灵芝三萜和金银花绿原酸生物合成途径关键酶基因的挖掘及分析
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摘要
阐明中药生物活性成分的次生代谢途径及其调控机制是现代中药研究的重要内容之一。次生代谢工程在提高药用植物目标产物含量上有着极大的应用潜能,但受传统研究方法和技术所限,目前我们对其次生代谢途径及调控机制的认知还较为粗略,因而期望通过次生代谢工程获取大量的目标次生代谢物仍面临着较大困难。功能基因组学(Functional Genomics)是在结构基因组学(Structural Genomics)的基础上,利用后者提供的信息,应用高通量测序产生的大量数据,在基因组或转录组水平上全面研究基因的表达、调控与功能,并探索基因之间、基因与蛋白质之间、基因及其产物与生长发育之间的相互联系和规律。通过全基因组学或转录组学系统分析次生代谢物的生物合成途径并发掘与之相关的基因,能够使我们更充分地了解中药的遗传信息与背景,也将使利用次生代谢工程生产重要药效成分成为可能。灵芝和金银花是具有极高药用价值和经济价值的传统中药,灵芝三萜和绿原酸分别是灵芝和金银花的主要药效成分之一,但目前对这些重要化合物的生物合成途径仍缺少系统的研究。本课题采用功能基因组学研究方法从全基因组水平上对药用真菌赤芝全基因组测序数据进行深入分析,以探索可能参与到灵芝三萜生物合成途径的关键酶基因；运用高通量测序技术对药用植物金银花的转录组进行研究,以阐明其重要成分绿原酸的生物合成途径,并对相关的关键基因进行克隆。本研究为灵芝三萜和绿原酸的生物合成研究奠定了基础。
灵芝GANODERMA,又称"Lingzhi",为赤芝Ganoderma lucidum或紫芝Ganoderma sinense的干燥子实体(中国药典2010版),是我国著名的药用真菌之一。现代药理研究表明灵芝有抗肿瘤,抗高血压,抗病毒和增强免疫能力的功效,灵芝三萜类和灵芝多糖为该功效的主要活性物质。赤芝全基因组已由本课题组完成测序,该物种基因组大小为43.3MB,共有16,113个预测蛋白的编码基因。本研究在赤芝全基因组数据库中,鉴定了参与灵芝三萜合成上游途径的11个关键酶,其中乙酰辅酶A乙酰基转移酶(AACT)和法尼基焦磷酸合成酶(FPS)各有两个编码基因,其余都为单编码基因；发现了214个可能参与到灵芝三萜下游合成途径的候选细胞色素氧化酶基因(CYP450),其中195个可能具有真正的P450功能包括6个兼性P450(bifunctional P450, BiP450),这195个P450s分属于24个基因簇。通过实时荧光定量PCR (QRT-PCR)检测,78个P450基因与羊毛甾醇合酶(LAS)共表达,说明此78个P450很有可能参与到灵芝三萜骨架的结构修饰中。78个P450中,有28个为赤芝所独有的新家族,另38个基因在其他物种中之前已被报道过。此外,24个基因簇中有5个与LAS共表达,它们极有可能是以基因簇的方式参与到灵芝三萜的合成途径中。
金银花LONICERA JAPONICA FLOS为忍冬Lonicera japonica Thunb.的干燥花蕾或待初开的花。为我国传统临床用药之一,具有抗炎,抗氧化和抗病毒的药理学特性,主要活性成分为绿原酸(Chlorogenic acid, CGA)和木犀草苷(Luteoloside)。绿原酸和木犀草苷的生物合成途径在其他物种中已有一定的研究,但在金银花中还未见报道与证实。本实验应用454GSFLxTitanium高通量测序平台,对金银花的转录组进行测序,完成了金银花叶和花2个cDNA文库测序,分别构建了花和叶的表达序列标签(Expressed sequence tag, EST)文库。从花的EST文库中拼接得到21849个叠连群(contig),38187个单一序列(singleton);从叶的EST文库中获得14242个叠连群,40557个单一序列。应用生物信息学方法对所得EST序列从功能基因组水平上研究了绿原酸的次生代谢途径。在金银花中发现了几乎所有的参与绿原酸生物合成的酶,其中包括羟基肉桂酰基辅酶A：奎尼酸羟基肉桂转移酶(HQT)和羟基肉桂酰基辅酶A：莽草酸/奎尼酸的羟基肉桂转移酶(HCT),同时也发现了所有参与木犀草苷生物合成的酶。本实验通过RACE技术克隆了8个HQT和HCT基因,得到全长cDNA序列。与其它物种中已知的HQT和HCT氨基酸序列进行比对,发现其中2个HQT和1个HCT具有真正的保守结构域。此外,分析了其它参与次生代谢过程的重要基因包括P450和转录因子等。最后,通过花与叶的EST数据库的比较,挖掘到分别在花和叶中表达的组织特异性基因。金银花转录组的测序工作为关键酶基因的挖掘提供了基础,并为进一步克隆其全长、研究其功能提供了依据,同时也作为金银花遗传标记、基因表达、基因组学和功能基因组学的重要数据来源。
全基因组及转录组分析在中药次生代谢途径的研究中有着至关重要的作用,为相关酶基因的克隆、鉴定,以及揭示完整的次生代谢途径提供了丰富的基因信息。本研究获得了灵芝三萜和绿原酸生物合成途径的信息,并挖掘了与金银花生长发育相关的基因,为中药次生代谢工程合成灵芝三萜及绿原酸奠定了理论基础。
The active ingredients in the medicinal plant usually belong to secondary metabolites, such as flavonoids, alkaloids, terpenoids. Since the majority of secondary metabolite biosynthesis pathways are complex, and involved a lot of enzymes. In Arabidopsis, some have been described. While, there is a lack of adequate genetic information in the medicinal plants, its secondary metabolic pathways and regulatory mechanisms of secondary metabolites are extreme lack of and thus the development of secondary metabolic engineering is still facing great difficulties. Based on the information provided by structural genomics and the application of high throughput, large-scale analysis, functional genomics is a comprehensive way of study in gene expression, regulation and function, as well as to explore relationship and laws between genes, genes and proteins, and both with the growth and development at the level of genome. Biological research is increased from a single gene or protein to the genome based on functional genomics, while a lot of genes and proteins are systematically studied at the same time. Clarifying the pathways and regulation of secondary metabolie pathway is one of the main contents of functional genomics in medicinal plants. Studies have focused on the transcriptome analysis, medicinal natural product biosynthesis, the key enzyme gene cloning and identification. Ganoderma lucidum and Lonicera japonica are important traditional medicine with high medicinal and economic value, one of the effective compositions of Ganoderma is Ganoderma triterpenoids, one of effective compositions of Lonicera japonica is chlorogenic acid. For these compositions, their biosynthetic pathway is still lack of systematic research. In this study, we make effort to explore the Ganoderma acid and chlorogenic acid biosynthetic pathway in the functional genomics level.
Ganoderma, also known as "Lingzhi" is a famous medicinal fungus in China. It is the dry fruiting bodies of G. lucidum and G. japonicrn. It had been proved to possess the pharmacological activities of antitumour, antihypertensive and antiviral. G. lucidum produces a large reservoir of bioactive which mainly included triterpenoids and polysaccharides. It had been reported with the genome size of43.3-Mb and16,113predicted genes. The pathway upstream of the cyclization step includes11enzymes encoded by13genes in G. lucidum. Acetyl-CoA C-acetyltransferases and farnesyl diphosphate synthase are each encoded by two genes in the G. lucidum genome, whereas the remaining nine enzymes are encoded by single-copy genes. A total of219CYP sequences (195functional genes and24pseudogenes) were identified in the G. lucidum genome, and they were classified into42families according to standardized CYP nomenclature. The expression of197CYP genes was investigated using real-time PCR. A total of78genes were found to be upregulated in the transition from mycelia to primordia and then downregulated in the transition from primordia to fruiting bodies. The expression profiles of these genes were highly correlated with that of LAS (correlation coefficient (r)>0.9). Furthermore, their expression profiles are positively correlated with triterpenoid content profiles during development, suggesting that some of these78CYP genes be involved in triterpenoid biosynthesis properly. In addition, there are5P450clusters were co-expressed with LSS.
LONICERA JAPONICA FLOS is the dry buds and flowers of Lonicera japonica. Ljaponica is a plant used in traditional Chinese medicine known for its anti-inflammatory, anti-oxidative, anti-carcinogenic, and antiviral pharmacological properties. The major active secondary metabolites of this plant are chlorogenic acid (CGA) and luteoloside. While the biosynthetic pathways of these metabolites are relatively well known, the genetic information available for this species, especially the biosynthetic pathways of its active ingredients, is limited. We obtained one million reads (average length of400bp) in a whole sequence run using a Roche/454GS FLX titanium platform. A total of60036unique sequences were obtained, including21849contigs and38187singletons from flowers of Jizhuahua. A total of54799unique sequences were obtained, inducing14242contigs and40557singletons from leaves of Jizhuahua. And a total of60031unique sequences were obtained, inducing20178contigs and39853singletons from flowers of Damaohua. A total of67954unique sequences were obtained, inducing13201contigs and54753singletons from leaves of Damaohua. All the genes involved in the pathway to biosynthesis of CGA have been found, including putative hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase partial genes. We got8putative HCT/HQT genes full length sequence by RACE.Nearly all of the possible enzymes involved in the biosynthesis of CGA and luteoloside were discovered in L. japonica. Three hydroxycinnamoyl transferase genes, including two hydroxycinnamoyl-CoA quinate hydroxycinnamoyl transferase genes and one hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) gene featuring high similarity to known genes from other species, were cloned. The HCT gene was discovered for the first time in L. japonica. In addition,188candidate cytochrome P450unigenes and245glycosyltransferase unigenes were found in the expressed sequence tag (EST) dataset. This study provides a high quality EST database for L. japonica by454pyrosequencing. Based on the EST annotation, a set of putative genes involved in CGA and luteoloside biosynthetic pathways were discovered. The database serves as an important source of public information on genetic markers, gene expression, genomics, and functional genomics in L. japonica.
Whole genome sequence and EST analysis have a crucial role in the study of medicinal plant secondary metabolic pathways, and provide a wealth of genetic information for the enzyme cloning, identification and speculated the secondary metabolic pathways. In the present study, we analyzed the information about biosynthesis pathway of Ganoderma acid and chlorogenic acid to provide theoretical support for the research of secondary metabolite biosynthesis pathways, and make better development of natural medicinal resources in the future for the purpose of metabolic engineering.
灵芝GANODERMA,又称"Lingzhi",为赤芝Ganoderma lucidum或紫芝Ganoderma sinense的干燥子实体(中国药典2010版),是我国著名的药用真菌之一。现代药理研究表明灵芝有抗肿瘤,抗高血压,抗病毒和增强免疫能力的功效,灵芝三萜类和灵芝多糖为该功效的主要活性物质。赤芝全基因组已由本课题组完成测序,该物种基因组大小为43.3MB,共有16,113个预测蛋白的编码基因。本研究在赤芝全基因组数据库中,鉴定了参与灵芝三萜合成上游途径的11个关键酶,其中乙酰辅酶A乙酰基转移酶(AACT)和法尼基焦磷酸合成酶(FPS)各有两个编码基因,其余都为单编码基因；发现了214个可能参与到灵芝三萜下游合成途径的候选细胞色素氧化酶基因(CYP450),其中195个可能具有真正的P450功能包括6个兼性P450(bifunctional P450, BiP450),这195个P450s分属于24个基因簇。通过实时荧光定量PCR (QRT-PCR)检测,78个P450基因与羊毛甾醇合酶(LAS)共表达,说明此78个P450很有可能参与到灵芝三萜骨架的结构修饰中。78个P450中,有28个为赤芝所独有的新家族,另38个基因在其他物种中之前已被报道过。此外,24个基因簇中有5个与LAS共表达,它们极有可能是以基因簇的方式参与到灵芝三萜的合成途径中。
金银花LONICERA JAPONICA FLOS为忍冬Lonicera japonica Thunb.的干燥花蕾或待初开的花。为我国传统临床用药之一,具有抗炎,抗氧化和抗病毒的药理学特性,主要活性成分为绿原酸(Chlorogenic acid, CGA)和木犀草苷(Luteoloside)。绿原酸和木犀草苷的生物合成途径在其他物种中已有一定的研究,但在金银花中还未见报道与证实。本实验应用454GSFLxTitanium高通量测序平台,对金银花的转录组进行测序,完成了金银花叶和花2个cDNA文库测序,分别构建了花和叶的表达序列标签(Expressed sequence tag, EST)文库。从花的EST文库中拼接得到21849个叠连群(contig),38187个单一序列(singleton);从叶的EST文库中获得14242个叠连群,40557个单一序列。应用生物信息学方法对所得EST序列从功能基因组水平上研究了绿原酸的次生代谢途径。在金银花中发现了几乎所有的参与绿原酸生物合成的酶,其中包括羟基肉桂酰基辅酶A：奎尼酸羟基肉桂转移酶(HQT)和羟基肉桂酰基辅酶A：莽草酸/奎尼酸的羟基肉桂转移酶(HCT),同时也发现了所有参与木犀草苷生物合成的酶。本实验通过RACE技术克隆了8个HQT和HCT基因,得到全长cDNA序列。与其它物种中已知的HQT和HCT氨基酸序列进行比对,发现其中2个HQT和1个HCT具有真正的保守结构域。此外,分析了其它参与次生代谢过程的重要基因包括P450和转录因子等。最后,通过花与叶的EST数据库的比较,挖掘到分别在花和叶中表达的组织特异性基因。金银花转录组的测序工作为关键酶基因的挖掘提供了基础,并为进一步克隆其全长、研究其功能提供了依据,同时也作为金银花遗传标记、基因表达、基因组学和功能基因组学的重要数据来源。
全基因组及转录组分析在中药次生代谢途径的研究中有着至关重要的作用,为相关酶基因的克隆、鉴定,以及揭示完整的次生代谢途径提供了丰富的基因信息。本研究获得了灵芝三萜和绿原酸生物合成途径的信息,并挖掘了与金银花生长发育相关的基因,为中药次生代谢工程合成灵芝三萜及绿原酸奠定了理论基础。
The active ingredients in the medicinal plant usually belong to secondary metabolites, such as flavonoids, alkaloids, terpenoids. Since the majority of secondary metabolite biosynthesis pathways are complex, and involved a lot of enzymes. In Arabidopsis, some have been described. While, there is a lack of adequate genetic information in the medicinal plants, its secondary metabolic pathways and regulatory mechanisms of secondary metabolites are extreme lack of and thus the development of secondary metabolic engineering is still facing great difficulties. Based on the information provided by structural genomics and the application of high throughput, large-scale analysis, functional genomics is a comprehensive way of study in gene expression, regulation and function, as well as to explore relationship and laws between genes, genes and proteins, and both with the growth and development at the level of genome. Biological research is increased from a single gene or protein to the genome based on functional genomics, while a lot of genes and proteins are systematically studied at the same time. Clarifying the pathways and regulation of secondary metabolie pathway is one of the main contents of functional genomics in medicinal plants. Studies have focused on the transcriptome analysis, medicinal natural product biosynthesis, the key enzyme gene cloning and identification. Ganoderma lucidum and Lonicera japonica are important traditional medicine with high medicinal and economic value, one of the effective compositions of Ganoderma is Ganoderma triterpenoids, one of effective compositions of Lonicera japonica is chlorogenic acid. For these compositions, their biosynthetic pathway is still lack of systematic research. In this study, we make effort to explore the Ganoderma acid and chlorogenic acid biosynthetic pathway in the functional genomics level.
Ganoderma, also known as "Lingzhi" is a famous medicinal fungus in China. It is the dry fruiting bodies of G. lucidum and G. japonicrn. It had been proved to possess the pharmacological activities of antitumour, antihypertensive and antiviral. G. lucidum produces a large reservoir of bioactive which mainly included triterpenoids and polysaccharides. It had been reported with the genome size of43.3-Mb and16,113predicted genes. The pathway upstream of the cyclization step includes11enzymes encoded by13genes in G. lucidum. Acetyl-CoA C-acetyltransferases and farnesyl diphosphate synthase are each encoded by two genes in the G. lucidum genome, whereas the remaining nine enzymes are encoded by single-copy genes. A total of219CYP sequences (195functional genes and24pseudogenes) were identified in the G. lucidum genome, and they were classified into42families according to standardized CYP nomenclature. The expression of197CYP genes was investigated using real-time PCR. A total of78genes were found to be upregulated in the transition from mycelia to primordia and then downregulated in the transition from primordia to fruiting bodies. The expression profiles of these genes were highly correlated with that of LAS (correlation coefficient (r)>0.9). Furthermore, their expression profiles are positively correlated with triterpenoid content profiles during development, suggesting that some of these78CYP genes be involved in triterpenoid biosynthesis properly. In addition, there are5P450clusters were co-expressed with LSS.
LONICERA JAPONICA FLOS is the dry buds and flowers of Lonicera japonica. Ljaponica is a plant used in traditional Chinese medicine known for its anti-inflammatory, anti-oxidative, anti-carcinogenic, and antiviral pharmacological properties. The major active secondary metabolites of this plant are chlorogenic acid (CGA) and luteoloside. While the biosynthetic pathways of these metabolites are relatively well known, the genetic information available for this species, especially the biosynthetic pathways of its active ingredients, is limited. We obtained one million reads (average length of400bp) in a whole sequence run using a Roche/454GS FLX titanium platform. A total of60036unique sequences were obtained, including21849contigs and38187singletons from flowers of Jizhuahua. A total of54799unique sequences were obtained, inducing14242contigs and40557singletons from leaves of Jizhuahua. And a total of60031unique sequences were obtained, inducing20178contigs and39853singletons from flowers of Damaohua. A total of67954unique sequences were obtained, inducing13201contigs and54753singletons from leaves of Damaohua. All the genes involved in the pathway to biosynthesis of CGA have been found, including putative hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase partial genes. We got8putative HCT/HQT genes full length sequence by RACE.Nearly all of the possible enzymes involved in the biosynthesis of CGA and luteoloside were discovered in L. japonica. Three hydroxycinnamoyl transferase genes, including two hydroxycinnamoyl-CoA quinate hydroxycinnamoyl transferase genes and one hydroxycinnamoyl-CoA shikimate/quinate hydroxycinnamoyl transferase (HCT) gene featuring high similarity to known genes from other species, were cloned. The HCT gene was discovered for the first time in L. japonica. In addition,188candidate cytochrome P450unigenes and245glycosyltransferase unigenes were found in the expressed sequence tag (EST) dataset. This study provides a high quality EST database for L. japonica by454pyrosequencing. Based on the EST annotation, a set of putative genes involved in CGA and luteoloside biosynthetic pathways were discovered. The database serves as an important source of public information on genetic markers, gene expression, genomics, and functional genomics in L. japonica.
Whole genome sequence and EST analysis have a crucial role in the study of medicinal plant secondary metabolic pathways, and provide a wealth of genetic information for the enzyme cloning, identification and speculated the secondary metabolic pathways. In the present study, we analyzed the information about biosynthesis pathway of Ganoderma acid and chlorogenic acid to provide theoretical support for the research of secondary metabolite biosynthesis pathways, and make better development of natural medicinal resources in the future for the purpose of metabolic engineering.
引文
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