro Val Ser Tyr Leu Ala Tyr
1 5 10 15
Pro Phe Ser Leu Pro Ser Ile Ala Thr Ala Val Phe Ser Cys Phe Leu
20 25 30
Cys Phe Phe Tyr Leu Tyr Phe Phe Gly Arg Gly Leu Ser Thr Asn Ala
35 40 45
Thr Trp Tyr Ala Leu Thr Glu Asp Ala Leu Ser Asn His Ser Lys Ala
50 55 60
Arg Glu Gln Trp Met Thr Asp Ala Gln Glu Leu Leu Tyr Gly Gly Leu
65 70 75 80
Lys Lys Ile Lys Gly Ala Ile Ile Val Thr Ser Pro Ile Gly Pro Thr
85 90 95
Ile Phe Leu Pro Asn Ser Phe Ala Gly Glu Ile Arg Asn Met Lys Glu
100 105 110
Leu Ser Phe Ser Arg Ser Ile Val Lys Asn Ala Leu Ala Arg Glu Pro
115 120 125
Gly Leu Asn Pro Ile Leu Ala Ile Asp Tyr His Gly Val Met Gln Glu
130 135 140
Val Ala Arg Leu Asp Leu Thr Arg Ser Leu Asp Ser Val Thr Glu Val
145 150 155 160
Met Asn Thr Glu Val Glu Ala Ala Leu Leu Glu Met Leu Gly Asp Ile
165 170 175
Ser Asp Trp Lys Thr Val Asp Leu Lys Pro Leu Ile His Arg Leu Val
180 185 190
Ala Arg Ile Ser Ser Arg Val Phe Leu Gly Pro Glu Leu Ser Asn Asn
195 200 205
Glu Glu Trp Leu Asn Ile Ala Leu Ser Tyr Val Thr Gln Ala Ser Met
210 215 220
Val Thr Arg Lys Leu Arg Gly Leu His Pro Leu Leu Arg Pro Leu Ala
225 230 235 240
Arg Trp Trp Phe Pro Glu Leu Gly Val Cys Arg Glu Gln Val Asp Lys
245 250 255
Ala Arg Lys Ile Ile Thr Pro Leu Val Gln Asp Arg Leu Gln Arg Lys
260 265 270
Ala Asn Gly Gln Ile Thr Glu Lys Thr Ala Asp Met Leu Ser Trp Leu
275 280 285
Asp Asp Lys Ala Lys Ala Lys Gly Val Lys Ile Asp Phe Ala Glu Phe
290 295 300
Gln Leu Leu Leu Val Val Ala Ala Val His Thr Thr Thr Glu Thr Ile
305 310 315 320
Ala Met Phe Met Ala Asp Leu Ile Glu Asn Lys Glu Ala Ile Ser Gln
325 330 335
Leu Arg Lys Glu Ile Ile Ser Thr Phe Ser Thr Ser Gly Trp Lys Lys
340 345 350
Thr Ser Leu Ala Ser Met Thr Leu Leu Asp Ser Ala Met Lys Glu Ser
355 360 365
Gln Arg Leu Asn Pro Ile Thr Asp Leu Ser Met Gln Arg Ile Ala Leu
370 375 380
Thr Asp Val Thr Leu Ser Asp Gly Thr Ile Ile Pro Lys Gly Tyr Arg
385 390 395 400
Leu Ala Val Glu His Arg Leu Arg Asp Pro Thr Leu Trp Ser Asp Val
405 410 415
Asn Lys Phe Gln Pro Asp Arg Phe Leu Lys Leu Arg Asp Thr Asp Arg
420 425 430
Ser Lys Trp Asn Phe Val Thr Gly Ser Pro Glu His Leu Gly Phe Gly
435 440 445
Tyr Gly Lys Gln Ser Cys Pro Gly Arg Phe Phe Ala Ser Asn Glu Ile
450 455 460
Lys Val Ile Val Ile His Met Leu Leu Lys Tyr Asp Trp Glu Phe Thr
465 470 475 480
Asp Gln Gly Arg Leu Pro Asn Gly Leu Ser Gly Thr Asp Arg Tyr Met
485 490 495
Asp Pro Arg Gln Lys Val Met Leu Lys Ser Arg Lys Glu Glu Ile Asn
500 505 510
Leu Gly Leu Pro
515
<210> 6
<211> 270
<212> PRT
<213> aasC氨基酸序列
<400> 6
Met Ala Thr Ile Gln Gly Ala Leu Ser Ala Gln Asn Ile Lys Ala Ile
1 5 10 15
Pro Ala Phe Ala Ser Pro Tyr Thr Arg Gly Asn Thr Ala Pro Arg Phe
20 25 30
Ser Asp Val Asp Ile Leu Lys Ile Arg Tyr Arg Thr Asp Gly Ala Ser
35 40 45
Ala Arg Glu Leu Ile Pro Glu Gln Leu Ser Phe Glu Arg Gln Pro Ile
50 55 60
Val Thr Thr Trp Val Leu Asp Tyr Gly Phe Thr Asn Ile Gly Pro Tyr
65 70 75 80
Lys Glu Leu Ile His Gln Ile Glu Val Thr Phe Gln Gly Arg Lys Tyr
85 90 95
Asp Tyr Ala Ile Leu Leu Val Leu Asp Asn Glu Asp Ala Val Tyr Gly
100 105 110
Gly Arg Glu Asn Phe Gly His Pro Lys Val Met Gly Glu Ile Asp Phe
115 120 125
Asn Val Thr Lys Arg Thr Gly Val Ala Ser Phe Val Thr Ala Thr Val
130 135 140
Ser Arg Pro Pro Gly Asn Pro Ile Ile Glu Tyr Leu Phe Lys Pro Ser
145 150 155 160
Asn Phe Ile Gly Thr Gly Pro Ile Pro Pro Arg Gly Asn Glu Gly Leu
165 170 175
Asn Leu Arg Val Ile Pro Asn Ile Ile Pro Gly Ala Lys Pro Asn Ile
180 185 190
Arg Gln Phe Ile Pro Ile Thr Phe Lys Pro Asp Val Gly Glu Arg Trp
195 200 205
Glu Gly Ile Gly Ser Leu Lys Phe Pro Ser Thr Ser Glu Phe Asp Pro
210 215 220
Leu His Lys Thr Pro Val Val Glu Tyr Leu Gly Ser Glu Leu Leu Arg
225 230 235 240
Asn Cys Gln Ala Ser Phe Gly Gly Phe Ser Thr Glu Ala Phe Asp Phe
245 250 255
Trp Ser Leu Ile Asp Leu Tyr Ser Arg Lys Cys Ser Tyr Pro
260 265 270
Claims (5)
1.一类合成二倍半萜化合物的基因簇,其特征在于,所述基因簇为sesteralterin二倍半萜生物合成基因簇aas,所述基因簇aas含有一个萜环化酶基因aasA和两个细胞色素P450酶基因aasB与aasC,其相应的基因序列如SEQ ID NO.1-3所示;
所述的二倍半萜化合物均含有5/8/6/5四环骨架,其结构式如1~9所示:
2.一种合成二倍半萜化合物的生物合成酶,其特征在于,所述生物合成酶为aasA、aasB与aasC基因表达的蛋白,其氨基酸序列如SEQ ID NO.4-6所示;
所述的二倍半萜化合物均含有5/8/6/5四环骨架,其结构式如1~9所示:
3.一种利用权利要求1所述的基因簇合成二倍半萜化合物的方法,其特征在于,包括以下步骤:
1)基因异源表达载体的构建
首先,利用PCR技术,以Alternaria alternata基因组DNA为模板扩增出目的基因aasA、aasB、aasC;然后,将目的基因分别连接到米曲霉表达质粒pTAex3或pUSA质粒中,构建重组表达质粒pTAex3-aasA、pTAex3-aasB、pUSA-aasC;
最后,以重组质粒pTAex3-aasB为模板,通过相应的引物扩增含有淀粉酶amyB启动子和终止子的DNA表达框,分别将含有aasB的DNA表达框连接到pAdeA质粒中,构建重组表达质粒pAdeA-aasB;所述引物为Inf-aasA-F/Inf-aasA-R、Inf-aasB-F/Inf-aasB-R、Inf-aasC-F/Inf-aasC-R、Inf-pAdeA-Parm-F/Inf-pAdeA-Tamy-R,所述引物的序列如SEQ ID NO.7-14所示;
2)米曲霉异源表达菌株的构建
将表达载体pTAex3-aasA转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasA;将表达载体pTAex3-aasA与pUSA-aasC共同转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasAC;将表达载体pTAex3-aasA与pAdeA-aasB共同转化至米曲霉A.oryzae NSAR1的原生质体中,得到转化子AO-aasAB;将表达载体pAdeA-aasB转化至米曲霉AO-aasAC的原生质体中,得到转化子AO-aasABC;
3)米曲霉异源表达菌株培养与发酵
将转化子AO-aasA、AO-aasAC、AO-aasAB、AO-aasABC的菌丝体分别接种于种子液培养基中进行种子液的培养,进一步将种子液转移到诱导培养基中进行培养,诱导外源基因表达,获得代谢产物;所述代谢产物经分离纯化步骤得到二倍半萜单体化合物:收集培养发酵5天后的菌体与菌液,菌体用适量丙酮浸没过夜,超声,减压浓缩得到浸膏提取物,菌液用乙酸乙酯萃取,减压浓缩得到浸膏提取物,获得的浸膏提取物经硅胶柱层析分离富集目标组分,菌液提取物经中低压ODS柱层析分离富集;然后通过半制备柱YMC-Pack ODS-Acolumn,5μm,10×250mm,进一步纯化,获得单体化合物;
所述二倍半萜化合物的结构如权利要求1中所示。
4.根据权利要求3所述的合成方法,其特征在于,所述步骤2)中表达载体的转化是通过PEG转化至米曲霉原生质体中。
5.根据权利要求3所述的合成方法,其特征在于,所述步骤3)中种子液培养基为DPY培养基,所述DPY培养基组成包括:2%dextrin,1%polypeptone,0.5%yeast extract,0.05%MgSO4·7H2O,0.5%KH2PO4;所述步骤3)中诱导培养基为CD-starch培养基,所述CD-starch培养基组成包括:0.3%NaNO3,0.2%KCl,0.05%MgSO4·7H2O,0.1%KH2PO4,0.002%FeSO4·7H2O,1%polypeptone,2%starch,pH为5.5。
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