CN110785496B - 利用色谱从d-阿洛酮糖硼酸盐复合物产生d-阿洛酮糖的方法及包含d-阿洛酮糖的组合物 - Google Patents
利用色谱从d-阿洛酮糖硼酸盐复合物产生d-阿洛酮糖的方法及包含d-阿洛酮糖的组合物 Download PDFInfo
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Abstract
本申请涉及用于产生D‑阿洛酮糖的方法，所述方法包括以下步骤：将包含D‑阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中；以及将包含D‑阿洛酮糖硼酸盐复合物的组合物分离成包含D‑阿洛酮糖的馏分(i)和包含硼酸盐的馏分(ii)。
Description
技术领域
本申请涉及利用色谱从D-阿洛酮糖硼酸盐复合物产生D-阿洛酮糖的方法及包含D-阿洛酮糖的组合物。
背景技术
D-阿洛酮糖是一种以极少量存在于诸如无花果和葡萄干等水果中的天然的糖，且是一种具有糖的70％甜度的单糖。众所周知，与果糖或糖不同，D-阿洛酮糖在人体中不会代谢，并因此几乎不含卡路里，不会影响高血糖症，并且由于其非生龋齿的和抗生龋齿的特性而对牙齿是健康的。
因此，对D-阿洛酮糖作为甜味剂的兴趣日益增长，但是由于天然D-阿洛酮糖存量很少，因此需要开发有效产生D-阿洛酮糖以用于食品工业的技术。
因此，作为产生D-阿洛酮糖的方法，本发明人报导了通过将葡萄糖异构化为果糖，并使果糖与固定的能够产生D-阿洛酮糖差向异构酶的细菌细胞反应(第10-2011-0035805号韩国专利公开，在下文中称为“酶促转化方法”)，而以较经济的方式产生D-阿洛酮糖的方法，并且已经知道以这样的酶促转化方法利用硼酸盐显著增加了D-阿洛酮糖转化率(Process Biochemistry 44(2009)822-828,APPLIED AND ENVIRONMENTAL MICROBIOLOGY,2008年5月,第3008-3013页)。
然而，为了将利用硼酸盐的酶促转化方法应用于工业生产，需要开发一种考虑到经济可行性的方法，其使得能够分离、收集和回收用于酶促转化方法的硼酸盐。另外，由于WHO(世界卫生组织(World Health Organization))建议饮用水中包含的硼含量为0.5ppm或更低，因此需要去除硼。
用于酶促转化方法的硼酸盐在通过酶促转化形成的糖溶液中以硼酸(H3BO3)形式存在，并且基本上不以离子态存在，因为硼酸盐的pKa值约为9，并且大多数硼酸盐以未离解的状态存在于酶促转化反应溶液(具有5至7的pH)中。
对于用于去除硼酸盐的常规技术，报道了一种方法，其中通过提供碱性试剂将pH调节为9-11来将硼酸盐转化为聚硼酸盐，然后进行低压反渗透过滤以除去硼酸盐(第10-1384992号韩国专利)，以及另外一种方法，其中将pH值调节至9.0-10.5以消除能够降低硼酸盐去除效率的水垢，然后进行反渗透处理以除去硼酸盐(第10-1030192号韩国专利申请)。然而，利用酶促转化方法产生液体阿洛酮糖糖存在的问题在于：由于当pH值转换为碱性范围时色值迅速下降，漂白成本增加；阿洛酮糖含量由于碱性聚合反应而存在差异；以及由于需要额外的处理来去除引入的碱性试剂，工业化的经济可行性变差。
在这样的情况下，作为认真进行研究以有效地分离和除去利用使用硼酸盐的酶促转化方法产生的阿洛酮糖中残留的硼酸盐的结果，本发明人通过确认使用模拟移动床色谱能够从包含果糖和硼酸盐的馏分有效分离包含阿洛酮糖的馏分而完成了本申请。
发明内容
技术问题
本申请的一个方面提供了产生D-阿洛酮糖的方法，所述方法包括：将包含D-阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中的步骤；以及将包含D-阿洛酮糖硼酸盐复合物的组合物分离成包含D-阿洛酮糖的馏分(i)和包含硼酸盐的馏分(ii)的步骤。
本申请的另一方面提供了包含D-阿洛酮糖的组合物，其中基于干物质，D-阿洛酮糖的含量为等于或高于99％(w/w)且低于100％(w/w)，并且硼酸盐的含量为多于0且低于0.5ppm(w/w)。
技术方案
在下文中将详细地描述本申请。
本文中公开的描述和示例性实施方案中的每一个都可适用于其他描述和示例性实施方案。即本文中公开的各种因素的所有组合都属于本公开的范围。此外，本申请的范围不应受到下文中提供的具体描述限制。
为了实现本申请的目标，本申请的一个方面提供了产生D-阿洛酮糖的方法，所述方法包括：将包含D-阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中的步骤；以及将包含D-阿洛酮糖硼酸盐复合物的组合物分离成包含D-阿洛酮糖的馏分(i)和包含硼酸盐的馏分(ii)的步骤。
另外，本申请中的用于产生D-阿洛酮糖的方法还可以包括在放置步骤之前，通过使D-果糖和硼酸盐与D-阿洛酮糖3-差向异构酶、表达此酶的菌株或此菌株的培养物而获得包含D-阿洛酮糖硼酸盐复合物的组合物的步骤。
如本文所用，术语“分馏(fractionation)”通常是指通过色谱方法等方式从各种成分、混合物或组合物中分离出各种组分或特定组的操作。因此，通过这样的操作获得的从特定组分分离的物质在本申请中表示为“馏分(fraction)”，以区别于分馏。
因此，包含D-阿洛酮糖的馏分是指通过色谱分离操作从包含D-阿洛酮糖硼酸盐复合物的组合物中获得的物质。另外，在包含D-阿洛酮糖硼酸盐复合物的组合物中，包含硼酸盐的馏分是指排除了包含D-阿洛酮糖的馏分的馏分。具体地，在本申请中阿洛酮糖馏分和硼酸盐馏分的分离可以分类为馏分后分离，其中硼酸盐和/或果糖的量基于硼酸盐和/或果糖的固相分数为最大的，以及馏分前分离，其中阿洛酮糖的量基于馏分中的阿洛酮糖的固相分数为最大的。另外，在其中硼酸盐和/或果糖的含量为最大的馏分后，可以在相比其中果糖的含量为最大的馏分，硼酸盐和/或果糖的纯度为80％(w/w)或更低、15％(w/w)或更低，或者1％(w/w)或更低之后分离馏分，并且在其中阿洛酮糖的含量为最大的馏分前，可以在相比其中阿洛酮糖的含量为最大的馏分，阿洛酮糖的纯度为70％(w/w)或更低、10％(w/w)或更低、1％(w/w)或更低，或者0.4％(w/w)或更低之前分级至某一点。
本申请的D-阿洛酮糖3-差向异构酶(在下文中称为“阿洛酮糖差向异构酶”)可以包括但不限于任何具有将D-果糖差向异构化为D-阿洛酮糖的活性的蛋白质，并且可以将内源性地表达该蛋白质的菌株、转化的用以表达该蛋白质的菌株、该菌株的培养物或从培养物分离的蛋白质用作阿洛酮糖差向异构酶。
本申请的D-阿洛酮糖3-差向异构酶可以是来源于根癌农杆菌(Agrobacteriumtumefaciens)或Kaistia granuli的野生型阿洛酮糖差向异构酶或它们的变体，以及具体地，与SEQ ID NO:1、2、3或4的氨基酸序列具有至少70％、至少80％、至少90％、至少95％、至少97％、至少99％或100％的同源性的阿洛酮糖差向异构酶。另外，应理解，只要具有这样的同源性的氨基酸序列具有阿洛酮糖差向异构酶活性，则该氨基酸序列(其中的某些已被部分缺失、修饰、取代或添加)就应被包括在本申请的氨基酸序列的范围内。更具体地，阿洛酮糖差向异构酶可以具有SEQ ID NO：1或4的氨基酸序列。
本申请的菌株可以为但不限于谷氨酸棒杆菌(Corynebacterium glutamicum)KCCM11403P(第10-1455795号韩国专利)。
可以通过水解蔗糖或异构化葡萄糖来产生本申请的D-果糖。这样，可能通过使用普遍的且廉价的原料如果糖、蔗糖和葡萄糖以高收率产生D-阿洛酮糖，来大量生产阿洛酮糖。另外，硼酸盐是其中硼酸的氢原子被金属元素取代的盐，并且可以原样使用市售产品。
另外，本申请的用于产生D-阿洛酮糖的方法可以另外包括通过使糖溶液流过药物再生型离子交换装置(例如两床三塔型离子交换装置或两床两塔型离子交换装置)来去除金属离子的步骤。可以在获取包含D-阿洛酮糖硼酸盐复合物的组合物的步骤之后，和/或在将包含D-阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中的步骤之前，另外地包括去除金属离子的步骤。
根据本申请，基于干物质，本申请的包含D-阿洛酮糖硼酸盐复合物的组合物可以具有低于25％(w/w)的硼酸盐含量。具体地，基于干物质，本申请的组合物可以具有6.25％-25％(w/w)或6.25％-21.05％(w/w)的硼酸盐含量。
根据本申请，基于干物质，本申请的包含D-阿洛酮糖的馏分可以具有低于0.5ppm(w/w)的硼酸盐含量。具体地，基于干物质，包含D-阿洛酮糖的馏分可以具有0.1-0.45ppm(w/w)、0.05-0.45ppm(w/w)、0.1-0.4ppm(w/w)、0.05-0.39ppm(w/w)、0.1-0.39ppm(w/w)或0.05-0.35ppm(w/w)的硼酸盐含量。
根据本申请，基于干物质，本申请的包含D-阿洛酮糖的馏分可以具有85％(w/w)或更多的D-阿洛酮糖含量。具体地，基于干物质，本申请的包含D-阿洛酮糖的馏分可以具有85％-99.9％(w/w)、90％-99.9％(w/w)、90％-99.5％(w/w)、91％-99.9％(w/w)、91％-99.5％(w/w)、98.0％-99.9％(w/w)、98.0％-99.5％(w/w)、99.0％-99.9％(w/w)或99.0％-99.5％(w/w)的D-阿洛酮糖含量。
另外，根据本申请，本申请的包含D-阿洛酮糖的馏分可以包含D-果糖，且具体地，可以具有基于干物质的10％(w/w)或更少的D-果糖含量，更具体地，0.1％-9.9％(w/w)、0.1％-9.5％(w/w)、0.2％-9.5％(w/w)、0.1％-9％(w/w)、0.1％-5％(w/w)、0.1％-2％(w/w)或0.1％-1％(w/w)的D-果糖含量。
根据本申请，色谱是模拟移动床(SMB)色谱，并且可以包含填充阳离子交换树脂的柱状形式。这样的二价阳离子可以是钙离子(Ca2+)、钡离子(Ba2+)、锶离子(Sr2+)等，并且具体地可以是钙离子。
另外，根据本申请，模拟移动床色谱可以包含4个或更多个柱子。另外，本申请的模拟移动床色谱可以利用50-70℃的水进行洗脱。具体地，可以利用55-65℃或58-62℃的水进行洗脱。
此外，根据本申请，包含D-阿洛酮糖硼酸盐复合物的组合物可以具有5-7的pH，并且可以在将包含D-阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中的步骤之前将组合物的pH调节或维持至5-7。通过使包含D-阿洛酮糖硼酸盐复合物的组合物的pH为5-7，可以避免诸如通过D-阿洛酮糖降解而着色的现象。
另外，根据本申请，可以另外地包括通过使包含D-阿洛酮糖的馏分(i)流过填充硼选择性离子交换树脂的离子交换塔来去除少量的残留硼酸盐的步骤。
任何可以选择性地吸附硼的物质都可以用作填充在本申请的柱子中的阳离子交换树脂(吸附剂)，且具体地，实例可以是Amberlite IRA743和Purolite S108，其中引入多元醇基团作为官能团。
另外，根据本申请，包含硼酸盐的馏分(ii)，相对于包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份数的硼酸盐含量，可以为95或更高重量份数。
另外，根据本申请，包含D-阿洛酮糖硼酸盐复合物的组合物还可以包含果糖。在该情形下，包含硼酸盐的馏分(ii)中的硼酸盐含量，相对于包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份数的硼酸盐含量，可以为95或更高重量份数，并且包含硼酸盐的馏分(ii)中的果糖含量，相对于包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份数的果糖含量，可以为95或更高重量份数。
包含硼酸盐的馏分(ii)中的硼酸盐含量和果糖含量可以为包含D-阿洛酮糖的馏分(i)和包含硼酸盐的馏分(ii)的总和，而非包含D-阿洛酮糖硼酸盐复合物的组合物的重量份数，且具体地，硼酸盐含量和果糖含量可以为95或更多的、96或更多的、97或更多的、98或更多的、99或更多的、99.1或更多的，或者99.5或更多的重量份数，并且可能不超过100重量份数。
可以通过在包含硼酸盐的馏分(ii)中包含在上述范围内的硼酸盐和果糖而重复使用包含硼酸盐的馏分(ii)中的硼酸盐。
在本申请的另一方面，本申请提供了包含D-阿洛酮糖的组合物，其中基于干物质，D-阿洛酮糖的含量为85％-99.9％(w/w)，且硼酸盐的含量为多于0且低于0.5ppm(w/w)。
包含D-阿洛酮糖的组合物包含基于干物质的10％(w/w)或更少的D-果糖。另外，包含D-阿洛酮糖的组合物是利用色谱分离的包含D-阿洛酮糖的馏分。
在本文中将省略与该方面有关的详细描述，因为与前述用于产生D-阿洛酮糖的方法有关的描述类似地适用于该方面。
现在将参照示出了D-阿洛酮糖生产流程图的图4来简单地解释本发明。首先，作为步骤(1)，将果糖和硼酸盐混合，并且作为步骤(2)，随后使D-阿洛酮糖3-差向异构酶与获自步骤(1)的混合物接触，以进行酶促反应过程。接下来，作为步骤(3)，获得D-阿洛酮糖、残留的果糖和D-阿洛酮糖硼酸盐复合物，即硼酸盐，其后，作为步骤(4)，使用SMB色谱分离D-阿洛酮糖馏分(i)和硼酸盐馏分(ii)。获自步骤(4)的硼酸盐馏分(ii)包括残留的果糖和硼酸盐，并因此可以通过回到步骤(1)进行重复使用。此外，如果必要，如上文所述，可以使获自步骤(4)的D-阿洛酮糖馏分(i)流过填充硼选择性离子交换树脂的离子交换塔，以另外去除少量的残留硼酸盐。
有益效果
在本申请中，用于分离硼酸盐的方法和用于产生阿洛酮糖的方法表现出如下效果：通过使用硼酸盐的酶促转化方法所产生的阿洛酮糖中残留的硼酸盐可被有效地分离和去除。
另外，当将本申请的方法用于产生阿洛酮糖时，可以有效地将作为原料的果糖和硼酸盐与阿洛酮糖分离，从而可以回收利用原料。
附图的简要说明
图1是转化D-果糖为D-阿洛酮糖的结果的HPLC色谱图，其分别在向本申请的实施例1的D-阿洛酮糖差向异构酶反应中添加硼酸盐(实验实施例1)和未添加(比较实施例1)时获得。
图2是通过本申请的模拟移动床(SMB)色谱分馏的D-阿洛酮糖馏分的HPLC色谱图。
图3是通过本申请的模拟移动床(SMB)色谱分馏的硼酸盐馏分的HPLC色谱图。
图4是本申请的D-阿洛酮糖生产流程图。
具体实施方式
在下文中，将参照所附实施例更详细地描述本发明。然而，实施例仅用于通过实例的方式解释本申请，因此本申请的范围不受实施例的限制。在提出本申请时，本领域技术人员容易认可和理解本文中未包括的细节，因此将省略其描述。
实施例
实施例1：使用硼酸盐和酶促转化方法产生D-阿洛酮糖
使用谷氨酸棒杆菌(KCCM11403P)进行酶促转化反应，其为一种来源于根癌农杆菌的已知能表达阿洛酮糖差向异构酶的变体的重组菌株(第10-1455759号韩国专利)。将0.1M果糖溶解于水中，并向其中加入0.05M硼酸盐和10mM的MnCl2(实验实施例1)，或仅向其中加入10mM的MnCl2(比较实施例1)，以制备用于酶促转化反应的原料。然后，向原料中加入菌株(20％w/w)，并在pH 8.0和55℃的温度条件下进行反应3小时。
然后，通过HPLC分析比较阿洛酮糖差向异构酶的底物(D-果糖)和产物(阿洛酮糖)的峰面积值来计算转化率，并在以下条件下进行HPLC分析：将样品注入设定在80℃的柱子(BP-100 Ca2+碳水化合物柱)中，并使用蒸馏水作为流动相，通过柱子的流速为0.6mL/min。
结果，比较实施例1的D-阿洛酮糖的转化率为25％，但实验实施例1为56％。因此，可以确认，与比较实施例1相比，实验实施例1的转化率提高了224％(图1)。
实施例2：硼酸盐分离
2-1.证实使用SMB色谱的硼酸盐分离
使用SMB(模拟移动床)色谱以从包含D-阿洛酮糖硼酸盐复合物(硼酸盐、D-果糖和D-阿洛酮糖，下文中被称为“进料”)组合物分离已去除硼酸盐的D-阿洛酮糖。SMB色谱使用先进的模拟移动床系统(Organo,Japan)仪器，并且该仪器包括依次连接的6个柱子(每个具有1.2m的高度和4.3cm的直径)、减料泵、循环泵、洗脱泵、热交换器和用于控制流速的阀门。SMB色谱的运行条件如下表1中所示。
[表1]
另外，填充并使用了作为二价离子的钡离子(Ba2+)和锶离子(Sr2+)，而非钙离子，并且另外进行了使用钠离子(Na+)作为一价阳离子的实验，以作为对照组。结果，证实了在使用钙离子、锶离子和钡离子的情况下在阿洛酮糖馏分中残留的硼酸盐的量分别为0.2ppm、0.3ppm和0.4ppm，这低于WHO推荐的饮用水中的硼含量标准(为0.5ppm)，并且去除率为99.999％(DS％,w/w)。另一方面，证实了在使用钠离子的情况下的阿洛酮糖馏分为62100ppm，这是相比0.5ppm显著更高的值。另外，阿洛酮糖馏分中阿洛酮糖的纯度分别为99.350％(DS％,w/w)(图3)、99.150％(DS％,w/w)和90.850％(DS％,w/w)。另外，相比于进料，发现硼酸盐的回收率为在使用钙离子和锶离子的情况下的硼酸盐馏分的约100％，且果糖的回收率为99.264％，这是一个较高的回收率(硼酸盐馏分中的硼酸盐含量/(阿洛酮糖馏分+硼酸盐馏分)*100)。因此，可以使用SMB色谱分离作为产生阿洛酮糖的原料的果糖和硼酸盐，同时获得高纯度的阿洛酮糖(参见表2和图3)，因此，可以证实生产阿洛酮糖后残余的果糖和硼酸盐可被重复使用(图4)。
[表2]
*DS：干物质
2-2.证实可通过SMB色谱分离的硼酸盐的含量
阿洛酮糖馏分中阿洛酮糖的纯度为99％(DS％,w/w)或更高，且满足WHO推荐的饮用水中的0.5ppm或更低的硼浓度，由此可以确认SMB色谱适用于进料中的硼酸盐含量。进料中硼酸盐、阿洛酮糖和D-果糖的含量如表3所示。
结果可以确认，当添加的硼酸盐的量为21.05％(DS％,w/w)或更少时，硼酸盐去除率均为99.999％，阿洛酮糖馏分中残留的硼酸盐的量为0.5ppm(w/w)或更低，并且阿洛酮糖的纯度为99％(DS％,w/w)或更高(表3)。
[表3]
*DS：干物质
上文中已经参照具体特征详细描述了本申请，并且对本领域技术人员显而易见的是，该详细描述仅针对优选的实施方案，并且不限制本申请的范围。因此，本发明的实质范围将由所附权利要求及其等同物来限定。
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Claims (11)
1.用于产生D-阿洛酮糖的方法，所述方法包括：
将包含D-阿洛酮糖硼酸盐复合物的组合物放置于包括二价阳离子的色谱中的步骤；以及
将所述包含D-阿洛酮糖硼酸盐复合物的组合物分离成包含D-阿洛酮糖的馏分和包含硼酸盐的馏分的步骤，其中所述二价阳离子是钙离子、钡离子和锶离子中的一种或多种，并且所述二价阳离子包含在填充阳离子交换树脂的柱状形式中，并且所述色谱是模拟移动床色谱。
2.如权利要求1所述的方法，还包括在所述放置步骤之前，通过使D-果糖和硼酸盐与D-阿洛酮糖3-差向异构酶、表达所述酶的菌株或所述菌株的培养物接触，来获得包含所述D-阿洛酮糖硼酸盐复合物的组合物的步骤。
3.如权利要求2所述的方法，其中所述D-阿洛酮糖3-差向异构酶为来源于根癌农杆菌(Agrobacterium tumefaciens)或Kaistia granuli的野生型阿洛酮糖差向异构酶或它们的变体。
4.如权利要求1所述的方法，其中基于干物质，所述包含D-阿洛酮糖硼酸盐复合物的组合物具有低于25％(w/w)的硼酸盐含量。
5.如权利要求1所述的方法，其中基于干物质，所述包含D-阿洛酮糖的馏分具有低于0.5ppm(w/w)的硼酸盐含量。
6.如权利要求1所述的方法，其中基于干物质，所述包含D-阿洛酮糖的馏分具有85％(w/w)或更多的D-阿洛酮糖含量。
7.如权利要求1所述的方法，其中所述模拟移动床色谱包含4个或更多个柱子。
8.如权利要求1所述的方法，其中所述模拟移动床色谱利用50-70℃的水进行洗脱。
9.如权利要求1所述的方法，其中所述包含硼酸盐的馏分的含量，相对于所述包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份的硼酸盐含量为95或更高的重量份。
10.如权利要求1所述的方法，其中所述包含D-阿洛酮糖硼酸盐复合物的组合物还包含果糖。
11.如权利要求10所述的方法，其中所述包含硼酸盐的馏分的硼酸盐含量相对于所述包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份的硼酸盐含量为95或更高的重量份，并且所述包含硼酸盐的馏分的果糖含量相对于所述包含D-阿洛酮糖硼酸盐复合物的组合物中的100重量份的果糖含量为95或更高的重量份。
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