CN113355367A - 酮酸还原酶在合成手性芳香2-羟酸中的应用 - Google Patents
酮酸还原酶在合成手性芳香2-羟酸中的应用 Download PDFInfo
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- CN113355367A CN113355367A CN202110401448.4A CN202110401448A CN113355367A CN 113355367 A CN113355367 A CN 113355367A CN 202110401448 A CN202110401448 A CN 202110401448A CN 113355367 A CN113355367 A CN 113355367A
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Abstract
本发明公开了一种酮酸还原酶在合成手性芳香2‑羟酸中的应用,所述酮酸还原酶氨基酸序列为SEQ ID NO.10所示;本发明提供一种来源于乳酸明串珠菌的高效酮酸还原酶,其能够催化广谱芳香族2‑酮酸,且以苯乙酮酸为底物的底物装载量由100mM提升至400mM。利用酮酸还原酶、2‑羟酸脱氢酶和葡萄糖脱氢酶建立的单菌双质粒三酶串联氧化还原级联体系,能够催化大多数外消旋芳香2‑羟酸高效去消旋化为手性芳香(R)‑2‑羟酸,收率和e.e.值均大于99%。
Description
本申请为“申请号201810239718.4,申请日2018年3月22日,名称为酮酸还原酶、基因、工程菌及在合成手性芳香2-羟酸中的应用”专利申请的分案申请
(一)技术领域
本发明涉及一种来源于乳酸明串珠菌(Leuconostoc lactis)的酮酸还原酶基因、编码酶、载体、工程菌及在合成手性芳香2-羟酸中的应用。
(二)背景技术
手性2-羟酸是一类在羧基(-COOH)侧C1位有羟基(-OH)取代的化合物,其分布广泛、性质活跃,是生产药物和精细化学品的重要手性砌块,在化工、医药等领域具有重要的应用价值。其中,比较具有代表性的是结构中含有苯环的一类衍生物,如(R)-扁桃酸是生产半合成青霉素、头孢菌素、抗肿瘤药和减肥药的关键中间体,同时是重要的手性拆分剂;(R)-邻氯扁桃酸是合成抗血栓药(氯吡格雷)的关键手性砌块,具有很高的市场需求和经济效益;(R)-4-氯扁桃酸是第一个商品化的扁桃酰胺类杀菌剂(双炔酰菌胺)的合成前体;(R)-4-羟基扁桃酸可用于生产左旋对羟基苯甘氨酸,进而合成多种广谱抗生素,如羟氨苄青霉素和羟氨苄头孢等。
正是由于手性2-羟酸在医药和精细化工领域的重要应用,使得如何获取光学纯的手性2-羟酸成为一直以来的研究热点。传统上,制备光学纯手性2-羟酸的方法主要依赖于化学动力学拆分,即选择合适的手性拆分试剂将外消旋混合物转化为非对映体盐,改变两种构型的物理性质,然后再进行后续的分离提取。然而,该方法存在很多的缺陷,如最大收率仅为50%、光学纯度低、拆分试剂昂贵、反应条件苛刻及污染环境等问题。近些年,生物催化法因其具有较高的立体选择性和催化活性、反应条件温和、环境友好等优势而得到越来越多的研究和开发,用于光学纯手性2-羟酸的高效生产。其中,比较具有代表性的包括酶法拆分、腈水解酶法、不对称还原和氧化还原级联去消旋。
①酶法拆分,酶法拆分制备光学纯手性2-羟酸属于动力学拆分,通常是指利用生物酶法选择性降解外消旋2-羟酸中的一种构型而获取另一目标构型。其保留了生物酶反应的优势,但最大的缺点是理论收率仅有50%。另外,还有利用脂肪酶拆分邻氯扁桃酸酯得到单一构型的酯化物,然后通过水解的方法获得光学纯邻氯扁桃酸,但是该方法步骤繁琐,不适用于工业化应用。
②腈水解酶法,腈水解酶是一类重要的水解酶,可以催化腈类底物一步转化为相应的羧酸,具有良好的催化特性,因此利用腈水解酶生物催化2-羟基腈制备光学纯手性2-羟酸得到广泛的研究。然而,由于该方法在催化过程中需用到大量剧毒的氢氰酸(HCN),从而导致在实际应用时存在一定的危险性和操作难度。
③不对称还原,利用微生物体内具有立体选择性的还原酶将前手性的2-酮酸不对称还原为光学纯2-羟酸。该法的优点是理论产率高,操作简单等;缺点是反应过程一般需要添加辅酶,辅酶价格昂贵,大大增加生产成本,不利于工业化应用。另外,相对于外消旋化合物,前手性的2-酮酸底物不易获取或价格昂贵,限制了其应用。
④氧化还原级联去消旋,利用具有对映体选择性的2-羟酸脱氢酶、酮酸还原酶和葡萄糖脱氢酶级联催化外消旋2-羟酸转化为单一构型产物。该法节约时间,省去中产物的提取或纯化,还有可能降低可逆反应向底物方向进行,因此是最具有价值的手性2-羟酸获取方法。同时,借助多基因共表达技术,可以成功构建三酶共表达体系用于外消旋2-羟酸的高效去消旋化。
在应用氧化还原级联去消旋的策略制备光学纯手性2-羟酸时,发现酮酸还原酶的活性限制了整体的催化效率,导致底物装载量和产率相对较低。因此,寻找具有高活性和底物耐受性的酮酸还原酶用于三酶共表达催化体系,对实现外消旋2-羟酸的高效去消旋化具有显著的意义。
酮酸还原酶是一类重要的氧化还原酶,能够催化前手性酮酸不对称还原为相应的羟基酸,同时需要NADH(烟酰胺腺嘌呤二核苷酸)或NADPH(烟酰胺腺嘌呤二核苷酸磷酸)作辅因子参与反应。在生物催化领域,生物酶作为催化剂往往具有特定的催化底物,单一酶通常不会对脂肪族和芳香族化合物同时具有催化活性。本研究中所挖掘的酮酸还原酶属于2-脱氢泛解酸-2-还原酶(2-dehydropantoate 2-reductase),已报道的可催化底物均为脂肪族化合物,但实验中却发现其可以高效地催化众多芳香族2-酮酸转化为手性芳香2-羟酸,这对于实现外消旋芳香2-羟酸的高效去消旋化具有重要的应用价值。
(三)发明内容
本发明目的是提供一种来源于乳酸明串珠菌(Leuconostoc lactis)的高效酮酸还原酶基因、编码酶、载体、工程菌及其在合成手性芳香2-羟酸中的应用。所挖掘的酮酸还原酶能够催化广谱芳香族2-酮酸,且具有较高的底物装载量和催化效率。
本发明采用的技术方案是:
本发明提供一种酮酸还原酶,所述酮酸还原酶氨基酸序列为SEQ ID NO.4、SEQ IDNO.8或SEQ ID NO.10之一所示,更优选所述酮酸还原酶氨基酸序列为SEQ ID NO.4所示。本发明是以来源于肠膜明串珠菌(Leuconostoc mesenteroides)的酮酸还原酶LeKAR(氨基酸序列为SEQ ID NO.2、核苷酸序列为SEQ ID NO.1)为模板,从NCBI数据库中筛选出5种氨基酸序列为SEQ ID NO.4、SEQ ID NO.6、SEQ ID NO.8、SEQ ID NO.10或SEQ ID NO.12的酮酸还原酶,分别来源于乳酸明串珠菌(Leuconostoc lactis)、假肠膜明串珠菌(Leuconostocpseudomesenteroides)、肠膜明串珠菌(Leuconostoc mesenteroides)、产酸克雷伯菌(Klebsiella oxytoca)和肠道沙门氏菌(Salmonella enterica),氨基酸序列同源性分别在84%、78%、74%、49%和49%,经验证只有SEQ ID NO.4、SEQ ID NO.8、SEQ ID NO.10的酮酸还原酶具有催化活性。
任何对SEQ ID NO.4、SEQ ID NO.8、SEQ ID NO.10所示氨基酸序列进行一个或多个氨基酸的缺失、***或替换处理获得的多肽片段或其变体,只要其与该氨基酸序列具有95%以上同源性,均属于本发明的保护范围。
本发明还提供一种所述酮酸还原酶的编码基因,所述编码基因的核苷酸序列为SEQ ID NO.3、SEQ ID NO.7、SEQ ID NO.9之一所示。任何对SEQ ID NO.3、SEQ ID NO.7、SEQID NO.9所示核苷酸序列进行一个或多个核苷酸的取代、缺失或***处理获得的核苷酸序列,只要其与该核苷酸序列具有90%以上的同源性,均属于本发明的保护范围。
本发明还涉及所述酮酸还原酶的编码基因构建的重组载体及重组基因工程菌,所述重组基因工程菌为下列之一:(1)将酮酸还原酶编码基因导入宿主菌获得的;(2)将酮酸还原酶编码基因、2-羟酸脱氢酶编码基因和葡萄糖脱氢酶编码基因导入宿主菌获得的。
此外,本发明还提供一种所述酮酸还原酶在催化合成手性芳香2-羟酸中的应用。
应用方法一:当重组基因工程菌是将酮酸还原酶编码基因导入宿主菌获得时,所述的应用方法为:以含酮酸还原酶编码基因的工程菌发酵培养获得的湿菌体经超声破碎后的酮酸还原酶上清液和含葡萄糖脱氢酶编码基因(核苷酸序列为SEQ ID NO.15所示)的工程发酵培养获得的湿菌体经超声破碎后的葡萄糖脱氢酶上清液为催化剂,以苯乙酮酸为底物,以NAD+为辅酶,以葡萄糖为辅助底物,以100mM、pH7.0的KH2PO4-K2HPO4缓冲液为反应介质,在35℃、700rpm条件下反应,反应完全后,获得含(R)-扁桃酸的反应液;所述酮酸还原酶上清液用量以酮酸还原酶酶活计为800U/mL缓冲液,所述葡萄糖脱氢酶上清液用量以葡萄糖脱氢酶酶活计为800U/mL缓冲液,所述葡萄糖用量以缓冲液体积计为200~800mM,所述底物用量以缓冲液体积计为100~400mM,NAD+用量以缓冲液体积计为0.5mM。
进一步,所述方法一中催化剂按如下方法制备:将含酮酸还原酶编码基因的工程菌接种到含50μg/mL卡那霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按2%(体积浓度)的接种量接入到含50μg/mL卡那霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.4~0.8(优选0.6),加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即得静息细胞;将静息细胞重悬于KH2PO4-K2HPO4缓冲液(100mM,pH7.0)中,冰浴条件下超声破碎20min(破碎功率40W,工作1s,停1s),破碎液于4℃,12000rpm下离心10min,收集酮酸还原酶上清液。所述葡萄糖脱氢酶上清液制备方法同酮酸还原酶上清液。
本发明应用方法一是利用微生物体内具有立体选择性的还原酶将前手性的2-酮酸不对称还原为光学纯2-羟酸。
应用方法二:当重组基因工程菌是将酮酸还原酶编码基因、2-羟酸脱氢酶编码基因和葡萄糖脱氢酶编码基因共同导入宿主菌获得时,所述的应用方法为:以含酮酸还原酶(优选LlKAR)、2-羟酸脱氢酶(HADH)和葡萄糖脱氢酶(GDH)编码基因的工程菌经发酵培养获得的湿菌体为催化剂,以外消旋芳香2-羟酸为底物,以葡萄糖为辅底物,以pH6.0~8.0的缓冲液(优选pH7.0的KH2PO4-K2HPO4缓冲液)为反应介质构成反应体系,在20~45℃(优选30℃)、700rpm条件下反应完全后,得到含有光学纯芳香(R)-2-羟酸的转化液。
进一步,所述外消旋芳香2-羟酸为下列之一:扁桃酸1a;2-氟扁桃酸1b;4-氟扁桃酸1c;2,4-二氟扁桃酸1d;3,5-二氟扁桃酸1e;2-氯扁桃酸1f;3-氯扁桃酸1g;4-氯扁桃酸1h;2-溴扁桃酸1i;3-溴扁桃酸1j;4-溴扁桃酸1k;4-甲基扁桃酸1l;4-三氟甲基扁桃酸1m;3-羟基扁桃酸1n;4-羟基扁桃酸1o;4-甲氧基扁桃酸1p;3-甲氧基-4-羟基扁桃酸1q;3-羟基-4-甲基扁桃酸1r;3-羟基-4-三氟甲基扁桃酸1s;3-甲基-4-甲氧基扁桃酸1t,优选1a-1m,字母只是编号,没有含义。
进一步,所述应用方法二反应体系中,底物终浓度为20-300mM,所述辅底物浓度为10-300mM,所述催化剂用量以湿菌体干重计为4-20g/L。
进一步,本发明应用方法二所述工程菌是将酮酸还原酶(优选LlKAR)、2-羟酸脱氢酶(HADH)和葡萄糖脱氢酶(GDH)的编码基因共同导入宿主菌E.coli BL21(DE3)中构建而成;所述2-羟酸脱氢酶的编码基因核苷酸序列为SEQ ID NO.13所示,所述葡萄糖脱氢酶的编码基因核苷酸序列为SEQ ID NO.15所示。
具体的,本发明所述含酮酸还原酶(LlKAR)、2-羟酸脱氢酶(HADH)和葡萄糖脱氢酶(GDH)编码基因的工程菌按如下步骤构建:
(1)构建E.coli BL21(DE3)/pET28b-LlKAR菌株
将酮酸还原酶LlKAR核苷酸序列连入到表达质粒pET28b中,得到重组质粒pET28b-LlKAR,转化到E.coli BL21(DE3)中,构建重组菌E.coli BL21(DE3)/pET28b-LlKAR。
(2)构建E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH菌株
将来源于Exiguobacterium sibiricum的葡萄糖脱氢酶(GDH)基因(核苷酸序列SEQ ID NO.15)和LlKAR基因先后与表达载体pCDFDuet-1连接,得到重组质粒pCDFDuet-LlKAR-GDH,转化到E.coli BL21(DE3)中,构建重组菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH。
(3)构建E.coli BL21(DE3)/pET28b-HADH菌株
将来源于Pseudomonas aeruginosa的2-羟酸脱氢酶(HADH)基因(核苷酸序列SEQID NO.13)经体外合成相应的核苷酸序列并连入到表达质粒pET28b中,得到重组质粒pET28b-HADH,转化到E.coli BL21(DE3)中,构建重组菌E.coli BL21(DE3)/pET28b-HADH。
(4)构建E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH菌株
分别从重组菌E.coli BL21(DE3)/pET28b-HADH和E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH中提取质粒pET28b-HADH和pCDFDuet-LlKAR-GDH,按1:1的摩尔浓度比混匀后,共同转化到E.coli BL21(DE3)中,涂布在含50μg/mL卡那霉素和50μg/mL链霉素的双抗LB平板上,筛选到同时含HADH、LlKAR和GDH基因的重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH,缩写为E.coli(HADH-LlKAR-GDH),从而构建单菌双质粒三酶串联氧化还原级联体系。
所述单菌双质粒三酶串联氧化还原级联体系的反应机制为:以外消旋芳香2-羟酸为底物,利用具有S-立体选择性的HAHD不对称氧化底物中的(S)-2-羟酸为2-酮酸,消耗的辅因子FMN可自我再生;再利用具有R-立体选择性的酮酸还原酶(优选LlKAR)将生成的2-酮酸不对称还原为(R)-2-羟酸,最终得到光学纯(R)-2-羟酸,其中的GDH可以实现辅酶NADH有效的循环再生,无需添加外源性辅酶。具体反应机制如图1所示,图中列出了具有代表性的20种外消旋芳香2-羟酸,本发明三酶共表达***催化的底物包括但不限于这20种外消旋芳香2-羟酸。
进一步,所述方法二中催化剂按如下方法制备:将含酮酸还原酶、2-羟酸脱氢酶和葡萄糖脱氢酶编码基因的工程菌接种到含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按2%(体积浓度)的接种量接入到含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.4~0.8(优选0.6),加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即得湿菌体。
所述重组菌E.coli(HADH-LlKAR-GDH)最终被进一步用于催化高浓度邻氯扁桃酸的去消旋化。反应以重组菌E.coli(HADH-LlKAR-GDH)的静息细胞为催化剂,以外消旋邻氯扁桃酸为底物,以葡萄糖为辅底物,以KH2PO4-K2HPO4缓冲液为反应介质。反应过程中用3.0M的NaOH自动控制pH在7.0,反应完全后得到含有(R)-邻氯扁桃酸的转化液。
与现有技术相比,本发明的有益效果主要体现在:
(1)本发明提供一种来源于乳酸明串珠菌(Leuconostoc lactis)的高效酮酸还原酶(优选LlKAR),其能够催化广谱芳香族2-酮酸,且以苯乙酮酸为底物的底物装载量由100mM提升至400mM。利用酮酸还原酶(优选LlKAR)、2-羟酸脱氢酶(HADH)和葡萄糖脱氢酶(GDH)建立的单菌双质粒三酶串联氧化还原级联体系,能够催化大多数外消旋芳香2-羟酸高效去消旋化为手性芳香(R)-2-羟酸,收率和e.e.值均大于99%。最终应用于去消旋300mM邻氯扁桃酸制备光学纯(R)-邻氯扁桃酸,收率高达83.8g/(L·d)。
(2)利用酮酸还原酶(优选LlKAR)、HADH和GDH构建的单菌双质粒三酶串联氧化还原级联体系,可用于外消旋手性芳香2-羟酸的高效去消旋化,制备具有较高利用价值的光学纯芳香(R)-2-羟酸。该反应具有成本低、绿色环保、工艺简单、催化效率高、无需添加外源性辅酶等优势,工业化前景广阔。
(四)附图说明
图1为单菌双质粒三酶串联氧化还原级联体系的反应机制。
图2为酮酸还原酶LeKAR、LlKAR、LmKAR和KoKAR底物装载量比较分析。
图3为重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH构建示意图。
图4为HADH、LlKAR和GDH共表达的蛋白电泳分析,泳道M为标准蛋白分子量marker,泳道1为未诱导的重组菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH,泳道2为经IPTG诱导的重组菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH,泳道3为未诱导的重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH,泳道4为经IPTG诱导的重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH。
图5为E.coli(HADH-LeKAR-GDH)催化200mM邻氯扁桃酸去消旋反应进程。
图6为E.coli(HADH-LlKAR-GDH)催化200mM邻氯扁桃酸去消旋反应进程。
图7为E.coli(HADH-LlKAR-GDH)催化300mM邻氯扁桃酸去消旋反应进程。
(五)具体实施方式
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:筛选高效的酮酸还原酶LlKAR
以已知酮酸还原酶LeKAR的氨基酸序列(SEQ ID NO.2所示,对应核苷酸序列为SEQID NO.1所示)为模板经NCBI-Blastp在线比对得到5种潜在的酮酸还原酶序列,分别为LlKAR(氨基酸序列SEQ ID NO.4所示,核苷酸序列为SEQ ID NO.3所示)、LpKAR(氨基酸序列SEQ ID NO.6所示,核苷酸序列为SEQ ID NO.5所示)、LmKAR(氨基酸序列SEQ ID NO.8所示,核苷酸序列为SEQ ID NO.7所示)、KoKAR(氨基酸序列SEQ ID NO.10所示,核苷酸序列为SEQID NO.9所示)和SnKAR(氨基酸序列SEQ ID NO.12所示,核苷酸序列为SEQ ID NO.11所示),氨基酸序列同源性分别在84%、78%、74%、49%和49%。后续经体外合成相应的核苷酸序列并连入到表达质粒pET28b中,得到6种重组质粒pET28b-LeKAR、pET28b-LlKAR、pET28b-LpKAR、pET28b-LmKAR、pET28b-KoKAR和pET28b-SnKAR,分别转化到E.coli BL21(DE3)中,涂布在含50μg/mL卡那霉素的LB平板上,筛选得到6种重组菌E.coli BL21(DE3)/pET28b-LeKAR、E.coli BL21(DE3)/pET28b-LlKAR、E.coli BL21(DE3)/pET28b-LpKAR、E.coli BL21(DE3)/pET28b-LmKAR、E.coli BL21(DE3)/pET28b-KoKAR和E.coli BL21(DE3)/pET28b-SnKAR。
将6种酮酸还原酶重组菌及葡糖糖脱氢酶重组菌E.coli BL21(DE3)/pET28b-GDH(GDH基因核苷酸序列为SEQ ID NO.15所示,氨基酸序列SEQ ID NO.16所示)分别接种到含50μg/mL卡那霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按2%(体积浓度)的接种量接入含50μg/mL卡那霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.4~0.8(优选0.6),加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即分别得到4种酮酸还原酶重组菌和葡糖糖脱氢酶重组菌的静息细胞。将静息细胞重悬于KH2PO4-K2HPO4缓冲液(100mM,pH7.0)中,冰浴条件下超声破碎20min(破碎功率40W,工作1s,停1s),破碎液于4℃,12000rpm下离心10min,收集上清液即为相应的粗酶液。
6种酮酸还原酶的酶活测定在1mL反应体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、苯乙酮酸(10mM)、NADH(5mM)和适量的粗酶(0.2μg)。反应体系和粗酶液分别在35℃下温育5min后,在35℃、700rpm条件下反应2min,用HCl(6.0M)终止反应。样品经离心(12000rpm、2min)、超纯水稀释2倍、0.22μm膜过滤后进行手性HPLC分析。单位酶活定义(1U):标准条件下,每min催化苯乙酮酸生成1μmol产物所需的酶量为一个单位酶活。比酶活单位:kU/mg粗酶。结果显示,6种酮酸还原酶LeKAR、LlKAR、LpKAR、LmKAR、KoKAR和SnKAR的比酶活分别为1.11kU/mg、3.71kU/mg、0kU/mg、3.37kU/mg、2.89kU/mg和0kU/mg,其中只有4种酮酸还原酶LeKAR、LlKAR、LmKAR和KoKAR具有催化活性,且LlKAR具有最高的比酶活。
对映体过量值(e.e.)的检测在1mL反应体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、苯乙酮酸(10mM)、NADH(15mM)和合适浓度的粗酶。在35℃、700rpm条件下反应10h后用HCl(6.0M)终止反应。样品经离心(12000rpm、2min)、超纯水稀释2倍、0.22μm膜过滤后进行手性HPLC分析。结果显示,4种酮酸还原酶LeKAR、LlKAR、LmKAR和KoKAR催化苯乙酮酸生成(R)-扁桃酸的e.e.值均大于99%。
4种酮酸还原酶LeKAR、LlKAR、LmKAR和KoKAR在高底物浓度下的进一步比较分析在10mL反应体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、苯乙酮酸(选择100mM和400mM两种浓度)、葡萄糖(浓度是苯乙酮酸的2倍,即分别为200mM和800mM)、NAD+(0.5mM)、KAR(酮酸还原酶,800U/mL)和GDH(葡萄糖脱氢酶,800U/mL)。在35℃、700rpm条件下反应3h后用HCl(6.0M)终止反应。样品经离心(12000rpm、2min)、超纯水稀释2倍、0.22μm膜过滤后进行手性HPLC分析。反应过程中用3.0M的NaOH自动控制pH在7.0。结果如图2所示,4种酮酸还原酶LeKAR、LlKAR、LmKAR和KoKAR在催化100mM苯乙酮酸不对称还原时的转化率和e.e.值均大于99%;在催化400m苯乙酮酸不对称还原时的e.e.值均大于99%,但转化率分别为65.8%、99.2%、75.5%和86.4%。只有LlKAR能够同时催化100mM和400mM的苯乙酮酸完全转化为(R)-扁桃酸,转化率和e.e.值均大于99%,故选择比酶活和底物装载量最高的LlKAR用于构建三酶共表达重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH。
手性HPLC分析方法如下:反相手性柱(型号ChirobioticTM R250×4.6mm,Sigma,USA),流动相为0.5%氨水:CH3OH(10:90,v/v),检测波长为215nm,进样量3μL。
e.e.值的计算方法:ee(%)=(R-S)/(R+S)×100%。式中R表示反应结束后(R)-2-羟酸的浓度,S表示反应结束后(S)-2-羟酸的浓度。
实施例2:构建重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH
将来源于Exiguobacterium sibiricum(WP_012369122.1)的葡萄糖脱氢酶(GDH)基因(核苷酸序列为SEQ ID NO.15所示,氨基酸序列SEQ ID NO.16所示)经体外合成相应的核苷酸序列并连入到表达质粒pET28b中,得到重组质粒pET28b-GDH,转化到E.coli BL21(DE3)中,涂布在含50μg/mL卡那霉素的LB平板上,筛选重组菌E.coli BL21(DE3)/pET28b-GDH。
借助无缝克隆试剂盒(II,Vazyme Biotech Co.,Ltd),将GDH和优选的LlKAR的核苷酸序列先后与表达载体pCDFDuet-1连接,得到重组质粒pCDFDuet-LlKAR-GDH,转化到E.coli BL21(DE3)中,涂布在含50μg/mL链霉素的LB平板上,筛选重组菌E.coliBL21(DE3)/pCDFDuet-LlKAR-GDH。
将来源于Pseudomonas aeruginosa(AGM49308.1)的2-羟酸脱氢酶(HADH)基因(核苷酸序列为SEQ ID NO.13所示,氨基酸序列SEQ ID NO.14所示)经体外合成相应的核苷酸序列并连入到表达质粒pET28b中,得到重组质粒pET28b-HADH,转化到E.coli BL21(DE3)中,涂布在含50μg/mL卡那霉素的LB平板上,筛选重组菌E.coli BL21(DE3)/pET28b-HADH。
分别从重组菌E.coli BL21(DE3)/pET28b-HADH和E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH中提取质粒pET28b-HADH和pCDFDuet-LlKAR-GDH,按1:1的摩尔浓度比混匀后,共同转化到E.coli BL21(DE3)中,涂布在含50μg/mL卡那霉素和50μg/mL链霉素的双抗LB平板上,筛选到同时含HADH、LlKAR和GDH基因的重组菌E.coli BL21(DE3)/pET28b-HADH/pCDFDuet-LlKAR-GDH,缩写为E.coli(HADH-LlKAR-GDH)。同样方法构建重组菌E.coli(HADH-LeKAR-GDH)。
重组质粒和重组菌的构建如图3所示。
实施例3:诱导重组菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH双酶共表达
将重组大肠杆菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH接种到含50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按2%(体积浓度)的接种量接入含50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.6,加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即得E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH的静息细胞。以未诱导的E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH作为对照,进行SDS-PAGE蛋白电泳分析,结果如图4所示,可以看出经IPTG诱导后在32kDa和28kDa附近各出现一条明显的条带,与LlKAR和GDH的理论蛋白分子量大小一致,证明重组菌E.coli BL21(DE3)/pCDFDuet-LlKAR-GDH构建成功。
实施例4:诱导重组菌E.coli(HADH-LlKAR-GDH)三酶共表达
将重组大肠杆菌E.coli(HADH-LlKAR-GDH)接种到含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按2%(体积浓度)的接种量接入含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.6,加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即得E.coli(HADH-LlKAR-GDH)的静息细胞。以未诱导的E.coli(HADH-LlKAR-GDH)作为对照,进行SDS-PAGE蛋白电泳分析,结果如图4所示,可以看出经IPTG诱导后在41kDa、32kDa和28kDa附近分别出现一条明显的条带,与HADH、LlKAR和GDH的理论蛋白分子量大小一致,证明重组菌E.coli(HADH-LlKAR-GDH)构建成功。同样方法制备重组菌E.coli(HADH-LeKAR-GDH)静息细胞。
实施例5:重组菌E.coli(HADH-LlKAR-GDH)催化条件优化
通过实施例4的方法,获得重组菌E.coli(HADH-LlKAR-GDH)的静息细胞,设计优化反应体系为10mL:选择终浓度为20mM的外消旋邻氯扁桃酸为底物,考察菌体浓度4g/L、8g/L、12g/L(以干菌重计),辅底物葡萄糖浓度10mM、20mM、30mM,反应介质KH2PO4-K2HPO4缓冲液pH 6.0、7.0、8.0,温度25℃、30℃、35℃等因素对反应的影响。700rpm下反应2h后用HCl(6.0M)终止反应,样品采用实施例1中的手性HPLC方法进行检测分析,以目标产物收率为评价指标,结果如下表:
表1
结果表明重组菌E.coli(HADH-LlKAR-GDH)催化20mM外消旋芳香2-羟酸去消旋化时,菌体浓度以干菌重计优选8g/L,辅底物浓度优选20mM,反应介质优选pH7.0的KH2PO4-K2HPO4缓冲液,温度优选30℃。
实施例6:重组菌E.coli(HADH-LlKAR-GDH)催化外消旋芳香2-羟酸的去消旋化
反应在10mL的转化体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、外消旋芳香2-羟酸(终浓度20mM,结构见图1和表2)、葡萄糖(终浓度20mM)、通过实施例4获取的三酶共表达重组菌(用量以菌体干重计为8g/L)。反应在30℃、700rpm条件下反应4h,每隔1h定时取样,样品用HCl(6.0M)终止反应,经离心(12000rpm、2min)、超纯水稀释4倍、0.22μm膜过滤后采用实施例1中的手性HPLC方法进行检测分析。结果如下表:
表2
催化结果显示,大多数外消旋芳香2-羟酸(1a-1m)经过2h的反应,均被高效地转化为相应的芳香(R)-2-羟酸,收率大于98%,e.e.值大于99%。即使外消旋芳香2-羟酸(1f-1h,1i-1k)在苯环上存在邻位、间位或对位取代,产生的立体效应却并未影响整体的催化效率。对于外消旋芳香2-羟酸(1n-1q),由于反应结束后有少量(S)-2-羟酸未转化完全或有少量中间体酮酸积累,导致收率相对偏低,但也均达到80%以上。而对于外消旋芳香2-羟酸(1r-1t),该三酶共表达体系基本上不具有催化活性。整体而言,由于挖掘到了一种高效的酮酸还原酶LlKAR,并发现其能够有效地催化芳香族2-酮酸转化为手性芳香2-羟酸,将其与HADH和GDH偶联构建单菌双质粒三酶共表达氧化还原级联体系,从而实现了对大多数外消旋芳香2-羟酸的高效去消旋化,在实际生产中具有重要的应用价值。
实施例7:重组菌E.coli(HADH-LlKAR-GDH)催化200mM邻氯扁桃酸去消旋化
反应在20mL的转化体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、外消旋邻氯扁桃酸(终浓度200mM)、葡萄糖(终浓度200mM)、通过实施例4获取的三酶共表达重组菌(用量以菌体干重计为20g/L)。反应在30℃、700rpm条件下反应20h,每隔2h定时取样,样品用HCI(6.0M)终止反应,经离心(12000rpm、2min)、稀释、过膜后采用实施例1中的HPLC方法进行检测分析。反应过程中用3.0M的NaOH自动控制pH在7.0,反应完全后得到含有(R)-邻氯扁桃酸的转化液。催化反应进程如图6所示,200mM的外消旋邻氯扁桃酸在16h时被完全转化为光学纯(R)-邻氯扁桃酸,收率和e.e.值均大于99%,空时得率高达55.9g/(L·d)。
同样条件下,以实施例4方法获得的重组菌E.coli(HADH-LeKAR-GDH)为催化剂,结果为:E.coli(HADH-LeKAR-GDH)在催200mM外消旋邻氯扁桃酸去消旋时,因中间体酮酸大量积累,反应直至22h,外消旋邻氯扁桃酸仍不能完全转化为(R)-邻氯扁桃酸,结果如图5所示。
实施例8:重组菌E.coli(HADH-LlKAR-GDH)催化300mM邻氯扁桃酸去消旋化
反应在20mL的转化体系中进行,体系包含KH2PO4-K2HPO4缓冲液(100mM,pH7.0)、外消旋邻氯扁桃酸(100mM)、葡萄糖(100mM)、通过实施例4获取的三酶共表达重组菌(用量以菌体干重计为20g/L)。反应在30℃、700rpm条件下开始后,每隔4h补加一次外消旋邻氯扁桃酸(100mM)和葡萄糖(100mM),共补加2次。反应每隔1h定时取样,样品用HCI(6.0M)终止反应,经离心(12000rpm、2min)、稀释、过膜后采用实施例1中的HPLC方法进行检测分析。反应过程中用3.0M的NaOH自动控制pH在7.0,反应完全后得到含有(R)-邻氯扁桃酸的转化液。催化反应进程如图7所示,最终300mM的外消旋邻氯扁桃酸在16h时被完全转化为光学纯(R)-邻氯扁桃酸,收率和e.e.值均大于99%,空时得率高达83.8g/(L·d)。(R)-邻氯扁桃酸是抗血栓药(氯吡格雷)合成的重要手性砌块,因此该催化反应具有重大的应用价值。
序列表
<110> 浙江工业大学
<120> 酮酸还原酶在合成手性芳香2-羟酸中的应用
<160> 16
<170> SIPOSequenceListing 1.0
<210> 1
<211> 954
<212> DNA
<213> 肠膜明串珠菌(Leuconostoc mesenteroides)
<400> 1
atgaaaatcg caattgccgg tttcggtgct ctgggcgcac gtctgggcgt gatgctgcaa 60
gccggtggtc atgaagtcac cggtattgac ggttggccgg cacacatcgc tgctatcaac 120
accaaaggcc tgaccgttgt taaagacaac gatgcaccgc agaaatactt cgtacctgta 180
atgccagctt ctgaggttac tggcactttc gatctgatca tcctgctgac caaaacccct 240
caactggacc gcatgctgac tgatatccag ccaatcatta ctgatactac taaactgctg 300
gttctgtcta acggtctggg taacatcgaa gtgatggcta aacacgtgtc ccgccaccag 360
atcctggccg gcgttacgct gtggacctct tctctgatca aaccgggtga aatccacgta 420
accggttctg gctctatcaa actgcaggct atcggtgacg cagacgtaca gtctattgct 480
gacgccctga accaggcagg tctgaacgct gaaatcactc ctgacgtcat gacggctatc 540
tggcataaag cgggcatcaa cgcggtactg aacccgctgt ccgtactgct gaatgcgaac 600
attgctgaat tcggcaccgc gggtaacgcg atggatctgg ctctgaacat cctggacgaa 660
atgaaacagg taggcgcttc tcagggtatc aaagtcgacg taagcggtat catgacggac 720
ctgtcccagc tgctgaagcc ggaaaatgct ggcaaccact ttccgtctat gtatcaagac 780
attcagaacg gtaaacgtac cgagatcgac ttcctgaacg gctacttcgc gaagattggc 840
cacgaatccg gtatcccgac tccgttcaac gcactggtta cgcgtctgat ccacgctaaa 900
gaggacatcg aacgcgttaa actggcgaaa cagcaagaga acttcgagat ctga 954
<210> 2
<211> 317
<212> PRT
<213> 肠膜明串珠菌(Leuconostoc mesenteroides)
<400> 2
Met Lys Ile Ala Ile Ala Gly Phe Gly Ala Leu Gly Ala Arg Leu Gly
1 5 10 15
Val Met Leu Gln Ala Gly Gly His Glu Val Thr Gly Ile Asp Gly Trp
20 25 30
Pro Ala His Ile Ala Ala Ile Asn Thr Lys Gly Leu Thr Val Val Lys
35 40 45
Asp Asn Asp Ala Pro Gln Lys Tyr Phe Val Pro Val Met Pro Ala Ser
50 55 60
Glu Val Thr Gly Thr Phe Asp Leu Ile Ile Leu Leu Thr Lys Thr Pro
65 70 75 80
Gln Leu Asp Arg Met Leu Thr Asp Ile Gln Pro Ile Ile Thr Asp Thr
85 90 95
Thr Lys Leu Leu Val Leu Ser Asn Gly Leu Gly Asn Ile Glu Val Met
100 105 110
Ala Lys His Val Ser Arg His Gln Ile Leu Ala Gly Val Thr Leu Trp
115 120 125
Thr Ser Ser Leu Ile Lys Pro Gly Glu Ile His Val Thr Gly Ser Gly
130 135 140
Ser Ile Lys Leu Gln Ala Ile Gly Asp Ala Asp Val Gln Ser Ile Ala
145 150 155 160
Asp Ala Leu Asn Gln Ala Gly Leu Asn Ala Glu Ile Thr Pro Asp Val
165 170 175
Met Thr Ala Ile Trp His Lys Ala Gly Ile Asn Ala Val Leu Asn Pro
180 185 190
Leu Ser Val Leu Leu Asn Ala Asn Ile Ala Glu Phe Gly Thr Ala Gly
195 200 205
Asn Ala Met Asp Leu Ala Leu Asn Ile Leu Asp Glu Met Lys Gln Val
210 215 220
Gly Ala Ser Gln Gly Ile Lys Val Asp Val Ser Gly Ile Met Thr Asp
225 230 235 240
Leu Ser Gln Leu Leu Lys Pro Glu Asn Ala Gly Asn His Phe Pro Ser
245 250 255
Met Tyr Gln Asp Ile Gln Asn Gly Lys Arg Thr Glu Ile Asp Phe Leu
260 265 270
Asn Gly Tyr Phe Ala Lys Ile Gly His Glu Ser Gly Ile Pro Thr Pro
275 280 285
Phe Asn Ala Leu Val Thr Arg Leu Ile His Ala Lys Glu Asp Ile Glu
290 295 300
Arg Val Lys Leu Ala Lys Gln Gln Glu Asn Phe Glu Ile
305 310 315
<210> 3
<211> 954
<212> DNA
<213> 乳酸明串珠菌(Leuconostoc lactis)
<400> 3
atgaaaatcg ctatcgctgg tttcggtgct ctgggtgctc gtctgggtat catgctgcag 60
gctgctggtc acgacgttac cggtatcgac ggttggccgg ctcacatcgc tgctatcaac 120
accaaaggtc tgaccgttgt tcacgacgac caggacccga aagtttacta cctgccggtt 180
atgaccccgc aggaagttac cggtaccttc gacctgatca tcctgctgac caaaaccccg 240
cagctggacc gtatgctgac cgacatcgct ccgatcatca ccgaccagac ccagctgctg 300
atcctgtcta acggtctggg taacatcgaa gttatggcta aacacgttgc taaatctcag 360
atcgttgctg gtgttaccct gtggacctct tctctggtta aaccgggtga aatccacacc 420
accggttctg gttctatcaa actgcaggct ctggctggtg gtgacgctca gccgatcgtt 480
gaagctctga acgaagctgg tctgaacgct gaactggttc cggacgttat gaccgctatc 540
tggcacaaag ctggtatcaa cgctgttctg aacccgctgt ctgttctgct ggacgctaac 600
atcgctgaat tcggtaccgc tggtaacgct atggacatgg ctctgaacat cctggacgaa 660
atgaaacagg ttggtgcttc tcagggtatc aaagttgacg ttgctggtat catcgctgac 720
ctgtctcgtc tgctgaaacc ggaaaacgct ggtaaccact acccgtctat gtaccaggac 780
atccagaacg gtaaacgtac cgaaatcgac ttcctgaacg gttacttcgc tcgtctgggt 840
cagcaggaag gtatcccgac cccgttcaac gctctggtta cccgtctgat ccacgctaaa 900
gaagacatcg ttcgtaccaa actggctaaa gaaaaagaaa acttcgaaat ctaa 954
<210> 4
<211> 317
<212> PRT
<213> 乳酸明串珠菌(Leuconostoc lactis)
<400> 4
Met Lys Ile Ala Ile Ala Gly Phe Gly Ala Leu Gly Ala Arg Leu Gly
1 5 10 15
Ile Met Leu Gln Ala Ala Gly His Asp Val Thr Gly Ile Asp Gly Trp
20 25 30
Pro Ala His Ile Ala Ala Ile Asn Thr Lys Gly Leu Thr Val Val His
35 40 45
Asp Asp Gln Asp Pro Lys Val Tyr Tyr Leu Pro Val Met Thr Pro Gln
50 55 60
Glu Val Thr Gly Thr Phe Asp Leu Ile Ile Leu Leu Thr Lys Thr Pro
65 70 75 80
Gln Leu Asp Arg Met Leu Thr Asp Ile Ala Pro Ile Ile Thr Asp Gln
85 90 95
Thr Gln Leu Leu Ile Leu Ser Asn Gly Leu Gly Asn Ile Glu Val Met
100 105 110
Ala Lys His Val Ala Lys Ser Gln Ile Val Ala Gly Val Thr Leu Trp
115 120 125
Thr Ser Ser Leu Val Lys Pro Gly Glu Ile His Thr Thr Gly Ser Gly
130 135 140
Ser Ile Lys Leu Gln Ala Leu Ala Gly Gly Asp Ala Gln Pro Ile Val
145 150 155 160
Glu Ala Leu Asn Glu Ala Gly Leu Asn Ala Glu Leu Val Pro Asp Val
165 170 175
Met Thr Ala Ile Trp His Lys Ala Gly Ile Asn Ala Val Leu Asn Pro
180 185 190
Leu Ser Val Leu Leu Asp Ala Asn Ile Ala Glu Phe Gly Thr Ala Gly
195 200 205
Asn Ala Met Asp Met Ala Leu Asn Ile Leu Asp Glu Met Lys Gln Val
210 215 220
Gly Ala Ser Gln Gly Ile Lys Val Asp Val Ala Gly Ile Ile Ala Asp
225 230 235 240
Leu Ser Arg Leu Leu Lys Pro Glu Asn Ala Gly Asn His Tyr Pro Ser
245 250 255
Met Tyr Gln Asp Ile Gln Asn Gly Lys Arg Thr Glu Ile Asp Phe Leu
260 265 270
Asn Gly Tyr Phe Ala Arg Leu Gly Gln Gln Glu Gly Ile Pro Thr Pro
275 280 285
Phe Asn Ala Leu Val Thr Arg Leu Ile His Ala Lys Glu Asp Ile Val
290 295 300
Arg Thr Lys Leu Ala Lys Glu Lys Glu Asn Phe Glu Ile
305 310 315
<210> 5
<211> 954
<212> DNA
<213> 假肠膜明串珠菌(Leuconostoc pseudomesenteroides)
<400> 5
atgaaaattg caattgcggg ttttggtgca ttgggtgcgc gagttggtgt aatgttgcaa 60
cgcgctggtc atgatgtaac tggtatagat ggctgggcag aacacattgc agcaatcaac 120
actaagggat tgactgtgac agaggatgac gggtcatcta aaaaatattt tattccagtc 180
atgacatcca aagaagttac tggtgaattt gatttggtga ttttattgac gaaaacgcca 240
caattggatc gtatgttaac tgatattcaa ccgcttatca caaaacaaac gcagttatta 300
gtcttgtcaa atggactagg taatgttgaa gtaatggcaa agcatgtgtc atcacaacaa 360
attattgctg gggtaacttt gtggacatct gatttggttc aacctggtga aattcatgtg 420
accggtacag gctccatcaa gttgcaagcg attgatcacg cagatattac cgctgttgtc 480
actgctttga atgaagcagg gcttaatgct gaggtatccg ataatgttgt agaagctatt 540
tggcataaag cgggcattaa ttctgtcctt aacccattga cagtcttact tgatgctaat 600
attgctgaat ttggcacagc agggaatggt atggatcttg cattgaacat tttagatgag 660
attaagcaag ttggtgacgt ggctggcgtt aatgtcgatg tgaatagtat tttaagcgat 720
ttgtcgaatt tgctaaaacc agaaaacgcg ggtaatcact acccatcaat gtaccaagat 780
attcaagctg gtaaacgaac tgaaatcgac tttttgaatg gctattttgc taaattggga 840
cgtgaaaatc atatcgccac accttttaat gcacttgtaa cacgattaat tcatgcaaaa 900
gaagatattg aacgtgttaa attggccaaa caacaagaaa cctttgaaat ttga 954
<210> 6
<211> 317
<212> PRT
<213> 假肠膜明串珠菌(Leuconostoc pseudomesenteroides)
<400> 6
Met Lys Ile Ala Ile Ala Gly Phe Gly Ala Leu Gly Ala Arg Val Gly
1 5 10 15
Val Met Leu Gln Arg Ala Gly His Asp Val Thr Gly Ile Asp Gly Trp
20 25 30
Ala Glu His Ile Ala Ala Ile Asn Thr Lys Gly Leu Thr Val Thr Glu
35 40 45
Asp Asp Gly Ser Ser Lys Lys Tyr Phe Ile Pro Val Met Thr Ser Lys
50 55 60
Glu Val Thr Gly Glu Phe Asp Leu Val Ile Leu Leu Thr Lys Thr Pro
65 70 75 80
Gln Leu Asp Arg Met Leu Thr Asp Ile Gln Pro Leu Ile Thr Lys Gln
85 90 95
Thr Gln Leu Leu Val Leu Ser Asn Gly Leu Gly Asn Val Glu Val Met
100 105 110
Ala Lys His Val Ser Ser Gln Gln Ile Ile Ala Gly Val Thr Leu Trp
115 120 125
Thr Ser Asp Leu Val Gln Pro Gly Glu Ile His Val Thr Gly Thr Gly
130 135 140
Ser Ile Lys Leu Gln Ala Ile Asp His Ala Asp Ile Thr Ala Val Val
145 150 155 160
Thr Ala Leu Asn Glu Ala Gly Leu Asn Ala Glu Val Ser Asp Asn Val
165 170 175
Val Glu Ala Ile Trp His Lys Ala Gly Ile Asn Ser Val Leu Asn Pro
180 185 190
Leu Thr Val Leu Leu Asp Ala Asn Ile Ala Glu Phe Gly Thr Ala Gly
195 200 205
Asn Gly Met Asp Leu Ala Leu Asn Ile Leu Asp Glu Ile Lys Gln Val
210 215 220
Gly Asp Val Ala Gly Val Asn Val Asp Val Asn Ser Ile Leu Ser Asp
225 230 235 240
Leu Ser Asn Leu Leu Lys Pro Glu Asn Ala Gly Asn His Tyr Pro Ser
245 250 255
Met Tyr Gln Asp Ile Gln Ala Gly Lys Arg Thr Glu Ile Asp Phe Leu
260 265 270
Asn Gly Tyr Phe Ala Lys Leu Gly Arg Glu Asn His Ile Ala Thr Pro
275 280 285
Phe Asn Ala Leu Val Thr Arg Leu Ile His Ala Lys Glu Asp Ile Glu
290 295 300
Arg Val Lys Leu Ala Lys Gln Gln Glu Thr Phe Glu Ile
305 310 315
<210> 7
<211> 954
<212> DNA
<213> 肠膜明串珠菌(Leuconostoc mesenteroides)
<400> 7
atgaaaatcg ctatcgctgg tttcggtgct ctgggtgctc gtgttggtgt tatgctgcag 60
caggctggtc acgaagttac cggtatcgac ggttgggctg ctcacatcgc tgctatctct 120
accgacggtc tgaccgttca ccaggacgac ggtgctacca aaaaatacta catcccggtt 180
atgaccgcta aagaaatcga cggtaaattc gacctgatca tcctgctgac caaaaccccg 240
cagctggaca tgatgctgac cgacatcaaa cacatcatca ccaaaaacac caaactgctg 300
gttctgtcta acggtctggg taacatcgaa gttatggaaa aacacgttaa ccgtaaccag 360
atcctggctg gtgttaccct gtggacctct gaactgatca acccgggtga aatccgtgtt 420
accggtaccg gttctatcaa actgcaggct atcggtgaag ctaacgctaa gccaatcgta 480
agcgctctga acaaagctgg tctgaacgtt accctgtctc agaacgttat cgaagctatc 540
tggcacaaag ctggtatcaa ctctgttctg aacccgctga ccgttctgct ggacgctaac 600
atcgctgaat tcggtatggc tggtaacggt atggacctgt ctctgaacat cctggacgaa 660
atcaaaaaaa tcggtgaact ggaaggtatc aacgttgacg ttaacgctat catgaaagac 720
ctggctctgc tgatccgtcc ggaaaacgct ggtaaccact acccgtctat gtaccaggac 780
atcaaagctg gtaaacacac cgaaatcgac ttcctgaacg gttacttcgc taaactgggt 840
tctgaacacg acgttgctat gccgttcaac gctctggtta cccgtctgat ccacgctaaa 900
gaagacatcg aacgtaccaa actggctaaa aaacaggaaa ccttcgaaat ctaa 954
<210> 8
<211> 317
<212> PRT
<213> 肠膜明串珠菌(Leuconostoc mesenteroides)
<400> 8
Met Lys Ile Ala Ile Ala Gly Phe Gly Ala Leu Gly Ala Arg Val Gly
1 5 10 15
Val Met Leu Gln Gln Ala Gly His Glu Val Thr Gly Ile Asp Gly Trp
20 25 30
Ala Ala His Ile Ala Ala Ile Ser Thr Asp Gly Leu Thr Val His Gln
35 40 45
Asp Asp Gly Ala Thr Lys Lys Tyr Tyr Ile Pro Val Met Thr Ala Lys
50 55 60
Glu Ile Asp Gly Lys Phe Asp Leu Ile Ile Leu Leu Thr Lys Thr Pro
65 70 75 80
Gln Leu Asp Met Met Leu Thr Asp Ile Lys His Ile Ile Thr Lys Asn
85 90 95
Thr Lys Leu Leu Val Leu Ser Asn Gly Leu Gly Asn Ile Glu Val Met
100 105 110
Glu Lys His Val Asn Arg Asn Gln Ile Leu Ala Gly Val Thr Leu Trp
115 120 125
Thr Ser Glu Leu Ile Asn Pro Gly Glu Ile Arg Val Thr Gly Thr Gly
130 135 140
Ser Ile Lys Leu Gln Ala Ile Gly Glu Ala Asn Ala Lys Pro Ile Val
145 150 155 160
Ser Ala Leu Asn Lys Ala Gly Leu Asn Val Thr Leu Ser Gln Asn Val
165 170 175
Ile Glu Ala Ile Trp His Lys Ala Gly Ile Asn Ser Val Leu Asn Pro
180 185 190
Leu Thr Val Leu Leu Asp Ala Asn Ile Ala Glu Phe Gly Met Ala Gly
195 200 205
Asn Gly Met Asp Leu Ser Leu Asn Ile Leu Asp Glu Ile Lys Lys Ile
210 215 220
Gly Glu Leu Glu Gly Ile Asn Val Asp Val Asn Ala Ile Met Lys Asp
225 230 235 240
Leu Ala Leu Leu Ile Arg Pro Glu Asn Ala Gly Asn His Tyr Pro Ser
245 250 255
Met Tyr Gln Asp Ile Lys Ala Gly Lys His Thr Glu Ile Asp Phe Leu
260 265 270
Asn Gly Tyr Phe Ala Lys Leu Gly Ser Glu His Asp Val Ala Met Pro
275 280 285
Phe Asn Ala Leu Val Thr Arg Leu Ile His Ala Lys Glu Asp Ile Glu
290 295 300
Arg Thr Lys Leu Ala Lys Lys Gln Glu Thr Phe Glu Ile
305 310 315
<210> 9
<211> 918
<212> DNA
<213> 产酸克雷伯菌(Klebsiella oxytoca)
<400> 9
atgaaaatcg ctatcgctgg tgctggtgct atgggttgcc gtttcggtta catgctgctg 60
ggtgctggtc acgacgttac cctgatcgac ggttggcacg aacacgttaa cgctatctgc 120
tctaacggtc tgttcgttga aaccgaagtt tctcagcagt actacccgat cccggctatg 180
ctggctgacg aatctcaggg tgaattcgaa ctgatcatcc tgttcaccaa agctatgcag 240
ctggaccgta tgctgcagca catcaaaccg ctgctgccgg ctgctaaagt tgttatgatc 300
ctgtctaacg gtctgggtaa catcgaaacc ctggaaaaat acgttgaccg tcagaaaatc 360
tacgctggtg ttaccctgtg gtcttctgaa ctggaaggtc cgggtcacat catggctacc 420
ggtaccggta ccatcgaact gcagccggtt gcttctcagg acgctgctct ggaagaaaac 480
atcgttgctg ttctgaactc tgctggtctg aacgctgaaa tctctccgga cgttctgctg 540
tctatctgga aaaaagctgc tttcaactct gttatgaaca cctactgcgc tctgctggac 600
tgcaacgttg gtggtttcgg tcagctgccg ggtgctctgg acctggctca ggctgttgtt 660
gacgaattcg ttctggttgc tgcttctcag aacatcccgc tgtctggtga acgtgttatg 720
aacaccgtta aaaaagtttt cgacccgcgt gaatctggtc accactaccc gtctatgtac 780
caggacctgc agaaaggtcg tctgaccgaa atcgactacc tgaacggtgc tatcgctcgt 840
atcggtatgc agaacaacat cccggttccg gttaacaccc tgctgaccca gctgatccac 900
gctaaagaag ctcagtaa 918
<210> 10
<211> 305
<212> PRT
<213> 产酸克雷伯菌(Klebsiella oxytoca)
<400> 10
Met Lys Ile Ala Ile Ala Gly Ala Gly Ala Met Gly Cys Arg Phe Gly
1 5 10 15
Tyr Met Leu Leu Gly Ala Gly His Asp Val Thr Leu Ile Asp Gly Trp
20 25 30
His Glu His Val Asn Ala Ile Cys Ser Asn Gly Leu Phe Val Glu Thr
35 40 45
Glu Val Ser Gln Gln Tyr Tyr Pro Ile Pro Ala Met Leu Ala Asp Glu
50 55 60
Ser Gln Gly Glu Phe Glu Leu Ile Ile Leu Phe Thr Lys Ala Met Gln
65 70 75 80
Leu Asp Arg Met Leu Gln His Ile Lys Pro Leu Leu Pro Ala Ala Lys
85 90 95
Val Val Met Ile Leu Ser Asn Gly Leu Gly Asn Ile Glu Thr Leu Glu
100 105 110
Lys Tyr Val Asp Arg Gln Lys Ile Tyr Ala Gly Val Thr Leu Trp Ser
115 120 125
Ser Glu Leu Glu Gly Pro Gly His Ile Met Ala Thr Gly Thr Gly Thr
130 135 140
Ile Glu Leu Gln Pro Val Ala Ser Gln Asp Ala Ala Leu Glu Glu Asn
145 150 155 160
Ile Val Ala Val Leu Asn Ser Ala Gly Leu Asn Ala Glu Ile Ser Pro
165 170 175
Asp Val Leu Leu Ser Ile Trp Lys Lys Ala Ala Phe Asn Ser Val Met
180 185 190
Asn Thr Tyr Cys Ala Leu Leu Asp Cys Asn Val Gly Gly Phe Gly Gln
195 200 205
Leu Pro Gly Ala Leu Asp Leu Ala Gln Ala Val Val Asp Glu Phe Val
210 215 220
Leu Val Ala Ala Ser Gln Asn Ile Pro Leu Ser Gly Glu Arg Val Met
225 230 235 240
Asn Thr Val Lys Lys Val Phe Asp Pro Arg Glu Ser Gly His His Tyr
245 250 255
Pro Ser Met Tyr Gln Asp Leu Gln Lys Gly Arg Leu Thr Glu Ile Asp
260 265 270
Tyr Leu Asn Gly Ala Ile Ala Arg Ile Gly Met Gln Asn Asn Ile Pro
275 280 285
Val Pro Val Asn Thr Leu Leu Thr Gln Leu Ile His Ala Lys Glu Ala
290 295 300
Gln
305
<210> 11
<211> 918
<212> DNA
<213> 肠道沙门氏菌(Salmonella enterica)
<400> 11
atgaaaattg caatcgcagg tgcaggcgct atggggtgtc gttttggcta tatgctgctg 60
gaggccgggc acgacgtgac gcttatcgat agctggcagg agcatgtcga cgctattcgt 120
agcaaggggt tgtttgtcga aacggaaacg acgcagaagt attaccccat ccctgctatg 180
ttggctgatg aatcccaggg ggagtttgag ctggttattc tgtttaccaa agccatgcag 240
ttggatagca tgttacagcg tatcaagcca ttactgccag ccgcgaaagt cgtgatgatt 300
ctatctaacg gtctgggaaa tattgaaacg ctggagaaat atgtcgatcg gcataaaatc 360
tatgcgggtg tgacgttatg gtccagcgaa ctggaggggg ctgggcatat tatggccacc 420
ggtaccggaa cgattgaact gcagccgatt gccagccagg attcggctca agaggctaag 480
gtcattgcca cccttaatag cgctggattg aatgctgaaa taagccctga cgtattatta 540
tcgatctgga agaaagcagc ctttaatagc gtaatgaaca cctattgcgc gctactggat 600
tgtaatatcg gcggatttgg tcagcggcct ggtgctttag atttagcgca agccgtagtt 660
gatgagtttg tgttagttgc tgccagccag aatatttcgt tgactgagca aatggtgatg 720
aatacggtga agaaagtgtt cgatccgcgt gagagcggcc accactatcc ttctatgcat 780
caggatttac ataaaggccg actgactgaa atcgactatt taaatggtgc gattgcgcga 840
atcggcgttc agaacaatat tgccgtaccg gttaacacac tcctgacgca attgattcac 900
gctaaagaag cgcaataa 918
<210> 12
<211> 305
<212> PRT
<213> 肠道沙门氏菌(Salmonella enterica)
<400> 12
Met Lys Ile Ala Ile Ala Gly Ala Gly Ala Met Gly Cys Arg Phe Gly
1 5 10 15
Tyr Met Leu Leu Glu Ala Gly His Asp Val Thr Leu Ile Asp Ser Trp
20 25 30
Gln Glu His Val Asp Ala Ile Arg Ser Lys Gly Leu Phe Val Glu Thr
35 40 45
Glu Thr Thr Gln Lys Tyr Tyr Pro Ile Pro Ala Met Leu Ala Asp Glu
50 55 60
Ser Gln Gly Glu Phe Glu Leu Val Ile Leu Phe Thr Lys Ala Met Gln
65 70 75 80
Leu Asp Ser Met Leu Gln Arg Ile Lys Pro Leu Leu Pro Ala Ala Lys
85 90 95
Val Val Met Ile Leu Ser Asn Gly Leu Gly Asn Ile Glu Thr Leu Glu
100 105 110
Lys Tyr Val Asp Arg His Lys Ile Tyr Ala Gly Val Thr Leu Trp Ser
115 120 125
Ser Glu Leu Glu Gly Ala Gly His Ile Met Ala Thr Gly Thr Gly Thr
130 135 140
Ile Glu Leu Gln Pro Ile Ala Ser Gln Asp Ser Ala Gln Glu Ala Lys
145 150 155 160
Val Ile Ala Thr Leu Asn Ser Ala Gly Leu Asn Ala Glu Ile Ser Pro
165 170 175
Asp Val Leu Leu Ser Ile Trp Lys Lys Ala Ala Phe Asn Ser Val Met
180 185 190
Asn Thr Tyr Cys Ala Leu Leu Asp Cys Asn Ile Gly Gly Phe Gly Gln
195 200 205
Arg Pro Gly Ala Leu Asp Leu Ala Gln Ala Val Val Asp Glu Phe Val
210 215 220
Leu Val Ala Ala Ser Gln Asn Ile Ser Leu Thr Glu Gln Met Val Met
225 230 235 240
Asn Thr Val Lys Lys Val Phe Asp Pro Arg Glu Ser Gly His His Tyr
245 250 255
Pro Ser Met His Gln Asp Leu His Lys Gly Arg Leu Thr Glu Ile Asp
260 265 270
Tyr Leu Asn Gly Ala Ile Ala Arg Ile Gly Val Gln Asn Asn Ile Ala
275 280 285
Val Pro Val Asn Thr Leu Leu Thr Gln Leu Ile His Ala Lys Glu Ala
290 295 300
Gln
305
<210> 13
<211> 1188
<212> DNA
<213> 铜绿假单胞菌(Pseudomonas aeruginosa)
<400> 13
atgtctcaga acctgttcaa cgttgaagac taccgtaaac tggctcagaa acgtctgccg 60
aaaatggttt acgactacct ggaaggtggt gctgaagacg aatacggtgt taaacacaac 120
cgtgacgttt tccagcagtg gcgtttcaaa ccaaagaggt tagttgacgt atcgcgtcgt 180
tctctgcagg ctgaagttct gggtaaacgt cagtctatgc cgctgctgat cggtccgacc 240
ggtctgaacg gtgctctgtg gccgaaaggt gacctggctc tggctcaggc tgctaccaaa 300
gctggtatcc cgttcgttct gtctaccgct tctaacatgt ctatcgaaga cctggctcgt 360
cagtgcgacg gtgacctgtg gttccagctg tacgttatcc accgtgaaat cgctcagggt 420
atggttctga aagctctgca ctctggttac accaccctgg ttctgaccac cgacgttgct 480
gttaacggtt accgtgaacg tgacctgcac aaccgtttca aaatgccgat gtcttacacc 540
ccgaaagtta tgctggacgg ttgcctgcac ccgcgttggt ctctggacct ggttcgtcac 600
ggtatgccgc agctggctaa cttcgtttct tctcagacct cttctctgga aatgcaggct 660
gctctgatgt ctaggcagat ggacgctagc ttcaactggg aagcgctgcg ttggctgcgt 720
gacctgtggc cgcacaaact gctggttaaa ggtctgctgt ctgctgaaga cgctgaccac 780
tgcatcgctg aaggtgctga cggtgttatc ctgtctaacc acggtggtcg tcagctggac 840
tgcgctgttt ctccgatgga agttctggct cagtctgttg ctaaaaccgg taaaccggtt 900
ctgatcgact ctggtttccg tcgtggttct gacatcgtta aagctctggc tctgggtgct 960
gaagctgttc tgctgggtcg tgctaccctg tacggtctgg ctgctcgtgg tgaaaccggt 1020
gttgacgaag ttctgaccct gctgaaagct gacatcgacc gtaccctggc tcagatcggt 1080
tgcccggaca tcacctctct gtctccggac tacctgcagt ctgaaggtgt tacctctacc 1140
gctccggttg accacctgat cggtaaaggt acccacgctc tcgagtga 1188
<210> 14
<211> 395
<212> PRT
<213> 铜绿假单胞菌(Pseudomonas aeruginosa)
<400> 14
Met Ser Gln Asn Leu Phe Asn Val Glu Asp Tyr Arg Lys Leu Ala Gln
1 5 10 15
Lys Arg Leu Pro Lys Met Val Tyr Asp Tyr Leu Glu Gly Gly Ala Glu
20 25 30
Asp Glu Tyr Gly Val Lys His Asn Arg Asp Val Phe Gln Gln Trp Arg
35 40 45
Phe Lys Pro Lys Arg Leu Val Asp Val Ser Arg Arg Ser Leu Gln Ala
50 55 60
Glu Val Leu Gly Lys Arg Gln Ser Met Pro Leu Leu Ile Gly Pro Thr
65 70 75 80
Gly Leu Asn Gly Ala Leu Trp Pro Lys Gly Asp Leu Ala Leu Ala Gln
85 90 95
Ala Ala Thr Lys Ala Gly Ile Pro Phe Val Leu Ser Thr Ala Ser Asn
100 105 110
Met Ser Ile Glu Asp Leu Ala Arg Gln Cys Asp Gly Asp Leu Trp Phe
115 120 125
Gln Leu Tyr Val Ile His Arg Glu Ile Ala Gln Gly Met Val Leu Lys
130 135 140
Ala Leu His Ser Gly Tyr Thr Thr Leu Val Leu Thr Thr Asp Val Ala
145 150 155 160
Val Asn Gly Tyr Arg Glu Arg Asp Leu His Asn Arg Phe Lys Met Pro
165 170 175
Met Ser Tyr Thr Pro Lys Val Met Leu Asp Gly Cys Leu His Pro Arg
180 185 190
Trp Ser Leu Asp Leu Val Arg His Gly Met Pro Gln Leu Ala Asn Phe
195 200 205
Val Ser Ser Gln Thr Ser Ser Leu Glu Met Gln Ala Ala Leu Met Ser
210 215 220
Arg Gln Met Asp Ala Ser Phe Asn Trp Glu Ala Leu Arg Trp Leu Arg
225 230 235 240
Asp Leu Trp Pro His Lys Leu Leu Val Lys Gly Leu Leu Ser Ala Glu
245 250 255
Asp Ala Asp His Cys Ile Ala Glu Gly Ala Asp Gly Val Ile Leu Ser
260 265 270
Asn His Gly Gly Arg Gln Leu Asp Cys Ala Val Ser Pro Met Glu Val
275 280 285
Leu Ala Gln Ser Val Ala Lys Thr Gly Lys Pro Val Leu Ile Asp Ser
290 295 300
Gly Phe Arg Arg Gly Ser Asp Ile Val Lys Ala Leu Ala Leu Gly Ala
305 310 315 320
Glu Ala Val Leu Leu Gly Arg Ala Thr Leu Tyr Gly Leu Ala Ala Arg
325 330 335
Gly Glu Thr Gly Val Asp Glu Val Leu Thr Leu Leu Lys Ala Asp Ile
340 345 350
Asp Arg Thr Leu Ala Gln Ile Gly Cys Pro Asp Ile Thr Ser Leu Ser
355 360 365
Pro Asp Tyr Leu Gln Ser Glu Gly Val Thr Ser Thr Ala Pro Val Asp
370 375 380
His Leu Ile Gly Lys Gly Thr His Ala Leu Glu
385 390 395
<210> 15
<211> 786
<212> DNA
<213> 西伯利亚微杆菌(Exiguobacterium sibiricum )
<400> 15
atgtataatt ctctgaaagg caaagtcgcg attgttactg gtggtagcat gggcattggc 60
gaagcgatca tccgtcgcta tgcagaagaa ggcatgcgcg ttgttatcaa ctatcgtagc 120
catccggagg aagccaaaaa gatcgccgaa gatattaaac aggcaggtgg tgaagccctg 180
accgtccagg gtgacgtttc taaagaggaa gacatgatca acctggtgaa acagactgtt 240
gatcacttcg gtcagctgga cgtctttgtg aacaacgctg gcgttgagat gccttctccg 300
tcccacgaaa tgtccctgga agactggcag aaagtgatcg atgttaatct gacgggtgcg 360
ttcctgggcg ctcgtgaagc tctgaaatac ttcgttgaac ataacgtgaa aggcaacatt 420
atcaatatgt ctagcgtcca cgaaatcatc ccgtggccta ctttcgtaca ttacgctgct 480
tctaagggtg gcgttaaact gatgacccag actctggcta tggaatatgc accgaaaggt 540
atccgcatta acgctatcgg tccaggcgcg atcaacactc caattaatgc agaaaaattc 600
gaggatccga aacagcgtgc agacgtggaa agcatgatcc cgatgggcaa catcggcaag 660
ccagaggaga tttccgctgt cgcggcatgg ctggcttctg acgaagcgtc ttacgttacc 720
ggcatcaccc tgttcgcaga tggtggcatg accctgtacc cgagctttca ggctggccgt 780
ggttga 786
<210> 16
<211> 261
<212> PRT
<213> 西伯利亚微杆菌(Exiguobacterium sibiricum )
<400> 16
Met Tyr Asn Ser Leu Lys Gly Lys Val Ala Ile Val Thr Gly Gly Ser
1 5 10 15
Met Gly Ile Gly Glu Ala Ile Ile Arg Arg Tyr Ala Glu Glu Gly Met
20 25 30
Arg Val Val Ile Asn Tyr Arg Ser His Pro Glu Glu Ala Lys Lys Ile
35 40 45
Ala Glu Asp Ile Lys Gln Ala Gly Gly Glu Ala Leu Thr Val Gln Gly
50 55 60
Asp Val Ser Lys Glu Glu Asp Met Ile Asn Leu Val Lys Gln Thr Val
65 70 75 80
Asp His Phe Gly Gln Leu Asp Val Phe Val Asn Asn Ala Gly Val Glu
85 90 95
Met Pro Ser Pro Ser His Glu Met Ser Leu Glu Asp Trp Gln Lys Val
100 105 110
Ile Asp Val Asn Leu Thr Gly Ala Phe Leu Gly Ala Arg Glu Ala Leu
115 120 125
Lys Tyr Phe Val Glu His Asn Val Lys Gly Asn Ile Ile Asn Met Ser
130 135 140
Ser Val His Glu Ile Ile Pro Trp Pro Thr Phe Val His Tyr Ala Ala
145 150 155 160
Ser Lys Gly Gly Val Lys Leu Met Thr Gln Thr Leu Ala Met Glu Tyr
165 170 175
Ala Pro Lys Gly Ile Arg Ile Asn Ala Ile Gly Pro Gly Ala Ile Asn
180 185 190
Thr Pro Ile Asn Ala Glu Lys Phe Glu Asp Pro Lys Gln Arg Ala Asp
195 200 205
Val Glu Ser Met Ile Pro Met Gly Asn Ile Gly Lys Pro Glu Glu Ile
210 215 220
Ser Ala Val Ala Ala Trp Leu Ala Ser Asp Glu Ala Ser Tyr Val Thr
225 230 235 240
Gly Ile Thr Leu Phe Ala Asp Gly Gly Met Thr Leu Tyr Pro Ser Phe
245 250 255
Gln Ala Gly Arg Gly
260
Claims (8)
1.一种酮酸还原酶在催化合成手性芳香2-羟酸中的应用,其特征在于所述酮酸还原酶氨基酸序列为SEQ ID NO.10所示。
2.如权利要求1所述的应用,其特征在于所述酮酸还原酶的编码基因的核苷酸序列为SEQ ID NO.9所示。
3.如权利要求1所述的应用,其特征在于所述的应用方法为:以含酮酸还原酶编码基因的工程菌发酵培养获得的湿菌体经超声破碎后的酮酸还原酶上清液和含葡萄糖脱氢酶编码基因的工程发酵培养获得的湿菌体经超声破碎后的葡萄糖脱氢酶上清液为催化剂,以苯乙酮酸为底物,以葡萄糖为辅助底物,以NAD+为辅酶,以100mM、pH7.0的KH2PO4-K2HPO4缓冲液为反应介质,在35℃、700rpm条件下反应,反应完全后,获得含(R)-扁桃酸的反应液;所述酮酸还原酶上清液用量以酮酸还原酶酶活计为800U/mL缓冲液,所述葡萄糖脱氢酶上清液用量以葡萄糖脱氢酶酶活计为800U/mL缓冲液,所述葡萄糖用量以缓冲液体积计为200~800mM,所述底物用量以缓冲液体积计为100~400mM,NAD+用量以缓冲液体积计为0.5mM。
4.如权利要求1所述的应用,其特征在于所述的应用方法为:以含酮酸还原酶、2-羟酸脱氢酶和葡萄糖脱氢酶编码基因的工程菌经发酵培养获得的湿菌体为催化剂,以外消旋芳香2-羟酸为底物,以葡萄糖为辅底物,以pH6.0~8.0的缓冲液为反应介质构成反应体系,在20~45℃、700rpm条件下反应完全后,得到含有光学纯芳香(R)-2-羟酸的转化液。
5.如权利要求4所述的应用,其特征在于所述外消旋芳香2-羟酸为下列之一:扁桃酸、2-氟扁桃酸、4-氟扁桃酸、2,4-二氟扁桃酸、3,5-二氟扁桃酸、2-氯扁桃酸、3-氯扁桃酸、4-氯扁桃酸、2-溴扁桃酸、3-溴扁桃酸、4-溴扁桃酸、4-甲基扁桃酸、4-三氟甲基扁桃酸、3-羟基扁桃酸、4-羟基扁桃酸、4-甲氧基扁桃酸、3-甲氧基-4-羟基扁桃酸、3-羟基-4-甲基扁桃酸、3-羟基-4-三氟甲基扁桃酸、3-甲基-4-甲氧基扁桃酸。
6.如权利要求4所述的应用,其特征在于所述反应体系中,底物终浓度为20-300mM,所述辅底物浓度为10-300mM,所述催化剂用量以湿菌体干重计为4-20g/L。
7.如权利要求4所述的应用,其特征在于所述工程菌是将酮酸还原酶、2-羟酸脱氢酶和葡萄糖脱氢酶的编码基因共同导入宿主菌构建而成;所述2-羟酸脱氢酶的编码基因核苷酸序列为SEQ ID NO.13所示,所述葡萄糖脱氢酶的编码基因核苷酸序列为SEQ ID NO.15所示。
8.如权利要求4所述的应用,其特征在于所述催化剂按如下方法制备:将含酮酸还原酶、2-羟酸脱氢酶和葡萄糖脱氢酶编码基因的工程菌接种到含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养8~10h,获得种子液;将种子液按体积浓度2%的接种量接入含50μg/mL卡那霉素和50μg/mL链霉素的LB液体培养基中,于37℃、150rpm条件下振荡培养至OD600达到0.4~0.8,加入IPTG至终浓度为0.1mM,于28℃、150rpm条件下振荡培养10~12h,离心收集湿菌体并用生理盐水洗涤两次,即得湿菌体。
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