CN102676549B - 一个参与丹参酮生物合成的cyp450基因及其编码产物与应用 - Google Patents
一个参与丹参酮生物合成的cyp450基因及其编码产物与应用 Download PDFInfo
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Abstract
本发明公开一个参与丹参酮生物合成的CYP450基因及其编码产物与应用，属于药用植物基因工程领域。该基因为首次从丹参中克隆得到，为丹参酮类化合物生物合成途径的关键酶基因，催化次丹参酮二烯至铁锈醇的关键步骤。本发明所提供的CYP76Q1基因具有SEQ ID NO.1所示的核苷酸序列。所述基因编码的蛋白质具有序列表中SEQ IDNo.2的氨基酸残基序列以及具有SEQ IDNo.2的氨基酸残基序列相同活性的由SEQ IDNo.2衍生的蛋白质。本发明提供的CYP76Q1基因与丹参酮类化合物生物合成密切相关，对于调节生产植物二萜类化合物和通过生物技术提高丹参中二萜类活性成分丹参酮类的含量具有重要的理论和实际意义，有助于丹参药材的品质改良，品种选育，同时可以通过利用该基因构建要程菌生产具有药理活性的铁锈醇单体，具有很好的应用前景。
Description
技术领域
本发明涉及利用丹参转录组文库筛选丹参酮类化合物代谢途径相关CYP450基因，并利用体外酶促反应的方法对该基因编码蛋白进行功能活性分析，涉及到丹参主要活性成分丹参酮类化合物生物合成途径中CYP450基因及其编码产物与应用，属于药用植物基因工程领域。
背景技术
药用植物有效成分的形成是植物次生代谢途径中特有基因表达的产物，随着植物功能基因组研究的广泛与深入，独具特色又有广阔应用前景的药用植物次生代谢合成相关功能基因的研究逐渐成为研究的热点，这些基因的克隆将为诠释药用植物有效成分的生物合成途径及其调控机制、为药材品质的形成提供理论基础，同时为利用生物技术提高目标成分含量或直接生产有效成分或中间体带来广阔的应用前景。
丹参为唇形科鼠尾草属药用植物丹参(Salvia miltiorrhiza Bunge)的干燥根及根茎，具有祛瘀止痛，活血通经，清心除烦等功效，其主要有效成分包括脂溶性的丹参酮和水溶性的丹酚酸。其中丹参酮类主要包括隐丹参酮、丹参酮IIA、丹参酮IIB和二氢丹参酮等，具有扩张血管、抗血栓、抗菌消炎以及抗肿瘤、抗氧化等多种药理作用，在制药以及美容、化妆品等领域得到广泛应用。丹参酮类化合物为松香烷型二萜琨类化合物，其生物合成在萜类化合物前体物质合成的基础上，通过异戊二烯基转移酶(Prenyl Transferases，PT)的作用产生20个碳原子的牻牛儿基牻牛儿基焦磷酸(Geranylgeranyl Diphosphate，GGPP)，GGPP进一步在丹参柯巴基焦磷酸合酶(S.miltiorrhiza Copalyl Diphosphate Synthase，SmCPS)和丹参类贝壳杉烯合酶(S.miltiorrhiza ent-kaurene Synthase，SmKS)的作用下形成丹参类化合物的基本骨架次丹参酮二烯(Miltiradiene)，在次丹参酮二烯的基础上经过甲基化和羟基化等形成丹参酮类化合物，其中细胞色素P450(CYP450)酶在修饰过程发挥着重要作用。
CYP450酶为血红蛋白结合蛋白，在所有已知的CYP450酶中都存在一个保守的血红素结合域，是鉴定该基因的一个重要特征。拟南芥基因组中有272个CYP450基因，水稻基因组注释显示有457个CYP450基因，如此庞大的基因家族反映了植物次生代谢物的复杂多变。各种CYP450酶催化的反应广泛并且复杂，包括：羟基化、N-、O-和S-端的脱烷基化、环氧基化、脱氨基作用、脱硫、脱卤作用利过氧化反应等。尽管催化反应各异，催化机理却相同，即通过NADPH或者NADH为CYP450传递电子，激活氧分子，将其中的一个氧插入到底物上，同时生成一分子水。CYP450酶作为萜类、黄酮类、脂肪酸类和植物激素等合成代谢途径的一类重要酶蛋白，不但催化相关代谢反应，由于大多数的CYP450蛋白均有一段内质网膜定位蛋白，因此在代谢区室(Metabolon)的酶复合体中还具有固定酶复合体的作用。随着分子生物学以及相关检测技术的不断发展，次生代谢途径相关的CYP450基因功能逐渐得以验证。真核表达、原核表达以及RNA干扰(RNA Interference)等技术在CYP450基因的功能验证中发挥了重要作用。近年来利用真核表达以及RNAi技术使得CYP450酶在紫杉酚、青蒿素、植物抗毒素等代谢途径中的重要作用逐渐被解析。但是作为在植物次生代谢中发挥作用的CYP450表达量相对较低，并且大多CYP450蛋白具有严格的催化底物结构特异性，同时基因组中广泛存在的CYP450基因为次生代谢相关基因的克隆和功能验证提供了难度，使之成为了近年来国际学术界的研究热点之一。
本实验室在前期研究的基础上已克隆到了丹参酮化合物合成途径的上游的相关关键酶基因，并通过构建工程菌产生了丹参酮化合物的前体次丹参酮二烯。本发明涉及的是催化次丹参酮二烯(Miltiradiene)在C-12的羟基化产生丹参酮类化合物合成途径中间产物铁秀醇(Ferruginol)的关键CYP450酶基因，该基因是首次从丹参中得到的丹参酮类生物合成的关键CYP450基因，依据CYP450基因命名法则命名为CYP76Q1。在本发明被公布之前，尚未有任何公开或报道过本专利申请中涉及的CYP76Q1基因及其氨基酸序列。
发明内容
本发明的目的在于提供一个丹参酮化合物生物合成代谢途径的CYP450基因CYP76Q1，其编码的蛋白在含有NADPH的缓冲体系中能催化次丹参酮二烯生成铁锈醇。
本发明提供了一种与丹参酮类化合物合成代谢有关的基因：CYP76Q1，它是序列表中SEQ ID No.1所示的DNA序列。以及一种由上述基因CYP76Q1编码的蛋白质，具有序列表中SEQ IDNo.2的氨基酸残基序列以及具有SEQ ID No.2的氨基酸残基序列相同活性的由SEQ ID No.2衍生的蛋白质。
本发明SEQ ID No.1的DNA序列由1488个碱基组成，编码序列表中由495个氨基酸残基组成的蛋白质序列SEQ ID No.2。
本发明克隆的基因CYP76Q1在积累丹参酮类化合物的丹参根中表达明显高于不积累丹参酮类化合物的茎叶等地上部分。
含有本发明基因CYP76Q1的表达载体、细胞系及宿主菌和使用该基因在调节和生产植物二萜类化合物及丹参育种中的应用也在本发明的保护范围之内。将SEQ ID No.1基因克隆到真核表达载体pESC-His的限制性内切酶EcoR I和Sep I位点间，构建带有CYP76Q1基因的重组表达载体pESC-CYP76Q1；转入酵母菌株WAT11表达宿主菌采用半乳糖诱导表达。通过提取表达菌株微粒体，加入到以次丹参酮二烯为底物的体外酶促反应体系中，正己烷萃取反应产物，GC-MS分析。GC-MS分析结果表明：次丹参酮二烯在CYP76Q1蛋白酶的催化下，生成了分子量为286(m/z)的新物质，通过分析新产物的分子离子峰与主要裂解方式，认为该产物为铁锈醇。研究结果表明，本发明与丹参酮类化合物合成有关的基因具有细胞色素P450基因的特征结构域，酶促反应分析发现该基因催化次丹参酮二烯的C-12羟基化形成丹参酮类化合物中间产物铁锈醇，对于调节和生产植物二萜类化合物及培育高品质的丹参具有重要的理论及实际意义。
附图说明
图1CYP76Q1基因在不同组织部位的表达情况
R：根，S：茎，L：叶
图2重组质粒pESC-CYP76Q1的PCR鉴定
M：DNA分子量标准(DL2000)；P：PCR产物
图3CYP76Q1基因编码蛋白酶促反应产物GC-MS分析
A：CYP76Q1催化反应产物总离子图；B：空载体催化反应产物总离子图；C：CYP76Q1催化产物峰铁锈醇(Ferruginol)对应质谱图；D：铁锈醇(Ferruginol)标样质谱图
图4CYP76Q1基因编码蛋白催化次丹参酮二烯至铁锈醇图示
具体实施方式
实施例1：丹参酮类化合物合成代谢途径CYP450基因的筛选
通过本实验构建的转录组数据库，挑选表达差异上调的CYP450基因进行生物信息学分析显示这些诱导表达上调的CYP450基因主要来自CYP76，CYP716，CYP81和CYP71等家族，其中CYP76和CYP71家族在萜类合成途径中起关键的催化作用，对其中来自这两个家族的15个候选CYP450基因进行分析。
实施例2：丹参中CYP450基因的克隆
1、取盛花期的丹参根，利用Trizol法提取丹参的总RNA，利用Invitrogen的5’RACE试剂盒对CYP450基因的5’末端进行扩增，共获得了15条CYP450基因的全长序列。
2、全长cDNA的克隆和测序
对5`RACE结果和转录组数据库中有的3’末端进行拼接，搜索ORF区域，设计全长基因引物，以eDNA为模板进行扩增。琼脂糖凝胶电泳表明约在1500bp处出现特异片段，琼脂糖凝胶回收试剂盒(Takara)回收目标片段，克隆至pGEM-T easy载体(Promega)中，鉴定阳性克隆并进行测序验证(北京华大基因)，用于表达载体的构建。
实施例3、CYP76Q1基因序列的生物信息学分析以及组织表达分析
1、本发明涉及的丹参二萜合成代谢途径CYP450基因CYP76Q1基因全长开放读码框(ORF)的长度为1488bp，编码495个氨基酸，详细序列见序列表中的SEQ ID No.1和SEQ ID No.2。将CYP76Q1全长开放读码框用BLAST程序在NCBI数据库中进行同源性检索，该基因在氨基酸水平上比对分析显示，丹参CYP76Q1基因编码的蛋白质氨基酸序列与其它物种的同源性较低，与未进行功能验证的Verbenax hybrida细胞色素P450基因具有最高约50％的同源性。
2、提取盛花期的丹参根、茎和叶的RNA，利用逆转录试剂盒(Fermentas)进行逆转录，以β-actin为内参，进行半定量PCR，半定量PCR的正向引物为：5’-TCGTGGATGAGTCGGCAAT-3’，反向引物为：5’-TGAGTATCTGAGTTCCCT-3’。结果表明CYP76Q1基因在丹参根中的表达明显比不积累丹参酮化合物的茎叶中高。
实施例4、CYP76Q1基因真核表达及功能分析
1、酵母表达载体的构建
通过设计带有EcoR I和Spe I酶切位点的引物，通过PCR扩增，将克隆到的丹参CYP450基因的开放阅读框，插入到酵母表达表达载体pESC-His的EcoR I和Spe I酶切位点之间，获得重组质粒pESC-CYP，进行PCR和酶切鉴定(图2)。
2、诱导表达
将构建的pESC-CYP质粒转化表达宿主菌WAT11，利用半乳糖进行诱导表达，所得菌体制成微粒体用于进行酶活检测。
3、丹参CYP76Q1的活性分析
在含有CYP76Q1表达蛋白微粒体的缓冲体系加入NADPH和底物次丹参酮二烯进行催化反应，缓冲体系包括50mM的Tric-HCl(pH 7.4)、1mM的EDTA、0.6M的山梨醇、20％的甘油，1mM NADPH和100μM底物次丹参酮二烯，另外在pH范围7.4-8.0的缓冲体系中均有相同的功能。催化反应温度20-40度之间，15分钟以上。反应完全加入等体积正己烷萃取催化产物，进行GC-MS分析。GC-MS仪器为Agilent19091S-433，分析条件为不分流模式，初始温度80度，最高温度325度，初始时间2分钟，平衡时间0.5分钟，升温速率为每分钟10度，最终温度280度，保留时间20分钟。结果发现以次丹参酮二烯为底物，包含有CYP76Q1基因重组表达载体pESC-CYP76Q1催化组与空载体对照以及其他基因表达载体反应产物相比在总离子图286(m/z)处有新物质产生(图3)，气质谱图如图3，与铁锈醇质谱图相一致，产物鉴定为铁锈醇。说明CYP76Q1基因编码的蛋白在丹参酮类化合物合成代谢途径中能催化次丹参酮二烯生成铁锈醇(图4)。
SEQUENCE LISTING
<110>中国中医科学院中药研究所
<120>一个参与丹参酮类化合物合成代谢的细胞色素P450基因及其编码产物与应用
<160>2
<170>PatentIn version 3.5
<210>1
<211>1488
<212>DNA
<213>丹参(Salvia miltiorrhiza Bunge)
<400>1
atggattctt ttcctctcct cgccgcgctc ttcttcatcg ccgcgacgat aacattcctc 60
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atgctgcaac tcggcgccaa ccctcaccag gtgttcgcga agctctcaaa gagatacggc 180
ccgctgatgt cgatccatct cggcagcctc tacaccgtga tcgtctcctc cccggagatg 240
gcgaaggaga tcctccacag gcacgggcag gtcttctccg gccgcaccat cgcgcaggcg 300
gtgcacgcgt gcgaccacga caagatctcc atggggttcc tccccgtggc cagcgagtgg 360
cgcgacatgc gcaagatatg caaggagcag atgttctcca accagagcat ggaggccagc 420
cagggcctcc gccgccagaa gctgcagcag ctcctcgacc acgtccagaa atgctccgac 480
agcggccgcg cggtcgacat ccgcgaggcc gccttcatca ccacgctcaa cctcatgtcg 540
gccacgctct tctcctcgca ggccaccgag ttcgactcca aggccaccat ggagttcaag 600
gagatcatcg agggcgtcgc caccatcgtc ggcgtgccca acttcgccga ctacttcccc 660
atcctccgcc ccttcgaccc gcagggtgtc aagcgcaggg cggatgtttt cttcggcaaa 720
ttgctcgcca aaatcgaagg gtatctcaat gagaggctcg aatcgaagag ggccaatccc 780
aatgcgccaa agaaggatga ctttttggag atagtggttg atattattca ggccaacgag 840
ttcaagttga agacgcatca cttcacccat ctcatgctgg acttgttcgt gggaggatcg 900
gacacgaaca cgacctcgat cgagtgggcc atgtcggagc tagtgatgaa cccggacaag 960
atggctcgac tgaaggcgga gctgaagagc gtggccggag acgagaagat cgtggatgag 1020
tcggcaatgc cgaagctgcc gtacctgcaa gccgtgataa aggaggtgat gcggatccac 1080
ccgccgggcc cactgctcct ccctcgcaaa gcggagagcg atcaggaggt gaacggctat 1140
ctcatcccca agggaactca gatactcatc aacgcgtatg cgatagggag ggatccgagt 1200
atctggaccg acccggagac gttcgacccg gaacgcttcc tcgataacaa gatagacttc 1260
aagggccagg attacgagct ccttccgttc gggtcgggta gacgggtctg ccccggcatg 1320
ccgctcgcga cccggatcct gcacatggct actgcgactc tggttcataa cttcgactgg 1380
aaactggaag atgactccac ggcggccgcc gatcacgccg gcgagttgtt tggggtggcc 1440
gtgcgcaggg cagttccgct taggattatc ccaatagtta agtcttag 1488
<210>2
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<212>PRT
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Claims (8)
1.一个与丹参酮类化合物生物合成相关的CYP450基因CYP76Q1，其核苷酸序列如SEQ IDNo.1所示。
2.根据权利要求1所述的基因，其特征在于：该基因的读码框为SEQ ID No.1的第1-1488位核苷酸。
3.一个由权利要求1所述的基因CYP76Q1编码的蛋白质，其氨基酸残基序列如SEQ ID No.2所示。
4.含有权利要求1所述基因的表达载体。
5.含有权利要求1所述基因的转基因细胞系。
6.含有权利要求1所述基因的宿主菌。
7.权利要求1所述的基因在调节和生产植物二萜类化合物铁锈醇中的应用。
8.权利要求1所述的基因在丹参育种中的应用。
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| WO2015113569A1 (en) | 2014-01-31 | 2015-08-06 | University Of Copenhagen | Biosynthesis of forskolin and related compounds |
| EP3215626A1 (en) * | 2014-11-07 | 2017-09-13 | University of Copenhagen | Biosynthesis of oxidised 13r-mo and related compounds |
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| CN106148360B (zh) * | 2015-03-19 | 2020-03-03 | 中国中医科学院中药研究所 | 催化丹参酮类化合物生物合成途径c20位甲基羟基化的关键cyp450基因 |
| CN106434703B (zh) * | 2016-03-24 | 2020-01-31 | 中国医学科学院药用植物研究所 | 参与丹参酮类化合物生物合成的细胞色素p450基因cyp71d410及其编码产物与应用 |
| CN106434704B (zh) * | 2016-03-24 | 2019-12-13 | 中国医学科学院药用植物研究所 | 参与丹参酮类化合物生物合成的细胞色素p450基因cyp76ah12及其编码产物与应用 |
| WO2018015512A1 (en) * | 2016-07-20 | 2018-01-25 | Evolva Sa | Biosynthesis of 13r-manoyl oxide derivatives |
| CN109554377A (zh) * | 2018-12-06 | 2019-04-02 | 江苏师范大学 | 大戟二萜类化合物合成基因cyp726a33、其编码的蛋白质与应用 |
| CN110777157B (zh) * | 2019-10-10 | 2023-07-04 | 广州中医药大学(广州中医药研究院) | 催化香树脂醇c-28位氧化的cyp450基因及其编码产物与应用 |
| CN111321128A (zh) * | 2020-03-03 | 2020-06-23 | 武汉轻工大学 | 一种榼藤细胞色素p450基因及其获得方法和应用 |
| CN116218799A (zh) * | 2023-01-12 | 2023-06-06 | 中国中医科学院中药研究所 | 催化β-香树脂醇16α位羟基化的CYP450酶蛋白及编码基因与应用 |
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