CN112029743A - 一种6-溴茚酮的生物酶催化合成方法 - Google Patents
一种6-溴茚酮的生物酶催化合成方法 Download PDFInfo
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- CN112029743A CN112029743A CN202010967924.4A CN202010967924A CN112029743A CN 112029743 A CN112029743 A CN 112029743A CN 202010967924 A CN202010967924 A CN 202010967924A CN 112029743 A CN112029743 A CN 112029743A
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- 238000007036 catalytic synthesis reaction Methods 0.000 title claims abstract description 6
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Abstract
本发明涉及一种6‑溴茚酮的生物酶催化合成方法，属于生物制药领域，将具有SEQ ID NO.2氨基酸序列的转肽酶定点突变型转肽酶具有SEQ ID NO.1所示的氨基酸序列，再将对溴苯丙酸加入到的甲醇中，搅拌充分溶解后，再加入pH＝2.0的磷酸二氢钾缓冲溶液，0.95KU的定点突变型转肽酶，室温下搅拌20h，蒸干溶剂后，过滤得粗品；再用甲醇/水重结晶得到6‑溴茚酮精品。本发明采用酶突变技术制备的活性转肽酶酶替代了传统的化学合成过程。反应条件温和简单，产生极少的三废。比传统的化学法合成效率更高，收率高，纯度高。
Description
技术领域
本发明属于生物制药领域，具体涉及一种采用酶突变技术制备药
物中间体的方法。
背景技术
茚环结构存在于天然产物、合成药物、农药等分子中，茚酮作为原料用于生物活性化合物的合成具有很强的工业应用前景，同时也再有机发光材料、染料合成方面也有应用，还作为可见光除去的有机保护基团。
天然存在的茚酮化合物有100多个，具有茚酮结构的分子显示出多样的生物活性，例如平滑肌松弛活性、环氧化酶抑制剂等，还有从海洋藻类青菌中分离的具有抑制人血管内皮因子生长的活性，在肿瘤血管生成调节方面具有很强的应用。但是天然提取的两远远赶不上实际需求，因此人工合成茚酮类化合物成为目前发展的趋势。
目前茚酮类化合物一般采用化学合成，步骤繁多，所需物料苛刻，而且所产三废较多，对环境所造成的污染较大。对于6-溴茚酮的合成，目前主要合成途径是以对溴苄溴为原料，经与丙二酸二乙酯反应，在碱性条件下生成二元羧酸，然后通过热脱去一个羧酸，然后酰化经傅克反应生成目标产物。此工艺涉及较多高危化学品，傅克反应还需用到大量的无水氯化铝，工艺要求高，收率低，且危险因素大，三废较多，对环境不友好。
酶作为高效的催化剂因绿色环保，反应条件温和而受到极大的关注。近些年来，越来越多的酶催化多功能性被发现。特别是转肽酶，因其稳定性好，对底物适应范围广以及能高效地催化多种类型的反应而被认为是最有用的酶之一。对酶多功能性的研究，不仅拓宽了我们对生物催化的认知，并且拓展了酶催化的应用范围。转肽酶催化多能性的工作已经被广泛报道，包括aldol反应，Michael反应，Mannich反应，马氏加成反应以及Henry反应等，本发明拟利用生物酶突变技术，获取一种可以有效催化傅克反应获得6-溴茚酮的突变型转肽酶，现有技术中尚未由关于转肽酶突变得到6-溴茚酮的技术报道。
发明内容
本发明针对6-溴茚酮的化学合成，充分利用定点突变型转肽酶在有机溶剂中的良好催化活性，对最后的傅克反应步骤进行了生物酶催化改造，结果获得了良好的产品转化率，而且产品单一，后处理简单，几乎没有三废产生，真正做到绿色环保。
本发明是通过以下方式实现的：
一种6-溴茚酮的生物酶催化合成方法，所述生物酶为定点突变型转肽酶，具有SEQID NO.1所示的氨基酸序列。
所述SEQ ID NO.1所示的氨基酸序列的突变型转肽酶在合成6-溴茚酮的应用。
所述的合成方法，具体包括以下步骤：
(1)将对溴苯丙酸加入到的甲醇中，搅拌充分溶解后，再加入pH＝2.0的磷酸二氢钾缓冲溶液，0.95KU的定点突变型转肽酶，室温下搅拌20h，蒸干溶剂后，过滤即得粗品；
(2)再用甲醇/水重结晶得到6-溴茚酮精品。
进一步的：
SEQ ID NO.1突变体的获得：突变体文库构建及高通量筛选方法。
突变体文库的构建：
为了提高转肽酶的活力，以重组表达载体PET-28a(+)-BS为DNA模板，通过易错PCR的方法构建一个随机突变体文库，并通过调整易错PCR反应体系中Mg2+和Mn2+浓度以及dCTP和dTTP寡核苷酸浓度，使该突变体文库的碱基错配率为千分之十，即保证一个突变体有2到6个氨基酸发生突变，构建突变体文库的具体过程如下。易错PCR反应体系和条件：
易错PCR反应体系：
易错PCR反应条件是：先90℃预变性10min；然后98℃变性60s，60℃退火2min，80℃1.5min，共30个循环；最后75℃延伸10min。
将上述得到的易错PCR产物切胶回收纯化，与原核表达载体pET28a(+)连接后转化重组基因工程菌，即得到一个库容量大的突变体文库。
筛选突变：
从上述突变子文库中筛选了约20000个克隆，得到10个数值变化明显的突变子。接着对这10个突变子进行摇瓶筛选。具体过程为：将这10个突变子接种于含100mlLB培养基的500ml摇瓶中进行发酵及诱导，并通过HPLC法测定活力，得到1个比对照酶活力高2-5倍的突变子，命名为SEQ ID NO.1，经过测序，结果显示如下位点发生突变：I24A、L94T、P179M、S389M、G579R、P726L、S862V、A1070D。
本发明的有益效果
(1)采用酶突变技术制备的活性转肽酶酶替代了传统的化学合成过程。反应条件温和简单，只产生极少的三废。
(2)比传统的化学法合成效产物率更高，收率高，纯度高。
具体实施方式
以下实施例及其说明用于解释本发明，但并不构成对本发明的不当限定。
本申请中下述实施例中所使用的方法如无特殊说明均为常规方法，如《分子克隆实验指南》(J.萨姆布鲁克，D.W.拉塞尔著，黄培堂，汪嘉玺，朱厚础，等译。第3版，北京：科学出版社，2002)中所述的方法进行。同时，本发明中的氨基酸无特别说明外均用其缩写或代号标明。
6-溴茚酮与突变型转肽酶傅克反应可能的机理为:
羰基被突变型转肽酶活性位点中的丝氨酸活化，然后质子化的羰基被富电子的其他基团进攻，形成一个烯胺正离子的中间体，在丝氨酸中氧负离子的作用下脱去质子，得到单取代的氧化物。在极性质子性溶剂甲醇中，单取代的产物中羟基被活泼质子夺走生成一分子水，然后生成亚胺离子，经过分子间的亚胺烯胺互变，得到了一个新的烯胺正离子，然后又一分子进攻此中间体，形成新的烯胺正离子，再次通过丝氨酸中氧负离子夺去中间体中的质子，最后从突变型转肽酶中脱落得到最终6-溴茚酮。
实施例1
SEQ ID NO.1突变体的制备：突变体文库构建及高通量筛选方法：
突变体文库的构建：
为了提高转肽酶的活力，以重组表达载体PET-28a(+)-BS为DNA模板，通过易错PCR的方法构建一个随机突变体文库，并通过调整易错PCR反应体系中Mg2+和Mn2+浓度以及dCTP和dTTP寡核苷酸浓度，使该突变体文库的碱基错配率为千分之十，即保证一个突变体有2到6个氨基酸发生突变，构建突变体文库的具体过程如下。易错PCR反应体系和条件：
易错PCR反应体系：
| 10×Buffer | 8μL |
| 2mmol/L dNTPS | 3μL |
| 100mmol/L dCTP | 0.7μL |
| 100mmol/L dTTP | 0.7μL |
| 10mmol/L MnCl | 2μL |
| 50mmol/L MgSO4 | 2μL |
| 引物T7 promoter | 0.5μL |
| 引物T7 Terminator | 1μL |
| 模板pET-7β-HSDH-wt | 0.5μL |
| Taq DNA聚合酶 | 0.7μL |
| ddH2O | 25μL |
易错PCR反应条件是：先90℃预变性10min；然后98℃变性60s，60℃退火2min，80℃1.5min，共30个循环；最后75℃延伸10min。
将上述得到的易错PCR产物切胶回收纯化，与原核表达载体pET28a(+)连接后转化重组基因工程菌，即得到一个库容量大的突变体文库。
筛选突变：
从上述突变子文库中筛选了约20000个克隆，得到10个数值变化明显的突变子。接着对这10个突变子进行摇瓶筛选。具体过程为：将这10个突变子接种于含100ml LB培养基的500ml摇瓶中进行发酵及诱导，并通过HPLC法测定活力，得到1个比对照酶活力高2-5倍的突变子，命名为SEQ ID NO.1，经过测序，结果显示如下位点发生突变：I24A、L94T、P179M、S389M、G579R、P726L、S862V、A1070D。
实施例2
将229g对溴苯丙酸(1.0mol)加入到1000ml的甲醇中，搅拌充分溶解后，再加入200ml 5mM的磷酸二氢钾缓冲溶液(pH＝2.0)，0.95KU的突变后转肽酶，室温下搅拌20h，蒸干有机溶剂后，过滤即得粗品，再用甲醇/水重结晶得到6-溴茚酮精品197.50g,转化率为93.83％。
对比例1
将229g对溴苯丙酸(1.0mol)加入到1000ml的甲醇中，搅拌充分溶解后，再加入200ml 5mM的磷酸二氢钾缓冲溶液(pH＝2.0)，0.95KU的未突变的转肽酶，其氨基酸序列如SEQ ID NO.2所示，室温下搅拌20h，蒸干有机溶剂后，过滤即得粗品，再用甲醇/水重结晶得到6-溴茚酮精品85.2g,转化率为40.5％。
序列表
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Claims (3)
1.一种6-溴茚酮的生物酶催化合成方法，其特征在于，所述生物酶为定点突变型转肽酶，具有SEQ ID NO.1所示的氨基酸序列。
2.权利要求1所述SEQ ID NO.1所示的氨基酸序列的突变型转肽酶在合成6-溴茚酮的应用。
3.根据权利要求1所述的合成方法，其特征在于：具体包括以下步骤：
(1)将对溴苯丙酸加入到的甲醇中，搅拌充分溶解后，再加入pH＝2.0的磷酸二氢钾缓冲溶液，0.95KU的定点突变型转肽酶，室温下搅拌20h，蒸干溶剂后，过滤即得粗品；
(2)再用甲醇/水重结晶得到6-溴茚酮精品。
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