蛇根木萝卡辛糖苷酶三维结构表征及底物特异性机制研究
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摘要
蛇根木(Rauvolfia serpentina Benth. ex Kurz)为夹竹桃科萝芙木属药用植物,富含生物碱类化合物,其主要活性成分为阿吗灵、阿吗碱和利血平等。其有退热、抗癫、消炎及治虫蛇咬伤等功效,现用于治疗高血压及心律失常。对其次生代谢产物生物合成途径关键酶的研究是进一步开发利用该药用植物、调控生物代谢方向、体外生物-化学合成活性化合物的基础。
本论文对蛇根木生物碱阿吗灵生物合成支链途径中催化萝卡辛水解形成萝芙木乐宁的萝卡辛糖苷酶(Raucaffricine Glucosidase, RG, EC3.2.1.125)进行了一系列的研究,主要涉及RG的异源表达、纯化、酶学表征、结晶、三维结构表征、催化机制及底物特异性机制和RG抑制剂的研究。同时,本论文对室温(RT)与冷冻条件下收集到的X-射线衍射数据进行了比较。
以pQE-2质粒为表达载体,在大肠杆菌M15中异源高效表达N端带有(His)6标签的RG并利用Ni-NTA亲和层析进行纯化。酶动力学考察表明RG对底物萝卡辛的Km值为0.78mM,对底物异胡豆苷的Km值为1.7mM。为进一步探明RG三维结构,活性中心及各配体的结合情况,本论文通过悬滴蒸发结晶法获得RG及无活性突变体RG-E186Q的晶体,并通过底物浸泡的方式制备其与配体复合物。本文共处理得到8套RG的结构模型：其中RG, RG-glycerol, RG-glucose, RG-inhibitor结构由冷冻条件下收集的衍射数据处理得到；RG-E186Q, RG-E186Q-dihydroraucaffricine, RG-E186Q-secologanin, RG-E186Q-glucose结构由室温条件下收集的衍射数据处理得到。
RG及其无活性突变体的整体三维结构呈典型的(β/α)8桶状结构,与同处于阿吗灵生物合成途径上游的异胡豆苷糖苷酶(SG)一致。通过结果比较,揭示两种酶底物特异性差异的机制：RG的活性空腔入口较宽,SG的天然底物异胡豆苷也可以进入到RG的活性中心；而SG狭长的活性空腔入口阻碍萝卡辛进入SG的活性中心。RG-Trp392与SG-Trp388影响了两酶活性空腔入口的形状,从而控制酶的底物接受能力。RG-Ser390直接影响着RG-Trp392侧链构象,间接调控底物接受能力。定点突变及活性数据进一步证实了结构分析的结果,深化对糖苷酶的底物特异性及催化机制的认识。
随后,本文考察了4种deoxypyranosylamine类抑制剂对RG的抑制情况,4种抑制剂的抑制效果差异较大,抑制剂常数Ki跨度从0.06到620μM。其中RG与抑制剂N-(cyclohexylmethyl)-β-D-gluco-1,5-deoxypyranosylamine复合物的三维结构已成功解析。三维结构显示,该抑制剂专一地结合于RG的活性位点,占据RG的底物结合部位,为竞争性抑制机制提供了结构依据。通过比较各抑制剂的抑制活性数据,并结合抑制剂复合物的结构信息,揭示抑制剂的糖苷模拟以及非糖苷模拟部分对抑制效果均有显著影响。
最后,本文通过比较冷冻与室温条件下收集的X-衍射数据及其处理后得到的结构质量,发现两者的结构基本吻合,而且由室温下收集数据处理得到的结构模型重复性更佳。室温与冷冻条件下,Glu476侧链的构象指向不一致,表明温度变化会导致部分氨基酸构象的变化。总体而言,目前室温条件下,仅仅利用一颗晶体便能快速收集到高质量的可用于三维结构解析的X-射线衍射数据,为室温衍射数据收集的广泛使用打下了坚实的基础。
Rauvolfia serpentina Benth. ex Kurz (Apocynaceae) has been used as a medicinal plant in India for thousands of years, mainly for curing fever, insanity, inflammation, and snake bites, and, nowadays hypertension, and arrhythmia. Its major active alkaloid constituents are ajmaline, ajmalicine, and reserpine. The research on enzymes involved in the biosynthesis of active compounds in plants allows better understanding and utilization of Rauvolfia, steering the metabolic flux in the direction of a desired product by pathway blocking and gene manipulation strategies, and using some of the crucial enzymes in vitro for the chemoenzymatic synthesis of complex alkaloid skeletons.
This thesis focuses on the detailed investigation of the Rauvolfia enzyme, raucaffricine glucosidase (RG, EC3.2.1.125), hydrolyzing the glucoalkaloid, raucafrricine, to its aglycone, vomilenine-a central intermediate of the ajmaline biosynthetic pathway. It describes the gene expression, as well as characterization, crystallization, structure elucidation, catalytic and substrate specificity mechanisms of RG. Moreover, it investigates the inhibition of RG activity by deoxypyranosylamine type inhibitor and its mechanism. X-ray diffraction data, collected at room temperature (RT,295K) and in typical cryo-conditions were compared in parallel.
RG was functionally expressed in E. coli with an N-terminal (His)6tag and was purified to homogeneity via affinity chromatography. Kinetic studies of RG revealed that its Km values towards raucaffricine and strictosidine were0.78and1.7mM, respectively. In order to clarify the3-D structure, the active center, and the ligand binding mode of RG, crystallization of RG and its inactive mutant RG-E186Q was performed by hanging drop vapor diffusion method. The enzyme-ligand complexes were obtained by soaking method. In total,8datasets were collected and solved to resolutions better than2.6A:RG, RG-glycerol, RG-glucose, RG-inhibitor structures were processed with the data collected in cryo-conditions; RG-E186Q, RG-E186Q-dihydroraucaffricine, RG-E186Q-secologanin, RG-E186Q-glucose structures were processed with data collected at RT.
The overall structures of RG and its inactive mutant possess the expected (β/α)8barrel fold characteristic of glycoside hydrolase family1(GH1), as seen earlier for the closely related strictosidine glucosidase (SG). Structural comparison between RG and SG revealed that it is the "wider gate" of RG that allows strictosidine to enter its catalytic site, whereas the "slot-like" entrance of SG prohibits the access of raucaffricine. The residues Trp392in RG and Trp388in SG control the gate shape and, ultimately, the acceptance of substrates. Moreover RG-Ser390proved to direct the conformation of the crucial Trp392.3-D structures, supported by the site-directed mutations and kinetic data of RG and SG, provided a structural and catalytic explanation for the substrate specificity of RG and deeper insights into the chemistry of O-glucosidase.
Inhibition constants of four deoxypyranosylamine inhibitors against RG were determined:the Ki values ranged from0.06to620μM. Structural complex of RG with N-(cyclohexylmethyl)-γ-D-gluco-1,5-deoxypyranosylamine is now available. This inhibitor anchors exclusively in the active site of RG by competition with its natural substrate, providing structural evidence for a competitive inhibition mechanism. The combined kinetic and structural information revealed the importance of both, the glycone mimic and the aglycone mimic parts of the inhibitor for inhibition efficacy.
The structural comparison of data collected at RT and cryo conditions suggested that the quality of obtained structure is similar, and measurements under RT conditions provide excellent measurement reproducibility. However, minor modifications were observed in side chain conformation of Glu476, probably due to changes in temperature. These results demonstrate that X-ray measurements under more "natural" conditions yield high quality datasets with single crystals, and provide unprecedented speed (2min), potentially paving the way for the renaissance of RT data collection.
本论文对蛇根木生物碱阿吗灵生物合成支链途径中催化萝卡辛水解形成萝芙木乐宁的萝卡辛糖苷酶(Raucaffricine Glucosidase, RG, EC3.2.1.125)进行了一系列的研究,主要涉及RG的异源表达、纯化、酶学表征、结晶、三维结构表征、催化机制及底物特异性机制和RG抑制剂的研究。同时,本论文对室温(RT)与冷冻条件下收集到的X-射线衍射数据进行了比较。
以pQE-2质粒为表达载体,在大肠杆菌M15中异源高效表达N端带有(His)6标签的RG并利用Ni-NTA亲和层析进行纯化。酶动力学考察表明RG对底物萝卡辛的Km值为0.78mM,对底物异胡豆苷的Km值为1.7mM。为进一步探明RG三维结构,活性中心及各配体的结合情况,本论文通过悬滴蒸发结晶法获得RG及无活性突变体RG-E186Q的晶体,并通过底物浸泡的方式制备其与配体复合物。本文共处理得到8套RG的结构模型：其中RG, RG-glycerol, RG-glucose, RG-inhibitor结构由冷冻条件下收集的衍射数据处理得到；RG-E186Q, RG-E186Q-dihydroraucaffricine, RG-E186Q-secologanin, RG-E186Q-glucose结构由室温条件下收集的衍射数据处理得到。
RG及其无活性突变体的整体三维结构呈典型的(β/α)8桶状结构,与同处于阿吗灵生物合成途径上游的异胡豆苷糖苷酶(SG)一致。通过结果比较,揭示两种酶底物特异性差异的机制：RG的活性空腔入口较宽,SG的天然底物异胡豆苷也可以进入到RG的活性中心；而SG狭长的活性空腔入口阻碍萝卡辛进入SG的活性中心。RG-Trp392与SG-Trp388影响了两酶活性空腔入口的形状,从而控制酶的底物接受能力。RG-Ser390直接影响着RG-Trp392侧链构象,间接调控底物接受能力。定点突变及活性数据进一步证实了结构分析的结果,深化对糖苷酶的底物特异性及催化机制的认识。
随后,本文考察了4种deoxypyranosylamine类抑制剂对RG的抑制情况,4种抑制剂的抑制效果差异较大,抑制剂常数Ki跨度从0.06到620μM。其中RG与抑制剂N-(cyclohexylmethyl)-β-D-gluco-1,5-deoxypyranosylamine复合物的三维结构已成功解析。三维结构显示,该抑制剂专一地结合于RG的活性位点,占据RG的底物结合部位,为竞争性抑制机制提供了结构依据。通过比较各抑制剂的抑制活性数据,并结合抑制剂复合物的结构信息,揭示抑制剂的糖苷模拟以及非糖苷模拟部分对抑制效果均有显著影响。
最后,本文通过比较冷冻与室温条件下收集的X-衍射数据及其处理后得到的结构质量,发现两者的结构基本吻合,而且由室温下收集数据处理得到的结构模型重复性更佳。室温与冷冻条件下,Glu476侧链的构象指向不一致,表明温度变化会导致部分氨基酸构象的变化。总体而言,目前室温条件下,仅仅利用一颗晶体便能快速收集到高质量的可用于三维结构解析的X-射线衍射数据,为室温衍射数据收集的广泛使用打下了坚实的基础。
Rauvolfia serpentina Benth. ex Kurz (Apocynaceae) has been used as a medicinal plant in India for thousands of years, mainly for curing fever, insanity, inflammation, and snake bites, and, nowadays hypertension, and arrhythmia. Its major active alkaloid constituents are ajmaline, ajmalicine, and reserpine. The research on enzymes involved in the biosynthesis of active compounds in plants allows better understanding and utilization of Rauvolfia, steering the metabolic flux in the direction of a desired product by pathway blocking and gene manipulation strategies, and using some of the crucial enzymes in vitro for the chemoenzymatic synthesis of complex alkaloid skeletons.
This thesis focuses on the detailed investigation of the Rauvolfia enzyme, raucaffricine glucosidase (RG, EC3.2.1.125), hydrolyzing the glucoalkaloid, raucafrricine, to its aglycone, vomilenine-a central intermediate of the ajmaline biosynthetic pathway. It describes the gene expression, as well as characterization, crystallization, structure elucidation, catalytic and substrate specificity mechanisms of RG. Moreover, it investigates the inhibition of RG activity by deoxypyranosylamine type inhibitor and its mechanism. X-ray diffraction data, collected at room temperature (RT,295K) and in typical cryo-conditions were compared in parallel.
RG was functionally expressed in E. coli with an N-terminal (His)6tag and was purified to homogeneity via affinity chromatography. Kinetic studies of RG revealed that its Km values towards raucaffricine and strictosidine were0.78and1.7mM, respectively. In order to clarify the3-D structure, the active center, and the ligand binding mode of RG, crystallization of RG and its inactive mutant RG-E186Q was performed by hanging drop vapor diffusion method. The enzyme-ligand complexes were obtained by soaking method. In total,8datasets were collected and solved to resolutions better than2.6A:RG, RG-glycerol, RG-glucose, RG-inhibitor structures were processed with the data collected in cryo-conditions; RG-E186Q, RG-E186Q-dihydroraucaffricine, RG-E186Q-secologanin, RG-E186Q-glucose structures were processed with data collected at RT.
The overall structures of RG and its inactive mutant possess the expected (β/α)8barrel fold characteristic of glycoside hydrolase family1(GH1), as seen earlier for the closely related strictosidine glucosidase (SG). Structural comparison between RG and SG revealed that it is the "wider gate" of RG that allows strictosidine to enter its catalytic site, whereas the "slot-like" entrance of SG prohibits the access of raucaffricine. The residues Trp392in RG and Trp388in SG control the gate shape and, ultimately, the acceptance of substrates. Moreover RG-Ser390proved to direct the conformation of the crucial Trp392.3-D structures, supported by the site-directed mutations and kinetic data of RG and SG, provided a structural and catalytic explanation for the substrate specificity of RG and deeper insights into the chemistry of O-glucosidase.
Inhibition constants of four deoxypyranosylamine inhibitors against RG were determined:the Ki values ranged from0.06to620μM. Structural complex of RG with N-(cyclohexylmethyl)-γ-D-gluco-1,5-deoxypyranosylamine is now available. This inhibitor anchors exclusively in the active site of RG by competition with its natural substrate, providing structural evidence for a competitive inhibition mechanism. The combined kinetic and structural information revealed the importance of both, the glycone mimic and the aglycone mimic parts of the inhibitor for inhibition efficacy.
The structural comparison of data collected at RT and cryo conditions suggested that the quality of obtained structure is similar, and measurements under RT conditions provide excellent measurement reproducibility. However, minor modifications were observed in side chain conformation of Glu476, probably due to changes in temperature. These results demonstrate that X-ray measurements under more "natural" conditions yield high quality datasets with single crystals, and provide unprecedented speed (2min), potentially paving the way for the renaissance of RT data collection.
引文
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