丹参酮生物合成相关基因的克隆及其代谢调控
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摘要
心脑血管疾病是威胁人类健康与生命的"头号杀手"。丹参(Salvia miltiorriza)为我国传统名贵中药材,其主要成分包括脂溶性的丹参酮化合物;而丹参酮是临床治疗心、脑血管疾病的重要药物资源,最近的研究还表明丹参酮具有抗癌作用,因此,丹参在临床上具有广泛的应用。然而,丹参可用资源有限及有效成分含量低使之应用受限。
本研究以丹参为材料,在本实验室前期工作基础之上,利用RACE技术克隆丹参酮代谢合成关键酶基因,克隆得到牻牛儿基牻牛儿基焦磷酸合成酶基因(SmGGPPS, GenBank Accession No. FJ643617)和3-羟基-3-甲基戊二酰CoA还原酶基因(SmHMGR, GenBank Accession No. EU680958)的全长cDNA序列,并对其进行生物信息学和表达模式的分析及在大肠杆菌中对SmGGPPS进行了颜色互补功能验证。
SmHMGR cDNA全长2115bp,包括1695bp的开放阅读框,编码565个氨基酸。氨基酸多重序列比对结果显示SmHMGR与其他植物的HMGR有较高的同源性。进化树分析表明,SmHMGR与胡黄连(Picrorhiza kurrooa) HMGR的亲缘关系最近。组织特异性表达分析结果表明,SmHMGR基因在丹参中为组成型表达,且根中的表达最强,茎中表达次之,叶片中表达最弱。水杨酸(SA)诱导实验表明,SmHMGR在叶片中受到水杨酸的诱导。甲基茉莉酸(MJ)诱导实验表明,SmHMGR在不同组织中都不同程度上受到诱导.暗示SmHMGR是一个诱导响应型的基因。
SmGGPPS全长1234bp,包括1092bp的开放阅读框,编码364个氨基酸。氨基酸多重序列比对结果显示SmGGPPS与其他植物的GGPPS有较高的同源性。进化树分析表明,SmGGPPS与烟草(Nicotiana attenuate) GGPPS的亲缘关系最近。在大肠杆菌中的功能验证表明SmGGPPS能够促进类胡萝卜素的合成,证明SmGGPPS编码一个有功能的蛋白。组织特异性表达分析结果表明,SmGGPPS基因在丹参中为组成型表达,且叶片中的表达最强,根中表达次之,茎中表达最弱。水杨酸(SA)诱导实验表明,SmGGPPS在叶片中也受到水杨酸的诱导。而甲基茉莉酸(MJ)诱导实验表明,SmGGPPS在不同组织中都受到MJ的抑制。暗示SmGGPPS也是一个诱导响应型的基因。
继而采用RT-PCR和HPLC等技术,较全面地分析了不同诱导子如MJ、Ag+、YE、YE+Ag+等处理丹参毛状根前后丹参酮合成相关基因如SmHMGR, SmGGPPS, SmDXR, SmAACT, SmCMK, SmIPPI, SmFPPS, SmCPS,SmKSL等的表达与丹参酮积累的相关性,结果表明,丹参酮的生物合成在转录水平上受到调控,在不同诱导子处理下,丹参毛状根中丹参酮含量的积累可能是丹参酮代谢途径上的多个基因共同上调表达的结果。同时,SmHMGR, SmDXS2, SmFPPS, SmGGPPS和SmCPS被鉴定为调控丹参酮生物合成可能的关键酶基因。以上研究工作为进一步阐释不同诱导子调控丹参酮生物合成的分子机理及进一步提高丹参中丹参酮含量奠定了坚实基础。
Cardiovascular disease and cerebral vascular disease are the top killers that threat human heath and life. Salvia miltiorrhiza is a well-known and very important traditional Chinese medicinal herb. As the major active constituents of S.miltiorrhiza, tanshinones are the important medical resources for the treatment of Cardiovascular disease and Cerebral vascular disease in clinical, recently studies also indicated that tanshinones had anti-tumor potential. Therefore, S.miltiorrhiza has been very widespread used in clinical. However, due to the limited available resources of S.miltiorrhiza and low content of bioactive components in S.miltiorrhiza, the application of tanshinone was restricted.
Herein, the cloning and characterization of full-length cDNAs encoding geranylgeranyl diphosphate synthase (SmGGPPS, GenBank Accession No.FJ643617) and 3-hydroxy-3-methylglutaryl-CoA reductase (SmHMGR, GenBank Accession No.EU680958) from S.miltiorrhiza by rapid amplification of cDNA ends (RACE) was investigated. The function of SmGGPPS was also confirmed by color complementation assay in E. coli DH5α.
The full-length cDNA of SmHMGR was 2115 bp containing a 1695 bp open reading frame (ORF) encoding a polypeptide of 565 amino acids. Bioinformatic analyses revealed that the deduced SmHMGR had extensive homology with other plant HMGRs containing two transmembrane domains and a catalytic domain. Phylogenetic tree analysis indicated that SmHMGR belongs to the plant HMGR super-family and has the closest relationship with HMGR from Picrorhiza kurrooa. Expression pattern analysis implied that SmHMGR expressed highest in root, followed by stem and leaf. The expression of SmHMGR could be up-regulated by salicylic acid (SA) and methyl jasmonate (MeJA), suggesting that SmHMGR was elicitor-responsive.
The full-length cDNA of SmGGPPS was 1234 bp containing a 1092 bp open reading frame (ORF) encoding a polypeptide of 364 amino acids. Analysis of SmGGPPS genomic DNA revealed that it contained two exons and one intron. Bioinformatic analyses revealed that the deduced SmGGPPS had extensive homology with other plant GGPPSs contained all five conserved domains and functional aspartate-rich motifs of the prenyltransferases. Phylogenetic tree analysis indicated that SmGGPPS belongs to the plant GGPPS super-family and has the closest relationship with GGPPS from Nicotiana attenuate. The functional identification in Escherichia coli showed that SmGGPPS could accelerate the biosynthesis of carotenoid, demonstrating that SmGGPPS encoded a functional protein. Expression pattern analysis implied that SmGGPPS expressed higher in leaves and roots, weaker in stems. The expression of SmGGPPS could be up-regulated by salicylic acid (SA) in leaves and inhibited by methyl jasmonate (MeJA) in three tested tissues, suggesting that SmGGPPS was elicitor-responsive.
The work further analyzed the relationship between the expressions of genes involving in tanshinones biosynthesis pathway (SmHMGR, SmGGPPS, SmDXR, SmAACT, SmCMK, SmIPPI, SmFPPS, SmCPS, SmKSL) and tanshinones accumulation in S.miltiorrhiza hairy roots under the treatment of MJ、Ag+、YE and YE+Ag+ respectively by RT-PCR and HPLC. Our results showed a tight correlation between gene expression and tanshinone accumulation, suggesting that tanshinone accumulation may be the result of the co-expression up-regulation of several genes involved in tanshinone biosynthesis under treatment of various elicitors. Meantime, SmHMGR, SmDXS2, SmFPPS, SmGGPPS and SmCPS were identified as the potential key enzymes in the pathway for targeted metabolic engineering to increase accumulation of tanshinone in S. miltiorrhiza hairy roots. This work provides useful information to further understand molecular regulation mechanism of genes encoding related enzymes involved in tanshinones biosynthesis.
本研究以丹参为材料,在本实验室前期工作基础之上,利用RACE技术克隆丹参酮代谢合成关键酶基因,克隆得到牻牛儿基牻牛儿基焦磷酸合成酶基因(SmGGPPS, GenBank Accession No. FJ643617)和3-羟基-3-甲基戊二酰CoA还原酶基因(SmHMGR, GenBank Accession No. EU680958)的全长cDNA序列,并对其进行生物信息学和表达模式的分析及在大肠杆菌中对SmGGPPS进行了颜色互补功能验证。
SmHMGR cDNA全长2115bp,包括1695bp的开放阅读框,编码565个氨基酸。氨基酸多重序列比对结果显示SmHMGR与其他植物的HMGR有较高的同源性。进化树分析表明,SmHMGR与胡黄连(Picrorhiza kurrooa) HMGR的亲缘关系最近。组织特异性表达分析结果表明,SmHMGR基因在丹参中为组成型表达,且根中的表达最强,茎中表达次之,叶片中表达最弱。水杨酸(SA)诱导实验表明,SmHMGR在叶片中受到水杨酸的诱导。甲基茉莉酸(MJ)诱导实验表明,SmHMGR在不同组织中都不同程度上受到诱导.暗示SmHMGR是一个诱导响应型的基因。
SmGGPPS全长1234bp,包括1092bp的开放阅读框,编码364个氨基酸。氨基酸多重序列比对结果显示SmGGPPS与其他植物的GGPPS有较高的同源性。进化树分析表明,SmGGPPS与烟草(Nicotiana attenuate) GGPPS的亲缘关系最近。在大肠杆菌中的功能验证表明SmGGPPS能够促进类胡萝卜素的合成,证明SmGGPPS编码一个有功能的蛋白。组织特异性表达分析结果表明,SmGGPPS基因在丹参中为组成型表达,且叶片中的表达最强,根中表达次之,茎中表达最弱。水杨酸(SA)诱导实验表明,SmGGPPS在叶片中也受到水杨酸的诱导。而甲基茉莉酸(MJ)诱导实验表明,SmGGPPS在不同组织中都受到MJ的抑制。暗示SmGGPPS也是一个诱导响应型的基因。
继而采用RT-PCR和HPLC等技术,较全面地分析了不同诱导子如MJ、Ag+、YE、YE+Ag+等处理丹参毛状根前后丹参酮合成相关基因如SmHMGR, SmGGPPS, SmDXR, SmAACT, SmCMK, SmIPPI, SmFPPS, SmCPS,SmKSL等的表达与丹参酮积累的相关性,结果表明,丹参酮的生物合成在转录水平上受到调控,在不同诱导子处理下,丹参毛状根中丹参酮含量的积累可能是丹参酮代谢途径上的多个基因共同上调表达的结果。同时,SmHMGR, SmDXS2, SmFPPS, SmGGPPS和SmCPS被鉴定为调控丹参酮生物合成可能的关键酶基因。以上研究工作为进一步阐释不同诱导子调控丹参酮生物合成的分子机理及进一步提高丹参中丹参酮含量奠定了坚实基础。
Cardiovascular disease and cerebral vascular disease are the top killers that threat human heath and life. Salvia miltiorrhiza is a well-known and very important traditional Chinese medicinal herb. As the major active constituents of S.miltiorrhiza, tanshinones are the important medical resources for the treatment of Cardiovascular disease and Cerebral vascular disease in clinical, recently studies also indicated that tanshinones had anti-tumor potential. Therefore, S.miltiorrhiza has been very widespread used in clinical. However, due to the limited available resources of S.miltiorrhiza and low content of bioactive components in S.miltiorrhiza, the application of tanshinone was restricted.
Herein, the cloning and characterization of full-length cDNAs encoding geranylgeranyl diphosphate synthase (SmGGPPS, GenBank Accession No.FJ643617) and 3-hydroxy-3-methylglutaryl-CoA reductase (SmHMGR, GenBank Accession No.EU680958) from S.miltiorrhiza by rapid amplification of cDNA ends (RACE) was investigated. The function of SmGGPPS was also confirmed by color complementation assay in E. coli DH5α.
The full-length cDNA of SmHMGR was 2115 bp containing a 1695 bp open reading frame (ORF) encoding a polypeptide of 565 amino acids. Bioinformatic analyses revealed that the deduced SmHMGR had extensive homology with other plant HMGRs containing two transmembrane domains and a catalytic domain. Phylogenetic tree analysis indicated that SmHMGR belongs to the plant HMGR super-family and has the closest relationship with HMGR from Picrorhiza kurrooa. Expression pattern analysis implied that SmHMGR expressed highest in root, followed by stem and leaf. The expression of SmHMGR could be up-regulated by salicylic acid (SA) and methyl jasmonate (MeJA), suggesting that SmHMGR was elicitor-responsive.
The full-length cDNA of SmGGPPS was 1234 bp containing a 1092 bp open reading frame (ORF) encoding a polypeptide of 364 amino acids. Analysis of SmGGPPS genomic DNA revealed that it contained two exons and one intron. Bioinformatic analyses revealed that the deduced SmGGPPS had extensive homology with other plant GGPPSs contained all five conserved domains and functional aspartate-rich motifs of the prenyltransferases. Phylogenetic tree analysis indicated that SmGGPPS belongs to the plant GGPPS super-family and has the closest relationship with GGPPS from Nicotiana attenuate. The functional identification in Escherichia coli showed that SmGGPPS could accelerate the biosynthesis of carotenoid, demonstrating that SmGGPPS encoded a functional protein. Expression pattern analysis implied that SmGGPPS expressed higher in leaves and roots, weaker in stems. The expression of SmGGPPS could be up-regulated by salicylic acid (SA) in leaves and inhibited by methyl jasmonate (MeJA) in three tested tissues, suggesting that SmGGPPS was elicitor-responsive.
The work further analyzed the relationship between the expressions of genes involving in tanshinones biosynthesis pathway (SmHMGR, SmGGPPS, SmDXR, SmAACT, SmCMK, SmIPPI, SmFPPS, SmCPS, SmKSL) and tanshinones accumulation in S.miltiorrhiza hairy roots under the treatment of MJ、Ag+、YE and YE+Ag+ respectively by RT-PCR and HPLC. Our results showed a tight correlation between gene expression and tanshinone accumulation, suggesting that tanshinone accumulation may be the result of the co-expression up-regulation of several genes involved in tanshinone biosynthesis under treatment of various elicitors. Meantime, SmHMGR, SmDXS2, SmFPPS, SmGGPPS and SmCPS were identified as the potential key enzymes in the pathway for targeted metabolic engineering to increase accumulation of tanshinone in S. miltiorrhiza hairy roots. This work provides useful information to further understand molecular regulation mechanism of genes encoding related enzymes involved in tanshinones biosynthesis.
引文
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