CN113975285A - Ggpp结合并变构激活人源fbp1在制备抗肝细胞癌药物中的应用 - Google Patents
Ggpp结合并变构激活人源fbp1在制备抗肝细胞癌药物中的应用 Download PDFInfo
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Abstract
本发明公开了GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用。所述的人源FBP1蛋白的氨基酸序列如SEQID No.1所示。本发明建立了正常肝脏中GGPP的直接结合蛋白作用网络，并筛选和验证了多个参与肝脏糖脂代谢调控的GGPP结合蛋白。所述的GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，可且抑制肝实质细胞和肝癌细胞的迁移。所述的GGPP通过敏化其靶点蛋白FBP1偶联糖脂代谢平衡，进而调节肝细胞癌发生、发展的分子机制，可应用于肝细胞癌的治疗。GGPP通过与其靶点蛋白FBP1特异性直接结合调控肝脏糖脂代谢平衡，并为HCC的治疗提供新的潜在靶点、药物和治疗方法。
Description
技术领域
本发明涉及生物技术领域，具体涉及香叶基香叶基焦磷酸GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用。
背景技术
糖脂代谢稳态的调控是维持机体生命活动的基础。在我国，由于近几十年生活方式及饮食结构的改变，部分人群糖脂代谢模式随之发生变化，肥胖、糖尿病等代谢综合征发病率显著上升。肝脏作为代谢的中枢器官首当其冲，长期的糖脂代谢紊乱引发非酒精性脂肪肝病(Non-alcoholic fatty liver disease，NAFLD)和肝纤维化(Liver fibrosis)等慢性肝病。近期研究结果表明，除了病毒性肝炎和酒精性肝病，代谢综合征以及NAFLD等慢性肝病也是原发性肝癌的重要诱因。与此同时，通过控制癌细胞的糖脂代谢，利用多种策略特异性阻断癌细胞的能量来源以达到癌症预防和治疗，也越来越受到重视。因此，糖脂代谢稳态在原发性肝癌的发生、发展以及预防、早期诊断和治疗中均占据重要地位。
作为原发性肝癌的主要类型，肝细胞癌(Hepatocellular carcinoma，HCC)是全球范围内最为常见的体内恶性肿瘤之一，也是肿瘤相关性死亡的最常见原因之一。除了手术治疗，针对晚期肝癌患者，多激酶抑制剂索拉非尼(Sorafenib)是唯一被多个国家批准的系统性治疗晚期HCC的药物，但其价格昂贵、存在特殊的不良反应，对不同患者有效性亦有待商榷。另外，在新药开发方面，其他分子靶向制剂如舒尼替尼(Sunitinib)、布立尼布(Brivanib)和利尼伐尼(Linifanib)等治疗肝癌的临床试验均得到一系列阴性结果。而“老药新用”，在高投入、高风险的药物研发过程中，由于可以极大程度缩短研发时间、成本及临床应用周期，成为药物研发的新趋势。作为临床上最为常见的一类降脂处方药，他汀类药物(Statins)用药人群广泛，主要应用于治疗和预防代谢综合征伴随的高脂血症以及各种心血管疾病。近期大量临床统计数据显示，他汀类药物可以降低HCC等多种癌症病人的死亡风险，提示了HCC作为Statins的新适应症的可能性。然而，他汀类药物在HCC预防及治疗中的作用仍然存在不确定性。这可能与他汀类药物抑制了位于甲羟戊酸途径上游的羟甲基戊二酸单酰辅酶A还原酶(3-hydroxy-3-methylglutaryl-CoA reductase，HMGCR)，导致其下游多种具有重要生物学功能的代谢小分子，例如法尼基焦磷酸(Farnesyl pyrophosphate，FPP)、鲨烯(Squalene)、胆固醇(Cholesterol)、香叶基香叶基焦磷酸(Geranylgeranylpyrophosphate，GGPP)和泛醌(Ubiquinone)等合成受阻有关(如图1所示)。
机体对这些代谢小分子缺失的应答极为复杂，这可能是他汀类药物对不同癌症类型甚至不同病人个体的治疗效果存在显著差异的重要原因之一。阐明甲羟戊酸代谢途径中的这些小分子在HCC发生、发展中的作用，对于他汀类药物在HCC治疗中的应用及相关治疗方案的进一步开发具有重要意义。图1为甲羟戊酸途径图。
其中，香叶基香叶基焦磷酸(Geranylgeranyl pyrophosphate，GGPP)是甲羟戊酸途径下游的重要代谢小分子之一，是法尼基焦磷酸(Farnesyl pyrophosphate，FPP)除胆固醇以外的另一重要产物(如图1所示)。FPP与GGPP已经被报道的主要功能是作为底物参与一类重要的蛋白质脂酰化修饰——异戊二烯化修饰，通过分别改变某些特定蛋白质的疏水性使其在膜系统的定位和活性发生变化，调控下游信号通路，从而发挥特定的功能。
香叶基香叶基焦磷酸合成酶1(Geranylgeranyl pyrophosphate synthase 1，GGPPS1)是体内负责催化将FPP转化为GGPP的合成酶。本实验室利用不同器官组织中Ggpps1特异性敲除小鼠研究FPP和GGPP水平相对变化对机体功能的影响。目前本发明关于Ggpps1敲除小鼠表型的解释集中在FPP/GGPP平衡被破坏后蛋白质异戊二烯化修饰模式的变化，即香叶基化修饰缺失，特定蛋白质发生过度法尼基化激活造成下游信号通路的改变，从而出现一系列表型，如成年小鼠心脏肥大、雄鼠生殖障碍和雌鼠卵母细胞发育障碍等。分析骨骼肌特异性Ggpps1敲除杂合子小鼠发现，GGPPS1缺失引发高脂诱导的全身胰岛素抵抗，证实GGPPS1参与脂质代谢调控。对肝脏特异性Ggpps1敲除小鼠的研究表明，Ggpps1敲除降低了小鼠肝脏中的GGPP水平，也减轻了肝脏中高脂食物导致的脂肪累积，暗示GGPP对于肝脏的糖脂代谢平衡具有重要的调节作用。更重要的是，肝脏特异性Ggpps1敲除小鼠在进行DEN化学诱变时更易于形成原发性肝癌；而临床上对HCC病人肝癌样本的检测发现，GGPP的合成酶GGPPS1表达水平与HCC的恶性程度呈正相关，且GGPPS1表达高的HCC病人预后较好，提示GGPPS1和GGPP可能在HCC恶化进程中通过代偿性的上调以保护肝脏。同时，科睿唯安的Metadrug软件分析也显示GGPP具有显著的抗肿瘤活性。这些结果提示GGPP在肝脏的糖脂代谢调控和肝癌的发生发展中具有重要作用，但是受其调控的直接靶点蛋白及相应的作用机制目前尚知之甚少。
FBP1是糖异生过程中的关键限速酶，同时也被证实是一种重要的抑癌蛋白。已有多个研究报道FBP1缺失、突变和表达降低会导致肝细胞癌、肾透明细胞癌、非小细胞肺癌、乳腺癌等多种癌症的发生、发展。在HCC中，FBP1的缺失或减少可能通过影响Warburg效应，导致糖脂代谢紊乱和脂质异常积累，为癌细胞提供大量物质和能量，加速HCC的发生、发展。而统计学数据也表明在HCC中FBP1表达水平高的病人预后明显好，这使得FBP1成为潜在的HCC预后的预测标志物。
目前，缺乏一种香叶基香叶基焦磷酸GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用。
发明内容
为了解决现有技术的不足，本发明提供了一种香叶基香叶基焦磷酸GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用。
为了达到上述发明目的，本发明所采用的技术方案如下：本发明的香叶基香叶基焦磷酸GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用，所述的香叶基香叶基焦磷酸GGPP的化学式如式(I)所示：
所述的人源FBP1蛋白的氨基酸序列如SEQID No.1所示。
进一步地，所述的香叶基香叶基焦磷酸GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，且抑制肝实质细胞和肝癌细胞的迁移。
进一步地，所述的香叶基香叶基焦磷酸GGPP通过敏化其靶点蛋白FBP1偶联糖脂代谢平衡，进而调节肝细胞癌发生、发展的分子机制，并作用于肝细胞癌。
更进一步地，合成带有Biotin标签的GGPP探针，利用生物素--链霉亲和素亲和纯化体系富集小鼠原代肝实质细胞中的GGPP结合蛋白并进行质谱检测，筛选出了多个与糖脂代谢相关的GGPP潜在靶点蛋白，糖异生途径的果糖-1，6-二磷酸酶1，糖酵解途径的肝脏丙酮酸激酶和参与脂质氧化的肉毒碱棕榈酰转移酶1。
进一步地，所述的GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，逆转肿瘤的Warburg效应从而抑制多种肿瘤的发生发展。
进一步地，所述的抗肿瘤药物为抗肝细胞癌药物。
有益效果：本发明采用高通量的化学蛋白质组学方法首次建立正常肝脏中香叶基香叶基焦磷酸GGPP的直接结合蛋白作用网络，并筛选和验证了多个参与肝脏糖脂代谢调控的GGPP结合蛋白。从分子水平、细胞水平、动物模型和临床病例等多个层面，阐明了GGPP通过与其靶点蛋白FBP1特异性直接结合调控肝脏糖脂代谢平衡，进而调控HCC发生、发展的分子机制，并为HCC的治疗提供新的潜在靶点、药物和治疗方法。
与现有技术相比，本发明具有如下优点：本发明对于香叶基香叶基焦磷酸GGPP和FBP1相互作用的进一步研究发现，GGPP可以特异地与FBP1结合并上调FBP1的酶活促进糖异生，且抑制肝实质细胞和肝癌细胞的迁移；借助于分子对接、FBP1突变体和冷冻电镜实验，本发明确认了GGPP与FBP1结合的模式、关键位点以及变构激活FBP1的机制。将深入阐明GGPP通过敏化其靶点蛋白FBP1偶联糖脂代谢平衡，进而调节肝细胞癌发生、发展的分子机制，并为肝细胞癌的治疗提供潜在的药物和靶点。
附图说明
图1为甲羟戊酸途径图。
图2为本发明的带有生物素标签的Biotin-GGPP(BGPP)分子图。
图3为本发明的代谢小分子GGPP靶点蛋白筛选技术路线图。
图4为本发明的代谢小分子GGPP靶点蛋白的亲和纯化图。
图5为本发明的GGPP潜在直接结合蛋白的生物信息学分析图。A-C.GGPP结合蛋白的Gene Ontology分析:包括生物学过程、分子功能以及细胞成分分析；D.GGPP结合蛋白的KEGG通路分析；E.GGPP结合蛋白的功能分类；F.GGPP结合蛋白中调控糖代谢和脂代谢的关键酶类的蛋白质-蛋白质相互作用网络分析。
图6为本发明的肝脏特异性Ggpps1敲除小鼠FPP/GGPP比值与表型图。A.肝脏特异性Ggpps1敲除小鼠原代肝实质细胞FPP/GGPP及FOH/GGOH的比值变化；B.野生型及肝脏特异性Ggpps1敲除正常饮食及高脂诱导下肝脏形态；C.野生型及肝脏特异性Ggpps1敲除的肝脏切片HE染色，WT的HFD组显示的空泡即脂滴；D.野生型及肝脏特异性Ggpps1敲除的肝脏切片油红染色，红点显示肝脏内脂滴。
图7为本发明的亲和纯化质谱鉴定到的GGPP结合蛋白FBP1肽段和二级谱图。A.两次亲和纯化质谱鉴定到的GGPP结合蛋白FBP1肽段情况；B.FBP1肽段DFDPAINEYLQR2+(m/z＝740.85)二级谱图。
图8为本发明的多个GGPP结合蛋白的Western blot和MST验证图。A.FBP1、ACADL和ACSL1等GGPP结合蛋白的Western blot验证；B.FBP1、ACADL和ACSL1与GGPP结合的验证；C.FBP1、ACADL和ACSL1与BGPP结合的验证。
图9为本发明的GGPP结合蛋白FBP1的竞争性结合实验以及SPR和BLI验证图。A.GGPP结合蛋白FBP1的竞争性结合实验；B.GGPP和FBP1结合的SPR验证；C.GGPP和FBP1结合的BLI验证。
图10为本发明的GGPP结合FBP1后显著上调FBP1酶活图。A.GGPP结合FBP1不影响FBP1同源四聚体的形成；B.GGPP和FBP1结合显著上调FBP1酶活，而FPP没有激活效应。
图11为本发明的负染电镜揭示GGPP结合FBP1后FBP1四聚体结构变化图。A-B.FBP1和GGPP添加后的FBP1四聚体的负染电镜整体结果；C-D.倍数放大后的FBP1和GGPP-FBP1颗粒不同构象的负染电镜采集；E-F.负染电镜FBP1和GGPP-FBP1颗粒构象的3D重构；G-J.3D重构揭示GGPP结合后FBP1四聚体的构象和转角改变。
图12为本发明的X射线晶体衍射揭示GGPP结合位于FBP1四聚体的中间空腔图。
图13为本发明的FBP1-R50位点突变抑制了FBP1响应GGPP刺激抑制肝癌细胞的活力图。A-B.R50的突变降低了FBP1响应GGPP刺激抑制肝癌细胞Huh7的活力和增殖的能力；C-D.R50的突变降低了FBP1响应GGPP刺激抑制肝癌细胞HepG2的活力和增殖的能力。
图14为本发明的人源FBP1蛋白GGPP结合位点的突变抑制了FBP1酶活对于GGPP刺激的响应图。A.GGPP结合位点突变不影响FBP1同源四聚体的形成；B.GGPP结合位点突变抑制了FBP1酶活对于GGPP刺激的响应。
图15为本发明的GGPP前体GGOH可以逆转小鼠肝细胞癌的发生发展图。A.高脂食物和化学诱变制造小鼠原发性肝细胞癌模型的时间线；B.正常对照组、高脂食物和化学诱变小鼠原发性肝细胞癌组以及GGOH回补后的逆转情况；C-E.B中三组小鼠肝细胞癌的恶性程度比较和肿瘤数量以及体积大小的统计分析。
图16为本发明的GGPP处理显著抑制肝癌细胞的活力和增殖图。A.GGPP处理显著抑制了肝癌细胞Huh7的活力和增殖；B.GGPP处理显著抑制了肝癌细胞HepG2的活力和增殖。
具体实施方式
为了便于理解本发明，下面将参照相关附图对本发明进行更加全面的描述，附图中给出了本发明的若干实施例，但是本发明可以通过不同的形式来实现，并不限于文本所描述的实施例，相反的，提供这些实施例是为了使对本发明公开的内容更加透彻全面。
本发明的香叶基香叶基焦磷酸GGPP结合并变构激活人源FBP1在制备抗肝细胞癌药物中的应用，所述的香叶基香叶基焦磷酸GGPP的化学式如式(I)所示：
所述的人源FBP1蛋白的氨基酸序列如SEQID No.1所示。
所述的香叶基香叶基焦磷酸GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，且抑制肝实质细胞和肝癌细胞的迁移。
所述的香叶基香叶基焦磷酸GGPP通过敏化其靶点蛋白FBP1偶联糖脂代谢平衡，进而调节肝细胞癌发生、发展的分子机制，并作用于肝细胞癌。
合成带有Biotin标签的GGPP探针，利用生物素--链霉亲和素亲和纯化体系富集小鼠原代肝实质细胞中的GGPP结合蛋白并进行质谱检测，筛选出了多个与糖脂代谢相关的GGPP潜在靶点蛋白，糖异生途径的果糖-1，6-二磷酸酶1，糖酵解途径的肝脏丙酮酸激酶和参与脂质氧化的肉毒碱棕榈酰转移酶1。
所述的GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，逆转肿瘤的Warburg效应从而抑制多种肿瘤的发生发展。
所述的抗肿瘤药物为抗肝细胞癌药物。
实施例1
带有Biotin标签的GGPP探针，利用生物素--链霉亲和素亲和纯化体系富集小鼠原代肝实质细胞中的GGPP结合蛋白并进行质谱检测，筛选出了多个与糖脂代谢相关的GGPP潜在靶点蛋白，例如糖异生途径的果糖-1，6-二磷酸酶1(Fructose-1,6-bisphosphatase，FBP1)，糖酵解途径的肝脏丙酮酸激酶(Liver pyruvate kinase，LPK)和参与脂质氧化的肉毒碱棕榈酰转移酶1(Carnitine palmitoyl transferase 1，CPT1)等。其中，FBP1由于与GGPP结合的显著性(如图5-8所示)、在糖脂代谢调控中的重要作用以及与多种癌症的相关性引起了关注。
1.建立富集和鉴定代谢小分子GGPP直接结合蛋白的技术路线
1.1 Biotin-GGPP探针的设计和合成
为了富集肝脏中与GGPP直接结合的蛋白，本发明合成了带有生物素标签的GGPP探针(BGPP，图2)。在该BGPP分子中，生物素被加在了带有生物素标签的GGPP分子长链碳骨架的C3位置，以保证GGPP前端疏水长链和后端焦磷酸的灵活性并且可以暴露出来和其结合蛋白相互作用。图2为本发明的带有生物素标签的Biotin-GGPP(BGPP)分子图。
所述的GGPP(中文名称：香叶基香叶基焦磷酸)化学式如式(I)所示：
1.2通用的代谢小分子或药物小分子靶点蛋白筛选技术路线
本发明建立了一种通用的代谢小分子或药物小分子靶点蛋白筛选技术路线(图3)。为了鉴定肝脏中与GGPP直接结合并受其调控的靶点蛋白，我们合成了带有生物素标签的GGPP分子，以单独的生物素和GGPP作为对照，分别处理分离、培养的8周龄C57BL/6J雄性小鼠原代肝实质细胞。裂解细胞提取总蛋白后，通过链霉亲和素磁珠亲和纯化GGPP结合蛋白，并利用2D LC-MS/MS进行质谱分析，进而结合基于谱图数计算的非标记蛋白质组学定量和生信分析，获得了成年小鼠原代肝实质细胞中可能的GGPP相互作用蛋白组。通过该技术路线，本发明可以筛选重要的代谢小分子或药物小分子在人体内或细胞内的直接结合蛋白，为解释这些小分子生物学活性和发挥作用的分子机制提供靶点和理论依据。图3为本发明的代谢小分子GGPP靶点蛋白筛选技术路线；图4为本发明的代谢小分子GGPP靶点蛋白的亲和纯化图。
本发明首先分离了8周龄C57BL/6J雄性小鼠原代肝实质细胞，将其分成三份分别培养。在添加小分子药物进行实验分组时，设置了两个阴性对照：分别为添加(Biotin&GGPP)组和(BGPP&8倍GGPP)竞争组，和添加BGPP组一起，分别处理分离培养的小鼠原代肝实质细胞。药物添加4小时后，裂解三组小鼠原代肝实质细胞提取总蛋白(Input)，通过加入链霉亲和素磁珠进行亲和纯化，获得了成年小鼠原代肝实质细胞中可能的GGPP作用蛋白(AP)。对Biotin-GGPP亲和纯化得到的结合蛋白进行银染后发现，Biotin-GGPP组较Biotin组有多个明显的差异条带(图4)，表明GGPP可能确实存在特异性的结合蛋白。因此，本发明对这些蛋白进行了进一步的LC-MS/MS质谱分析。图5为本发明的GGPP潜在直接结合蛋白的生物信息学分析图；A-C.GGPP结合蛋白的Gene Ontology分析:包括生物学过程、分子功能以及细胞成分分析；D.GGPP结合蛋白的KEGG通路分析；E.GGPP结合蛋白的功能分类；F.GGPP结合蛋白中调控糖代谢和脂代谢的关键酶类的蛋白质-蛋白质相互作用网络分析。
将质谱原始数据进行数据库搜索后，Biotin对照组与Biotin-GGPP处理组分别检测到259与479个蛋白。将两组的数据整合进行Label Free相对定量比较，以相对丰度在Biotin-GGPP组比Biotin对照组上调1.5倍以上、且检测到的肽段数大于1为标准，得到潜在的GGPP结合蛋白共211个。对这211个蛋白进行生物信息学分析，包括Gene Ontology分析(图5A-C)、KEGG Pathway分析(图5D)、蛋白质功能分类分析(图5E)和蛋白－蛋白相互作用网络分析(图5F)，结果显示：这些蛋白大量参与各种代谢过程，尤其显著参与脂肪酸代谢和糖酵解/糖异生途径。这些糖脂代谢相关的蛋白如CPT1α和FBP1可作为后续探讨GGPP调控肝脏代谢性疾病和肝细胞癌发生机制的候选蛋白(表1)。本发明的GGPP直接结合蛋白中调控肝脏糖脂代谢的关键酶类如表1所示：
试验例1
肝脏特异性Ggpps1敲除小鼠构建及表型分析
为了研究GGPP缺失对于肝脏脂质代谢的影响，本发明成功构建了Ggpps1-/-Mx1-Cre肝脏特异性诱导敲除小鼠，并进行了相关的表型分析。在肝脏特异性敲除Ggpps1的小鼠肝原代细胞中，代谢组学质谱检测表明FPP/GGPP及FOH/GGOH的比值均表现显著上升(图6A)，而GGPP含量的降低和FPP含量的升高显著抑制了肝脏特异性Ggpps1敲除小鼠甘油三脂(TG)的堆积，使得敲除小鼠对于高脂饮食诱导不敏感，不会出现明显的脂肪肝表型(图6B-D)。图6为本发明的肝脏特异性Ggpps1敲除小鼠FPP/GGPP比值与表型；A.肝脏特异性Ggpps1敲除小鼠原代肝实质细胞FPP/GGPP及FOH/GGOH的比值变化；B.野生型及肝脏特异性Ggpps1敲除正常饮食及高脂诱导下肝脏形态；C.野生型及肝脏特异性Ggpps1敲除的肝脏切片HE染色，WT的HFD组显示的空泡即脂滴；D.野生型及肝脏特异性Ggpps1敲除的肝脏切片油红染色，红点显示肝脏内脂滴。
试验例2
GGPP通过结合FBP1调控肝脏糖脂代谢参与肝细胞癌的发生发展
FBP1是糖异生过程中的关键限速酶，同时也被证实是一种重要的抑癌蛋白。已有多个研究报道FBP1缺失、突变和表达降低会导致肝细胞癌、肾透明细胞癌、非小细胞肺癌、乳腺癌等多种癌症的发生、发展。在干细胞癌HCC中，FBP1的缺失或减少可能通过影响Warburg效应，导致糖脂代谢紊乱和脂质异常积累，为癌细胞提供大量物质和能量，加速HCC的发生、发展。而统计学数据也表明在HCC中FBP1表达水平高的病人预后明显好，这使得FBP1成为潜在的HCC预后的预测标志物。
而临床上，对HCC病人样本检测发现，GGPP的合成酶GGPPS1表达水平与HCC的恶性程度呈正相关，且GGPPS1表达高的HCC病人预后较好，提示GGPPS1和GGPP可能在HCC恶化进程中通过代偿性的上调以保护肝脏。由此推测GGPP可能通过结合FBP1并上调其活性影响糖脂代谢平衡，参与HCC的发生、发展。因此，本发明从分子水平、细胞水平、动物模型和临床病例等多个层面，阐明了GGPP通过与其靶点蛋白FBP1特异性直接结合调控糖脂代谢平衡，进而调控HCC的发生、发展的分子机制，并为HCC的治疗提供新的潜在靶点、药物和治疗方法。
1 GGPP结合蛋白FBP1肽段的二级谱图
在两次以BGPP为探针的亲和纯化重复实验中，本发明都鉴定到了人源FBP1蛋白，蛋白质谱鉴定到的肽段数分别为7和5，人源FBP1蛋白的整体覆盖率分别为28.7％和26％(图7A)。FBP1肽段DFDPAINEYLQR2+(m/z＝740.85)二级谱图的b系列和y系列子离子峰完美覆盖了整个肽段(图7B)，不容置疑的表明本发明确实在BGPP结合蛋白中鉴定到了FBP1。图7为本发明的亲和纯化质谱鉴定到的GGPP结合蛋白FBP1肽段和二级谱图；A.两次亲和纯化质谱鉴定到的GGPP结合蛋白FBP1肽段情况；B.FBP1肽段DFDPAINEYLQR2+(m/z＝740.85)二级谱图。
2 GGPP结合蛋白FBP1的Western blot和MST验证
通过Western blot，本发明验证了BGPP结合蛋白中的FBP1、ACADL和ACSL1：与Biotin&GPPP的阴性对照组相比，BGPP组的AP样品中含有明显富集的FBP1、ACADL和ACSL1蛋白(图8A)。同时，为了进一步验证FBP1、ACADL和ACSL1等糖脂代谢相关蛋白与GGPP的直接结合，本发明利用大肠杆菌原核表达系统表达并纯化了带有EGFP标签的融合蛋白进行了微量热泳动分析(MST)，进一步证实了FBP1、ACADL和ACSL1蛋白可以与GGPP特异性直接结合，而FBP1和GGPP结合的解离常数KD值为250nM(图8B-C)。图8为本发明的多个GGPP结合蛋白的Western blot和MST验证图；A.FBP1、ACADL和ACSL1等GGPP结合蛋白的Western blot验证；B.FBP1、ACADL和ACSL1与GGPP结合的验证；C.FBP1、ACADL和ACSL1与BGPP结合的验证。
3 GGPP结合FBP1的竞争结合实验、SPR和BLI
FBP1作为后续生物学功能研究的候选分子，被进一步采用多种方式进行GGPP的结合验证。GGPP竞争结合实验表明，当有高剂量的游离的GGPP分子存在时，BGPP和人源FBP1蛋白的结合呈剂量依赖性的下降。当游离GGPP的浓度达到40μM(8倍于BGPP探针)时，BGPP和FBP1的结合几乎被完全破坏，证明BGPP特异性的和人源FBP1蛋白直接结合(图9A)。表面等离子共振(SPR)(图9B)和分子互作(BLI)(图9C)等实验也表明，从大肠杆菌纯化获得的FBP1重组蛋白可以在体外和GGPP特异结合。SPR检测到FBP1和GGPP结合的解离常数KD值为262nM(图9B)。图9为本发明的GGPP结合蛋白FBP1的竞争性结合实验以及SPR和BLI验证图；A.GGPP结合蛋白FBP1的竞争性结合实验；B.GGPP和FBP1结合的SPR验证；C.GGPP和FBP1结合的BLI验证。
4 GGPP结合上调FBP1酶活；图10.GGPP结合FBP1后显著上调FBP1酶活；A.GGPP结合FBP1不影响FBP1同源四聚体的形成；B.GGPP和FBP1结合显著上调FBP1酶活，而FPP没有激活效应。
FBP1是糖异生过程中的一个关键限速酶。因此，研究GGPP结合FBP1是否影响其酶活具有重要意义。为了阐明GGPP与FBP1直接结合的生物学功能，本发明进一步检测了GGPP对于FBP1活性的影响。体外试验证实GGPP不影响FBP1同源四聚体的形成(图10A)，但是可以剂量依赖性的显著上调FBP1的活性(图10B)，而与GGPP结构类似的FPP并无这一作用，这表明GGPP结合FBP1并调控其活性具有特异性。而文献已报道的FBP1活性抑制剂AMP则剂量依赖性的降低FBP1的活性，证明了该检测体系的有效性。
5 GGPP和FBP1结合模式的表征；图11为本发明的负染电镜揭示GGPP结合FBP1后FBP1四聚体结构变化；A-B.FBP1和GGPP添加后的FBP1四聚体的负染电镜整体结果；C-D.倍数放大后的FBP1和GGPP-FBP1颗粒不同构象的负染电镜采集；E-F.负染电镜FBP1和GGPP-FBP1颗粒构象的3D重构；G-J.3D重构揭示GGPP结合后FBP1四聚体的构象和转角改变。
为了阐明GGPP激活FBP1活性的分子机制，本发明通过冷冻电镜解析了GGPP加入后FBP1同源蛋白四聚体的构象变化。结果表明，GGPP的结合缩小了FBP1四聚体中上下两个FBP1二聚体之间的夹角，引起了一个6度左右的偏转(图11)。GGPP加入后，可以更好的稳定FBP1四聚体中两个二聚体的相对位置，降低它们之间的相对角度。进一步的X射线晶体衍射结果表明，GGPP分子特异性的结合在FBP1四聚体的中间空腔位置，与其直接相互作用的FBP1氨基酸残基包括R50，S46，P189和A190等(图12)。GGPP的这一结合像一根“门栓”，阻碍了FBP1四聚体中上下两个二聚体的转动转变为非活性状态的R态，从而将FBP1四聚体较大程度的停留在活性状态的T态，上调了FBP1的活性。图12为本发明的X射线晶体衍射揭示GGPP结合位于FBP1四聚体的中间空腔图。
根据上述结构实验的结果，本发明构建了FBP1的突变体并观察了它们形成FBP1四聚体的能力以及酶活的变化。结果表明，人源FBP1蛋白GGPP结合位点的突变几乎不影响FBP1四聚体的形成(图14A)，但是明显抑制了FBP1酶活对于GGPP刺激的响应(图14B)，证实了这些位点对于FBP1和GGPP的结合至关重要。图14为本发明的人源FBP1蛋白GGPP结合位点的突变抑制了FBP1酶活对于GGPP刺激的响应图；A.GGPP结合位点突变不影响FBP1同源四聚体的形成；B.GGPP结合位点突变抑制了FBP1酶活对于GGPP刺激的响应。
6 GGPP和FBP1结合调控肝细胞癌发生发展
鉴于GGPP对于FBP1活性的重要调控作用以及FBP1自身作为一个肿瘤抑制蛋白的重要功能，本发明研究了GGPP和FBP1结合在抑制小鼠肝细胞癌发生发展进程中的作用。结果表明，在利用高脂食物和化学诱变制造小鼠原发性肝细胞癌模型时，野生型小鼠会形成肝癌(图15A-B)；而给肝癌造模小鼠回补GGOH，可以显著抑制小鼠肝癌的发生发展(图15C-E)。图15为本发明的GGOH可以逆转小鼠肝细胞癌的发生发展图；A.高脂食物和化学诱变制造小鼠原发性肝细胞癌模型的时间线；B.正常对照组、高脂食物和化学诱变小鼠原发性肝细胞癌组以及GGOH回补后的逆转情况；C-E.B中三组小鼠肝细胞癌的恶性程度比较和肿瘤数量以及体积大小的统计分析。
同样，在肝癌细胞系Huh7和HepG2中，GGPP处理也可以显著抑制肝癌细胞的活力和增殖(图16)。在Huh7或HepG2中转入FBP1-WT和FBP1-R50N时，这两种细胞的活力没有明显变化；而转入FBP1-WT和FBP1-R50N同时加入GGPP处理，则FBP1-WT/GGPP组较FBP1-R50N/GGPP显著降低，表明FBP1-R50位点对于其响应GGPP刺激至关重要(图13)。图16为本发明的GGPP处理显著抑制肝癌细胞的活力和增殖图；A.GGPP处理显著抑制了肝癌细胞Huh7的活力和增殖；B.GGPP处理显著抑制了肝癌细胞HepG2的活力和增殖。图13.FBP1-R50位点突变抑制了FBP1响应GGPP刺激抑制肝癌细胞的活力图；A-B.R50的突变降低了FBP1响应GGPP刺激抑制肝癌细胞Huh7的活力和增殖的能力；C-D.R50的突变降低了FBP1响应GGPP刺激抑制肝癌细胞HepG2的活力和增殖的能力。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，本发明要求保护范围由所附的权利要求书、说明书及其等效物界定。
序列表
<110> 南京大学
<120> GGPP 结合并变构激活人源FBP1 在制备抗肝细胞癌药物中的应用
<130> 2020
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 338
<212> PRT
<213> 人工序列(人源FBP1蛋白的氨基酸序列)
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Val Arg Lys Ala Gly Ile Ala His Leu Tyr Gly Ile Ala Gly Ser Thr
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Val Ala Ala Gly Tyr Ala Leu Tyr Gly Ser Ala Thr Met Leu Val Leu
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Ala Met Asp Cys Gly Val Asn Cys Phe Met Leu Asp Pro Ala Ile Gly
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Asp Val Ile Pro Thr Asp Ile His Gln Arg Ala Pro Val Ile Leu Gly
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Ala Gln
Claims (6)
1.香叶基香叶基焦磷酸GGPP结合并变构激活人源果糖-1，6-二磷酸酶1FBP1制备抗肝细胞癌药物中的应用，其特征在于：所述的GGPP的化学式如式(I)所示：
所述的人源FBP1蛋白的氨基酸序列如SEQID No.1所示。
2.根据权利要求1所述的应用，其特征在于：所述的香叶基香叶基焦磷酸GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，且抑制肝实质细胞和肝癌细胞的迁移。
3.根据权利要求2所述的应用，其特征在于：所述的香叶基香叶基焦磷酸GGPP通过敏化其靶点蛋白FBP1偶联糖脂代谢平衡，进而调节肝细胞癌发生、发展的分子机制，可应用于肝细胞癌的治疗。
4.根据权利要求3所述的应用，其特征在于：合成带有Biotin标签的GGPP探针，利用生物素--链霉亲和素亲和纯化体系富集小鼠原代肝实质细胞中的GGPP结合蛋白并进行质谱检测，筛选出了多个与糖脂代谢相关的GGPP潜在靶点蛋白，糖异生途径的果糖-1，6-二磷酸酶1，糖酵解途径的肝脏丙酮酸激酶和参与脂质氧化的肉毒碱棕榈酰转移酶1。
5.根据权利要求1或4所述的应用，其特征在于：所述的GGPP特异地与FBP1结合并上调FBP1的酶活促进糖异生，逆转肿瘤的Warburg效应从而抑制多种肿瘤的发生发展。
6.根据权利要求1或4所述的应用，其特征在于：所述的抗肿瘤药物为抗肝细胞癌药物。
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| CA2387734A1 (en) * | 1999-10-18 | 2001-04-26 | Washington State University Research Foundation | Geranyl diphosphate synthase large subunit, and methods of use |
| WO2005007090A2 (en) * | 2003-07-03 | 2005-01-27 | President And Fellows Of Harvard College | Inhibitors of the map kinase pathway |
| WO2012048303A2 (en) * | 2010-10-07 | 2012-04-12 | Columbia University | METHOD FOR TREATING CANCER HARBORING A p53 MUTATION |
| CN112955174A (zh) * | 2018-07-09 | 2021-06-11 | 旗舰先锋创新V股份有限公司 | 融合剂脂质体组合物和其用途 |
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| CA2387734A1 (en) * | 1999-10-18 | 2001-04-26 | Washington State University Research Foundation | Geranyl diphosphate synthase large subunit, and methods of use |
| WO2005007090A2 (en) * | 2003-07-03 | 2005-01-27 | President And Fellows Of Harvard College | Inhibitors of the map kinase pathway |
| WO2012048303A2 (en) * | 2010-10-07 | 2012-04-12 | Columbia University | METHOD FOR TREATING CANCER HARBORING A p53 MUTATION |
| CN112955174A (zh) * | 2018-07-09 | 2021-06-11 | 旗舰先锋创新V股份有限公司 | 融合剂脂质体组合物和其用途 |
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| AMBER ILYAS: "The effect of alendronate on proteome of hepatocellular carcinoma cell lines", 《INTERNATIONAL JOURNAL OF PROTEOMICS》 * |
| HIDENARI HIRATA: "Decreased Expression of Fructose-1,6-bisphosphatase Associates with GlucoseMetabolism and Tumor Progression inHepatocellular Carcinoma", 《CANCER RES》 * |
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