CN110790806B - 新型罗汉果苷衍生物及其用途 - Google Patents
新型罗汉果苷衍生物及其用途 Download PDFInfo
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- CN110790806B CN110790806B CN201810866066.7A CN201810866066A CN110790806B CN 110790806 B CN110790806 B CN 110790806B CN 201810866066 A CN201810866066 A CN 201810866066A CN 110790806 B CN110790806 B CN 110790806B
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Abstract
本发明公开了一类新型罗汉果苷衍生物，包括罗汉果苷IVf、IVg和异‑赛门苷I，这类化合物具有较高的甜度，可被用于开发新型非营养型甜味剂或药用辅料。此外，本发明还公开了该类新型罗汉果苷衍生物的绿色生物合成方法。
Description
技术领域
本发明属于食品添加剂和药用辅料技术领域，具体涉及一类新型罗汉果苷衍生物及其用途，这类化合物通过酶工程方法修饰天然植物来源的化合物制备获得，具有很强的甜度，可以作为新型非糖型天然甜味剂，替代高热量的蔗糖和存在安全性隐患的合成类甜味剂。
背景技术
罗汉果苷是一类从罗汉果(Siraitia grosvenorii)中分离得到的甜度较高的四环三萜皂苷，也是罗汉果提取物的主要活性成分。自1983年Takemoto等从罗汉果果实中分离出甜味化合物罗汉果苷(Mogroside,MG)IV、V和VI后，目前已有超过30种同系列化合物被陆续分离鉴定，它们均为罗汉果苷元([10α-cucurbit-5-ene-3β,11α,24(R),25-tetraol])连接2至6个葡萄糖单元的四环三萜皂苷(Li C,et al.Chin.J.Nat.Med.,2014,12:89-102)。由于甜度高、热量极低和口感好等优点，罗汉果苷系列化合物已成为各大食品企业和研究机构开发新型非糖类甜味剂的重要来源(Itkin M,et al.Proc.Natl.Acad.Sci.,2016,113:E7619-E7628；万艳娟,等.食品与发酵技术,2015,51:51-56.)。此外，有报道显示，罗汉果苷类化合物还具有抗炎、降血糖、抗氧化、保肝、防止动脉粥样硬化和抑癌等多种生物学活性(万艳娟,等.食品与发酵技术,2015,51:51-56.)。同时，急性毒性试验证明了该类化合物是一类基本无毒物质(苏小建,等.食品科学,2005,26:221-224.)。因此，罗汉果苷也是新药开发的一类重要先导化合物。
近些年来，由于人们过多摄入传统甜味剂，糖尿病、肥胖症以及相关代谢性疾病的患者大量增加，成为威胁。随着生活水平不断提高，人们对食品的需求不仅限于美味，更追求健康。因此，开发低热量和健康的非糖型新型甜味剂逐渐成为行业的需求。目前，非糖类甜味剂主要可分为两类：第一类为从自然界提取的天然甜味剂如甜菊苷；第二类为化学合成甜味剂如阿斯巴甜、糖精钠、三氯蔗糖、甜蜜素等。由于存在潜在的健康问题，化学甜味剂的市场接受度逐年降低，很多国家也采取了相应的管控措施(Weihrauch MR,etal.Ann.Oncol.,2004,15:1460-1467)。在此背景下，以罗汉果苷类系列化合物为物质基础开发低(无)热量、新型非糖类天然甜味剂受到了各大型食品和饮料生产企业的重视。
罗汉果苷结构和甜味的构效关系研究推测，含3个葡萄糖单元是罗汉果苷类化合物具有较好甜味的结构基础，但口味存在一定差别(Wang L,et al.Molecules,2014,19:12676-12689.)。目前市场上应用最多的罗汉果苷类甜味剂为罗汉果甜苷提取物，其为“一般公认安全(Generally Recognized as Safe，GRAS)”的食品添加剂。虽然我国已于2016年颁布《食品安全国家标准—食品添加剂罗汉果甜苷》的国家标准，但是罗汉果甜苷提取物的成分复杂，质量控制难度很大。近年来，可口可乐等大型饮料企业正在积极开发单一成分的罗汉果苷类甜味剂，例如罗汉果苷IV、V和赛门苷I，形成专利保护(US20130136838)。由此可见，甜度高、口味好的罗汉果苷衍生物的甜味剂开发前景广阔。
发明内容
本发明公开了一类新型的罗汉果苷衍生物，该类衍生物在未见文献报道，具有极高的甜度等药理活性。此外，本发明还公开了该类化合物的绿色生物合成方法。
本发明技术方案具体如下：
一种罗汉果苷衍生物，其特征在于具有下式结构：
结构中的R1、R2、R3代表α-或β-糖苷键连接的葡萄糖或H，且R1、R2和R3不同时为葡萄糖或H。
所述葡萄糖选自α-D-葡萄糖，β-D-葡萄糖，可以为α-D-呋喃葡萄糖、β-D-呋喃葡萄糖、α-D-吡喃葡萄糖或β-D-吡喃葡萄糖。
本发明优选的罗汉果苷类衍生物化合物如下：
罗汉果苷IVf：R1为β-糖苷键连接的葡萄糖，R2为H，R3为H；
罗汉果苷IVg：R1为H，R2为β-1，2-糖苷键连接的葡萄糖，R3为H；
异-赛门苷I：R1为H，R2为H，R3为α-1,6-糖苷键连接的葡萄糖；
本发明以具有三糖结构的罗汉果苷IIIE为底物，采用不同的糖基转移酶针对其R1、R2和R3位羟基进行定点糖基化修饰，分别获得了R1位以β-糖苷键连接的糖基化罗汉果苷IIIE即罗汉果苷IVf，R2位羟基形成β-1，2-糖苷键连接的衍生物2即罗汉果苷IVg以及R3位以α-1，6-糖苷键连接的糖基化衍生物3即异-赛门苷I。经过甜度和口感测试发现：罗汉果苷IVf甜味消失，有苦涩味；罗汉果苷IVg甜度约为蔗糖的100～200倍，略带苦味；异-赛门苷I甜度约为蔗糖的500～600倍，高于已知最甜的赛门苷I(400～500倍)，无苦味。上述衍生物的甜度变化情况表明，R1～R3位的结构修饰和改造对罗汉果苷的甜度影响明显，可成为基于罗汉果苷开发新型甜味剂的结构改造位点。由甜度和口味可知，本发明制备的罗汉果苷IVf、罗汉果苷IVg和异-赛门苷I是开发非糖型甜味剂的理想物质基础，可用于食品、饮料、药品、药用辅料、酒类、营养保健品、调味品、日用化工品、口腔卫生产品和化妆品等众多领域。
此外，本发明还公开了利用糖基转移酶催化罗汉果苷IIIE绿色生物合成罗汉果苷IVf、罗汉果苷IVg和异-赛门苷I的方法。
本发明具有如下优点：
1)本发明公开的罗汉果苷衍生物是一类高甜度非营养型甜味化合物，甜度优于其他非营养型甜味剂，可应用于食品、饮料、药品、药用辅料、酒类、营养保健品、调味品、日用化工品、口腔卫生产品和化妆品等领域。
3)本发明公开的罗汉果苷衍生物是以罗汉果中天然存在的罗汉果苷IIIE为基础上，采用糖基转移酶糖基化修饰产生的全新天然化合物，因此安全性好。
4)本发明采用糖基转移酶制备罗汉果苷衍生物的方法先进绿色，不涉及有机溶剂和有害物质，无需从罗汉果中提取分离，易于规模化制备。
综上所述，本发明公开的罗汉果苷衍生物性质优异，安全性好，可作为新型甜味剂，潜在应用价值巨大，市场前景广阔。此外，利用糖基转移酶定点糖基化修饰罗汉果苷IIIE的制备方法绿色，先进，易于规模化。
附图说明
图1为OleD催化罗汉果苷IIIE糖基化反应的HPLC色谱图。
图2为罗汉果苷IVf的氢谱。
图3为罗汉果苷IVf的碳谱。
图4为罗汉果苷IVf的HMBC图谱。
图5为罗汉果苷IVf的HMQC图谱。
图6为罗汉果苷IVf的COSY图谱。
图7为罗汉果苷IVf的DEPT图谱。
图8为罗汉果苷IVg的氢谱。
图9为罗汉果苷IVg的碳谱。
图10为罗汉果苷IVg的HMBC图谱。
图11为罗汉果苷IVg的HMQC图谱。
图12为罗汉果苷IVg的COSY图谱。
图13为罗汉果苷IVg的DEPT图谱。
图14为HXSW-GT-101催化罗汉果苷IIIE糖基化反应的HPLC色谱图。
图15为异-赛门苷I的氢谱。
图16为异-赛门苷I的碳谱。
图17为异-赛门苷I的HMBC图谱。
图18为异-赛门苷I的HMQC图谱。
图19为异-赛门苷I的COSY图谱。
图20为异-赛门苷I的DEPT图谱。
具体实施方式
以下通过实施例说明本发明的具体步骤，但不受实施例限制。
在本发明中使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明，应理解，这些实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1糖基转移酶OleD及其突变体的重组表达
OleD一种是来源自链霉菌Streptomyces antibioticus的UDP-葡萄糖依赖的糖基转移酶，其同源蛋白HXSW-GT-09、HXSW-GT-10、HXSW-GT-11、HXSW-GT-12的设计及氨基酸序列见发明人前期的公开专利CN107164435A。OleD及其同源蛋白可在大肠杆菌、酵母菌、枯草芽孢杆菌、乳酸菌和链霉菌中可溶性表达，其表达条件和表达效果见专利CN107164435A。
实施例2糖基转移酶OleD及其突变体生物合成罗汉果苷IVf和IVg
鉴于糖基转移酶在大肠杆菌中表达的经济性、简便性和高效性，故本发明优选大肠杆菌表达系统对罗汉果苷IIIE的糖基化修饰进行说明，但不限制本发明的应用范围。
1mL反应体系中，底物罗汉果苷IIIE为5mM(4.82mg/ml)，UDP-葡萄糖为60mM，0.05M磷酸钾缓冲液(pH 7.0)，表达糖基转移酶OleD或其同源蛋白的重组大肠杆菌20mg/mL，30℃振摇反应10小时。反应结束后，加热除蛋白，再加入1倍体积甲醇处理，离心过滤获得的滤液进行HPLC分析。
HPLC检测条件：色谱柱：Agilent C18,5μm,250×4.6mm；流动相：A：超纯水(含0.1％甲酸)；B：乙腈(含0.1％甲酸)；梯度分析时间：20min，进样量：10μL，柱温：30℃，检测波长：210nm；流速：1.0ml/min，梯度洗脱：10％B-90％B。
在上述HPLC分析条件下，罗汉果苷IIIE的保留时间为11.51min，产物1和2的保留时间分别为9.74min和10.05min。经制备高效液相纯化后分别获得纯度大于95％的产物1和2，NMR图谱解析后确证产物即为罗汉果苷IVf和IVg，罗汉果苷IVf的核磁谱图如图2-7所示，罗汉果苷IVg的核磁谱图如图8-13所示。由此可看出，OleD以及与其同源性≥89.5％的同源蛋白可催化罗汉果苷IIIE同时产生罗汉果苷IVf和IVg。
表1糖基转移酶催化合成罗汉果苷IVf和IVg
| 糖基转移酶 | 与OleD的氨基酸序列同源性 | 罗汉果苷IVf的产率 | 罗汉果苷IVg的产率 |
| OleD | 100％ | 56.4％ | 30.7％ |
| HXW-GT-09 | 98.3％ | 54.8％ | 28.3％ |
| HXW-GT-10 | 89.5％ | 28.5％ | 15.8％ |
| HXW-GT-11 | 69.5％ | 0 | 0 |
| HXW-GT-12 | 58.2％ | 0 | 0 |
实施例3原位生物合成罗汉果苷IVf和罗汉果苷IVg
50mL的原位体系中，罗汉果苷IIIE为5mM，UDP-葡萄糖为60mM或不添加外源性UDP-葡萄糖，调节含表达OleD大肠杆菌的发酵液pH至7.0，30℃振摇反应24小时。反应结束后，进行HPLC分析，分析方法见实施例2。结果显示，在不加UDP-葡萄糖的条件下，罗汉果苷IVf和IVg的产率分别是13.1％和5.6％；在外加UDP-葡萄糖的条件下，罗汉果苷IVf和IVg的产率分别为58.0％和36.5％。
实施例4借助UDP-葡萄糖循环再生系统生物合成罗汉果苷IVf和IVg
采用蔗糖、蔗糖合成酶以及UDP组成UDP-葡萄糖再生体系用于OleD生物合成罗汉果苷IVf和IVg。10mL反应体系中，罗汉果苷IIIE为5mM，UDP为5mM，共表达OleD和蔗糖合成酶的菌液或其粗酶液，蔗糖0.1M，反应体系的pH为7.0，37℃振摇反应24小时。反应结束后进行HPLC分析，分析方法见实施例2。
表2罗汉果苷IVf和IVg的合成效率
实施例5葡萄糖基转移酶HXSW-GT-101的重组表达
葡萄糖基转移酶HXSW-GT-101为来源自Bacillus sp.的转糖苷酶。委托苏州金唯智生物科技有限公司合成并利用pET28a(+)载体构建表达质粒pET28a-gt-01。将上述重组表达质粒分别转化至E.coli BL21表达宿主，得到大肠杆菌工程菌株，命名为E.coli-GT-101。
将上述工程菌接种至50mL的LB培养基(含50μg/ml卡那霉素)，37℃、220rpm振摇过夜培养获得相应种子液。将种子液按5％接种量转接至LB培养基(含50μg/ml卡那霉素)中，37℃振摇培养至OD600＝0.9时，加入诱导剂IPTG使其终浓度为1.0mM，在35℃条件下，诱导表达12小时。SDS-PAGE分析可溶性表达情况，结果显示，HXSW-GT-01的可溶性表达量约为16.7％，目标蛋白条带的分子量大小约75kDa。
实施例6葡萄糖基转移酶HXSW-GT-101生物合成异-赛门苷I
1mL反应体系中，底物罗汉果苷IIIE为10mg/mL(10.4mM)，淀粉为50mg/mL，0.1MTris-HCl缓冲液(pH 8.0)，表达HXSW-GT-101的大肠杆菌20mg/mL，30℃振摇反应12小时。反应结束后，加热除蛋白，再加入1倍体积甲醇处理，离心过滤获得的滤液进行HPLC分析。
HPLC检测条件：色谱柱：Agilent C18,5μm,250×4.6mm；流动相：A：超纯水(含0.1％甲酸)；B：乙腈(含0.1％甲酸)；梯度分析时间：20min，进样量：10μL，柱温：30℃，检测波长：210nm；流速：1.0ml/min，梯度洗脱：10％B-90％B。
在上述HPLC分析条件下，罗汉果苷IIIE的保留时间为11.89min，糖基化产物为10.73min，如图14所示。经制备高效液相纯化后获得纯度为95.1％的白色糖基化产物，NMR图谱(图15-20)解析后确证产物为异-赛门苷I。由此可看出，HXSW-GT-101能催化罗汉果苷IIIE生物合成衍生物3，转化效率可达到45.8％。
实施例7原位生物合成异-赛门苷I
50mL的原位体系中，罗汉果苷IIIE为10mg/mL(10.4mM)，淀粉用量为50mg/mL，调节含表达HXSW-GT-101大肠杆菌的发酵液pH至8.0，30℃振摇反应12小时。反应结束后，进行HPLC分析，分析方法见实施例6。结果显示，异-赛门苷I的产率为38.6％。
实施例8粗酶液催化合成异-赛门苷I
采用0.1M Tris-HCl缓冲液(pH 8.0)按照1：10(g：ml)的质量体积比稀释表达HXSW-GT-101的大肠杆菌，然后高压破碎和离心后获得HXSW-GT-101的粗酶液。10mL的催化体系中，罗汉果苷IIIE为10mg/mL(10.4mM)，淀粉用量为50mg/mL，HXSW-GT-101的粗酶液5ml，用Tris-HCl缓冲液将反应体系补齐至10ml，30℃振摇反应12小时。反应结束后，进行HPLC分析，分析方法见实施例6。结果显示，异-赛门苷I的产率为47.5％。
实施例9罗汉果苷衍生物的甜度测试
根据文献的甜度测试方案，按照不同的质量体积百分数(0.1％、0.05％、0.025％、0.017％、0.0125％、0.01％、0.0083％)分别将赛门苷I、罗汉果苷IIIE和3个新型罗汉果苷衍生物配制成不同稀释比的测试溶液。选定男女各半的测试人员共12人，进行甜度和口味测试。
结果显示，90％以上受试者认为赛门苷I的甜度为5％蔗糖的400到500倍，无不良口感；90％以上受试者认为罗汉果苷IIIE的甜度为5％蔗糖的200到300倍之间，30％以上受试者认为有后滞苦味；所有受试者认为罗汉果苷IVf基本无甜味，80％以上受试者认为苦味明显；90％以上受试者认为罗汉果苷IVg的甜度为5％蔗糖的100到200倍之间，80％以上受试者认为苦味明显；90％以上受试者认为异-赛门苷I的甜度为5％蔗糖的500到600倍，无任何不良口感。
Claims (5)
1.一种罗汉果苷衍生物，其特征在于具有下式结构：
2. 根据权利要求 1所述的罗汉果苷衍生物作为甜味剂的应用。
3.根据权利要求2所述的应用，其特征在于所述罗汉果苷衍生物为高甜度非营养型甜味剂。
4.根据权利要求 2所述的应用，其特征在于所述罗汉果苷衍生物作为甜味剂应用于人或者动物消费的食品、饮品、药品、药用辅料、保健品、调味品、日用化工品。
5.根据权利要求 2所述的应用，其特征在于所述罗汉果苷衍生物作为甜味剂应用于人或者动物消费的口腔卫生产品或化妆品。
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