岩黄连中小檗碱型生物碱生物合成途径相关基因的研究及藜芦中甾体生物碱的微生物转化
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摘要
岩黄连为罂粟科植物石生黄堇(Corydalis saxicola Bunting)的全草,是一种名贵的中药材主要分布在贵州,云南,四川,广西等省,对环境条件要求十分苛刻,野生状态下只生长在石灰岩地区阴湿的岩洞口,被列入中国南部濒危植物名录。岩黄连具有清热解毒、利湿、止痛止血之功效,在临床上主要药理活性有抗菌,抗病毒,抗癌。岩黄连中的活性成分为小檗碱型生物碱类化合物,而这类化合物具有潜在的抗HBV活性和肝保护活性。
本文对岩黄连中小檗碱类生物碱生物合成途径中的相关酶基因进行了克隆、表达及功能分析。
岩黄连中(S)-四氢小檗碱氧化酶的克隆,表达及功能分析
(S)-四氢小檗碱氧化酶是小檗碱生物合成途径中的关键酶,是黄连小檗碱的合成途径中最后一个酶,将(S)-四氢小檗碱氧化成小檗碱。通过RACE获得了(S)-四氢小檗碱氧化酶cDNA全长序列,其长度为1127bp,含有5'-UTR, 3'-UTR,ploy (A)+结构以及一个699bp的开放阅读框架,编码232个氨基酸残基,预测分子量为25.20 kDa。将该基因注册到GenBank,编号为HQ393909。RT-PCR分析表示(S)-THBO在岩黄连植株的根、茎、叶、花中都有表达,在根中表达量最高。诱导实验表明(S)-THBO具有明显的防御作用。
将(S)-四氢小檗碱氧化酶构建表达载体并在大肠杆菌中表达,并对表达(S)-四氢小檗碱氧化酶的大肠杆菌对底物进行体内转化。表达(S)-四氢小檗碱氧化酶的大肠杆菌可以体内转化(S)-四氢小檗碱氧化成小檗碱,但对底物有一定的选择性,不能将内消旋四氢小檗碱转化完全。
岩黄连中(S)-去甲乌药碱合成酶的克隆
(S)-去甲乌药碱合成酶是原小檗碱生物合成途径中的第一个酶,它可以将多巴胺(Dopamine)和(4-羟苯乙酮4-hydroxyphenylhydroxyphenylacetaldehyde,(4-HPAA) )催化成(S)-去甲乌药碱( (S)-Norcoclaurine)。对岩黄连的总RNA进行PT-PCR得到一段(S)-去甲乌药碱合成酶的核心片段。通过RACE获得了(S)-去甲乌药碱合成酶cDNA全长序列,其长度为1003bp,含有5'-UTR, 3'-UTR,ploy (A)+结构以及一个621bp的开放阅读框架,编码207个氨基酸残基。将该基因注册到GenBank,编号为JF488074。
岩黄连中氢化小檗碱合酶的克隆
氢化小檗碱合酶位是原小檗碱类生物碱生物合成途径的下游基因,它的功能是将(S)-四氢非洲防己碱( (S)-THC)催化成(S)-四氢小檗碱( (S)-THB),使化合物形成特殊的亚甲基双氧环结构。通过RACE获得了氢化小檗碱合酶cDNA全长序列,其长度为1256bp,含有5'-UTR, 3'-UTR结构以及一个783bp的开放阅读框架,编码261个氨基酸残基。将该基因注册到GenBank,编号为HQ393908。
第二部分藜芦中甾体生物碱的微生物转化
藜芦(Veratrum Linn. )为百合科(Liliaceae)多年生草本植物,味辛、苦,性寒,有毒。中医用藜芦(V.nigrum L. )、兴安藜芦(V.dahuricum(Turcz.)Loes.f.)、天目藜芦(V.Schindleri L)等的根和茎共同入药,用于中风痰壅、癫痫、喉痹不通、头痛、疥癣、疟疾。藜芦属植物中的生物碱类成分为其主要的活性成分,现代临床药理研究表明,甾体生物碱具有降血压作用、抗肿瘤作用、杀虫、抗血吸虫、抗真菌及等作用。据统计数据表明从我国所有藜芦属植物中分离得到100余种甾体生物碱。藜芦的毒素同样为生物碱类成分。
微生物转化反应是利用微生物的酶对底物的某一部位进行特定的化学反应来获得一定的产物,其在药物生产中占有重要地位。因为藜芦属植物中甾体生物碱具有良好的抗肿瘤活性,在实验室前期研究结果的基础上对藜芦中有效的甾体生物碱成分利用微生物转化的方法对其进行结构修饰和改造,合成系列衍生物,以期获得高效、低毒、高特异性的Hedgehog通路抑制剂,为新型抗肿瘤药物的开发提供理论基础。
本课题利用刺孢小克银汉霉对生物碱藜芦胺进行微生物转化,共得到了5个化合物,都为新化合物。
Corydalis saxicola Bunting (Yanhuanglian) is one of rare medicinal plants for the treatment of hepatic disease which belongs to the Fumariaceae family. C. saxicola grows in south China, such as Guizhou, Yunnan, Szechwan and Guangxi province and only grows in limestone hills in the wild state. It was labeled as endangered plants in southern China because of its hard growth environment. C. saxicola has the effect of clearing away heat, relieve pain and arrest blood.It has been demonstrated to have many pharmacological activities, including antibacterial, antiviral, and anticancer activities. The main active constituent in C. saxicola is berberine alkaloids (e.g. berberine, dehydrocavidine), which has potential activity to treat hepatitis, hepatocirrhosis and liver cancer.
(S)-tetrahydroberberine oxidase ((S)-THBO) is a key enzyme in the biosynthesis of berberine alkaloids which catalyzes the dehydrogenation of four hydrogen atoms of (S)-Tetrahydroberberine to produce berberine, the final step of berberine biosynthesis. A (S)-THB gene, designated as Cs(S)-THBO (Genbank accession No.HQ393909), was cloned from a C. saxicola cDNA library. The full-length of Cs(S)-THBO was 1127bp contains an open reading frame 699bp and predicted to encode a 232-amino acid polypeptide, with a predicted molecular mass of 25.20 kDa. Cs(S)-THBO was the first (S)-THBO gene found in C. saxicola. Real-time quantitative PCR analysis indicated that Cs(S)-THBO was constitutively expressed in roots, stems, leaves and flowers of C. saxicola, with the highest expression level in roots. The results from treatment experiment for plant defense responses revealed that expression of Cs(S)-THBO had a prominent diversity. Recombinant Cs(S)-THBO protein expressed in E. coli strain BL21 (DE3) was active. The results of feeding experiment and HPLC-DAD-ESI-MSn analysis shown that Cs(S)-THBO had the fuction of catalyzing (S)-Tetrahydroberberine to berberine but it cannot catalyze (R)-etrahydroberberine to berberine.
(S)-norcoclaurine synthase, the first step of the berberine alkaloids biosynthetic pathways, catalyzes from dopamine and 4-hydroxyphenylhydroxyphenylacetaldehyde (4-HPAA)to (S)-Norcoclaurine. Based on the core sequence obtained by RT-PCR, several gene-specific primers were designed to obtain the sequences of 5'-end and 3'-end by RACE. According to the result of RACE,PCR was performed and a full-length cDNA of Cs(S)-NCS.The full-length cDNA of Cs(S)-NCS was 1003 bp containing 5'-UTR, 3'-UTRand a ORF of 621bp encoding a 207-amino acid polypeptide(Genbank accession No.JF488074).
Canadine synthase catalyzes the eighth step in the biosynthesis of berberine alkaloids. The enzyme catalyzes the conversion of (S)-tetrahydrocolumbamine ((S)-THC) to (S)-tetrahydroberberine ((S)-THB) and it play an important role in the pathway of berberine. A CSN gene, designated as CsCSN (Genbank accession No.HQ393908), was cloned from a C. saxicola cDNA library. The full-length of Cs(S)-THBO was 1256bp contains 5'-UTR, 3'-UTR and an open reading frame 783bp and predicted to encode a 261-amino acid polypeptide, with a predicted molecular mass of 29.19 kDa.
Part 2 Microbial transformation of steroidal alkaloids in Veratrum nigrum Linn.
Veratrum Linn. (Liliaceae) is a kind of Perennial herb which characterizes by acrid and bitter in taste and cold in nature. The roots and rhizomes of several Veratrum species, such as V.nigrum L., V.dahuricum(Turcz.)Loes.f.and V.Schindleri L, are used in traditional Chinese medicine as‘‘Li-Lu’’for treatment of aphasia arising from apoplexy, dysentery, jaundice, headache, scabies and chronic malaria. The main active components in Veratrum Linn. is steroidal alkaloids. Pharmacological research indicated that steroidal alkaloids had cardic, hypotensive and antithrombotic activities , and the stilbenes had antitumor and anticoagulant function. According to the statistical data shows that there are more than 100 kind of steroidal alkaloids had isolated from Veratrum in China. However, it is well-known for V. nigrum L. that the toxic component is also steroidal alkaloids.
Microbial transformation is the process by which an organism or its isolated enzyme brings out chemical change on molecules that not part of their metabolism. Microbial transformation is important in the production of commercially valuable compounts for the pharmaceutical industry. Because the well antitumor activity of steroidal alkaloids in Veratrum Linn. , we has been done some structure modification of steroidal alkaloids in Veratrum Linn.by microbial transformation with a view to obtaining more new inhibitors(low toxicity, high activity and special mode of action.) of Hedgehog pathway.
Microbial transformation of veratramin by Cunninghamella echinulata in present study and obtained 4 new compounds.
本文对岩黄连中小檗碱类生物碱生物合成途径中的相关酶基因进行了克隆、表达及功能分析。
岩黄连中(S)-四氢小檗碱氧化酶的克隆,表达及功能分析
(S)-四氢小檗碱氧化酶是小檗碱生物合成途径中的关键酶,是黄连小檗碱的合成途径中最后一个酶,将(S)-四氢小檗碱氧化成小檗碱。通过RACE获得了(S)-四氢小檗碱氧化酶cDNA全长序列,其长度为1127bp,含有5'-UTR, 3'-UTR,ploy (A)+结构以及一个699bp的开放阅读框架,编码232个氨基酸残基,预测分子量为25.20 kDa。将该基因注册到GenBank,编号为HQ393909。RT-PCR分析表示(S)-THBO在岩黄连植株的根、茎、叶、花中都有表达,在根中表达量最高。诱导实验表明(S)-THBO具有明显的防御作用。
将(S)-四氢小檗碱氧化酶构建表达载体并在大肠杆菌中表达,并对表达(S)-四氢小檗碱氧化酶的大肠杆菌对底物进行体内转化。表达(S)-四氢小檗碱氧化酶的大肠杆菌可以体内转化(S)-四氢小檗碱氧化成小檗碱,但对底物有一定的选择性,不能将内消旋四氢小檗碱转化完全。
岩黄连中(S)-去甲乌药碱合成酶的克隆
(S)-去甲乌药碱合成酶是原小檗碱生物合成途径中的第一个酶,它可以将多巴胺(Dopamine)和(4-羟苯乙酮4-hydroxyphenylhydroxyphenylacetaldehyde,(4-HPAA) )催化成(S)-去甲乌药碱( (S)-Norcoclaurine)。对岩黄连的总RNA进行PT-PCR得到一段(S)-去甲乌药碱合成酶的核心片段。通过RACE获得了(S)-去甲乌药碱合成酶cDNA全长序列,其长度为1003bp,含有5'-UTR, 3'-UTR,ploy (A)+结构以及一个621bp的开放阅读框架,编码207个氨基酸残基。将该基因注册到GenBank,编号为JF488074。
岩黄连中氢化小檗碱合酶的克隆
氢化小檗碱合酶位是原小檗碱类生物碱生物合成途径的下游基因,它的功能是将(S)-四氢非洲防己碱( (S)-THC)催化成(S)-四氢小檗碱( (S)-THB),使化合物形成特殊的亚甲基双氧环结构。通过RACE获得了氢化小檗碱合酶cDNA全长序列,其长度为1256bp,含有5'-UTR, 3'-UTR结构以及一个783bp的开放阅读框架,编码261个氨基酸残基。将该基因注册到GenBank,编号为HQ393908。
第二部分藜芦中甾体生物碱的微生物转化
藜芦(Veratrum Linn. )为百合科(Liliaceae)多年生草本植物,味辛、苦,性寒,有毒。中医用藜芦(V.nigrum L. )、兴安藜芦(V.dahuricum(Turcz.)Loes.f.)、天目藜芦(V.Schindleri L)等的根和茎共同入药,用于中风痰壅、癫痫、喉痹不通、头痛、疥癣、疟疾。藜芦属植物中的生物碱类成分为其主要的活性成分,现代临床药理研究表明,甾体生物碱具有降血压作用、抗肿瘤作用、杀虫、抗血吸虫、抗真菌及等作用。据统计数据表明从我国所有藜芦属植物中分离得到100余种甾体生物碱。藜芦的毒素同样为生物碱类成分。
微生物转化反应是利用微生物的酶对底物的某一部位进行特定的化学反应来获得一定的产物,其在药物生产中占有重要地位。因为藜芦属植物中甾体生物碱具有良好的抗肿瘤活性,在实验室前期研究结果的基础上对藜芦中有效的甾体生物碱成分利用微生物转化的方法对其进行结构修饰和改造,合成系列衍生物,以期获得高效、低毒、高特异性的Hedgehog通路抑制剂,为新型抗肿瘤药物的开发提供理论基础。
本课题利用刺孢小克银汉霉对生物碱藜芦胺进行微生物转化,共得到了5个化合物,都为新化合物。
Corydalis saxicola Bunting (Yanhuanglian) is one of rare medicinal plants for the treatment of hepatic disease which belongs to the Fumariaceae family. C. saxicola grows in south China, such as Guizhou, Yunnan, Szechwan and Guangxi province and only grows in limestone hills in the wild state. It was labeled as endangered plants in southern China because of its hard growth environment. C. saxicola has the effect of clearing away heat, relieve pain and arrest blood.It has been demonstrated to have many pharmacological activities, including antibacterial, antiviral, and anticancer activities. The main active constituent in C. saxicola is berberine alkaloids (e.g. berberine, dehydrocavidine), which has potential activity to treat hepatitis, hepatocirrhosis and liver cancer.
(S)-tetrahydroberberine oxidase ((S)-THBO) is a key enzyme in the biosynthesis of berberine alkaloids which catalyzes the dehydrogenation of four hydrogen atoms of (S)-Tetrahydroberberine to produce berberine, the final step of berberine biosynthesis. A (S)-THB gene, designated as Cs(S)-THBO (Genbank accession No.HQ393909), was cloned from a C. saxicola cDNA library. The full-length of Cs(S)-THBO was 1127bp contains an open reading frame 699bp and predicted to encode a 232-amino acid polypeptide, with a predicted molecular mass of 25.20 kDa. Cs(S)-THBO was the first (S)-THBO gene found in C. saxicola. Real-time quantitative PCR analysis indicated that Cs(S)-THBO was constitutively expressed in roots, stems, leaves and flowers of C. saxicola, with the highest expression level in roots. The results from treatment experiment for plant defense responses revealed that expression of Cs(S)-THBO had a prominent diversity. Recombinant Cs(S)-THBO protein expressed in E. coli strain BL21 (DE3) was active. The results of feeding experiment and HPLC-DAD-ESI-MSn analysis shown that Cs(S)-THBO had the fuction of catalyzing (S)-Tetrahydroberberine to berberine but it cannot catalyze (R)-etrahydroberberine to berberine.
(S)-norcoclaurine synthase, the first step of the berberine alkaloids biosynthetic pathways, catalyzes from dopamine and 4-hydroxyphenylhydroxyphenylacetaldehyde (4-HPAA)to (S)-Norcoclaurine. Based on the core sequence obtained by RT-PCR, several gene-specific primers were designed to obtain the sequences of 5'-end and 3'-end by RACE. According to the result of RACE,PCR was performed and a full-length cDNA of Cs(S)-NCS.The full-length cDNA of Cs(S)-NCS was 1003 bp containing 5'-UTR, 3'-UTRand a ORF of 621bp encoding a 207-amino acid polypeptide(Genbank accession No.JF488074).
Canadine synthase catalyzes the eighth step in the biosynthesis of berberine alkaloids. The enzyme catalyzes the conversion of (S)-tetrahydrocolumbamine ((S)-THC) to (S)-tetrahydroberberine ((S)-THB) and it play an important role in the pathway of berberine. A CSN gene, designated as CsCSN (Genbank accession No.HQ393908), was cloned from a C. saxicola cDNA library. The full-length of Cs(S)-THBO was 1256bp contains 5'-UTR, 3'-UTR and an open reading frame 783bp and predicted to encode a 261-amino acid polypeptide, with a predicted molecular mass of 29.19 kDa.
Part 2 Microbial transformation of steroidal alkaloids in Veratrum nigrum Linn.
Veratrum Linn. (Liliaceae) is a kind of Perennial herb which characterizes by acrid and bitter in taste and cold in nature. The roots and rhizomes of several Veratrum species, such as V.nigrum L., V.dahuricum(Turcz.)Loes.f.and V.Schindleri L, are used in traditional Chinese medicine as‘‘Li-Lu’’for treatment of aphasia arising from apoplexy, dysentery, jaundice, headache, scabies and chronic malaria. The main active components in Veratrum Linn. is steroidal alkaloids. Pharmacological research indicated that steroidal alkaloids had cardic, hypotensive and antithrombotic activities , and the stilbenes had antitumor and anticoagulant function. According to the statistical data shows that there are more than 100 kind of steroidal alkaloids had isolated from Veratrum in China. However, it is well-known for V. nigrum L. that the toxic component is also steroidal alkaloids.
Microbial transformation is the process by which an organism or its isolated enzyme brings out chemical change on molecules that not part of their metabolism. Microbial transformation is important in the production of commercially valuable compounts for the pharmaceutical industry. Because the well antitumor activity of steroidal alkaloids in Veratrum Linn. , we has been done some structure modification of steroidal alkaloids in Veratrum Linn.by microbial transformation with a view to obtaining more new inhibitors(low toxicity, high activity and special mode of action.) of Hedgehog pathway.
Microbial transformation of veratramin by Cunninghamella echinulata in present study and obtained 4 new compounds.
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