CN103184182A - 青霉素酰化酶、其高产菌株及应用 - Google Patents
青霉素酰化酶、其高产菌株及应用 Download PDFInfo
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- CN103184182A CN103184182A CN2013101248137A CN201310124813A CN103184182A CN 103184182 A CN103184182 A CN 103184182A CN 2013101248137 A CN2013101248137 A CN 2013101248137A CN 201310124813 A CN201310124813 A CN 201310124813A CN 103184182 A CN103184182 A CN 103184182A
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- penicillin acylase
- ala
- penicillin
- gly
- acylase
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Abstract
本发明提供青霉素酰化酶、其高产菌株及应用，属于生物制药领域。菌株为木糖氧化无色杆菌（Achromobacter xylosoxidans）K18，保藏号为CCTCC NO：M2012541。通过发酵菌株K18，得到青霉素酰化酶。所述青霉素酰化酶，氨基酸序列如SEQIDNO：2，基因序列如SEQIDNO：1。本发明还提供青霉素酰化酶在合成β-内酰胺类抗生素中的应用。菌株K18是青霉素酰化酶的高产菌，以含有诱导剂的培养基进行发酵时，青霉素酰化酶的产量可达200U/L以上。菌株K18所产青霉素酰化酶耐高温、在酸性环境下能保持较高活力、底物特异性较高、有机溶剂耐受性强等优点。
Description
技术领域
本发明属于生物制药技术领域，具体涉及青霉素酰化酶、其高产菌株及应用。
背景技术
青霉素酰化酶（penicillin acylase，EC3.5.1.11）又称为青霉素酰胺酶或青霉素氨基水解酶，是β-内酰胺抗生素酰基转移酶家族的一个亚类。这类酶是目前为数不多的已被大规模工业化应用的重要酶。
青霉素酰化酶在医药工业中发挥着重要的作用，主要应用于半合成青霉素和头孢菌素类的工业生产中，可以催化制备高效、广谱、适用于不同用途的新型β-内酰胺抗生素。该酶一方面可以催化青霉素或头孢霉素水解，得到半合成抗生素的重要中间体6-氨基青霉烷酸（6-APA）和7-氨基头孢霉烷酸（7-ACA）；另一方面可以催化酰化反应由6-APA合成新型青霉素或由7-ACA合成新型头孢霉素。此外，青霉素酰化酶作为一种生物催化剂应用于许多有潜在价值的反应中，如在肽的合成过程中用于保护氨基和羟基，以及用于拆分手性化合物的外消旋混合物等。
β-内酰胺类抗生素是临床上十分重要的一类抗生素，但是由于其大规模使用也带来了一些负面影响，滥用抗生素导致越来越多的细菌对其产生耐药性，克服这个问题的一个重要方法就是开发和使用新的半合成抗生素。与传统的化学半合成法相比，酶法制备β-内酰胺类抗生素不仅可以减少反应步骤，而且还可减少废弃物的产生，有利于保护环境，降低生产成本，产品易分离且质量优异，所含杂质极少。因此，随着人们对β-内酰胺抗生素的酶法合成深入研究，相关的工业技术快速发展，人类对自身生存环境状况日益重视，β-内酰胺抗生素的酶法合成将是21世纪 β-内酰胺抗生素发展的必然趋势之一。
尽管青霉素酰化酶的研究已开展多年并取得重要进展，但基础性的深入研究和大规模工业生产应用所必需的优良酶类仍然缺乏，因此筛选性能更优越的青霉素酰化酶及其高产菌株对酶法催化半合成β-内酰胺类抗生素具有重要意义。
发明内容
本发明的目的是提供青霉素酰化酶高产菌株。
本发明的另一目的是提供利用所述菌株制备青霉素酰化酶的方法。
本发明的再一目的是提供所述菌株产生的青霉素酰化酶的氨基酸序列及基因序列。
为了实现本发明的目的，本发明首先从南京、苏州等地药厂周边土壤中筛选获得青霉素酰化酶高产菌株，该菌株为木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18，其保藏登记号为CCTCC NO：M 2012541。
本发明对木糖氧化无色杆菌（Achromobacter xylosoxidans）K18的生物学特征进行鉴定，该菌株为革兰氏阴性菌株，无芽孢，菌落呈淡黄色，轻微隆起，圆形，边缘整齐，湿润、半透明、光滑；显微镜观察菌体为杆菌，0.5～1.2×0.5～2.6μm，专性好氧，最适生长温度为28℃～37℃。其生理生化特性表现在：过氧化氢酶反应、氧化酶反应、硝酸还原反应结果为阳性，明胶反应结果为阴性，有动力，氧化木糖产酸，可利用木糖、果糖、甘露糖等，不可利用海藻糖、甘露醇、阿拉伯糖。
经BIOLOG全自动细菌鉴定仪鉴定，该菌与Achromobacter属的Sim值为0.747；后经16S rDNA序列分析，结果表明该菌株与多株Achromobacter
xylosoxidans菌的同源性为99%。综合BIOLOG和16S rDNA分析结果，该菌株鉴定为木糖氧化无色杆菌（Achromobacter xylosoxidans），命名为木糖氧化无色杆菌（Achromobacter xylosoxidans） K18。
一种利用所述菌株制备青霉素酰化酶的方法，通过发酵木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18，得到青霉素酰化酶。
发酵木糖氧化无色杆菌（Achromobacter xylosoxidans）K18采用的培养基中含有诱导剂，所述诱导剂选自苯甲酸、苯乙酸、4-羟基苯乙酸、苯氧乙酸、苯丙酸和苯甘氨酸中的一种或两种以上。
所述诱导剂浓度为1-4 g/L。
所述培养基的碳源为甘油，氮源为酵母粉、蛋白胨或其混合物，表面活性剂为Span-20、Tween 80和Triton X-100中的一种或两种以上；所述培养基中碳源浓度为5～25
g/L，氮源浓度为7.5～15g/L，表面活性剂浓度为0.1～1 mL/L。
发酵培养条件为：发酵温度为25～30 ˚C，摇床转速为150-200 rpm，250
mL三角瓶中培养基的装液量30-50 mL，发酵时间为40～60h。
一种所述菌株产生的青霉素酰化酶，其氨基酸序列如SEQ ID NO：2所示。
编码所述青霉素酰化酶的基因，其序列如SEQ ID NO：1所示。DNA全序列分析结果表明，该青霉素酰化酶基因全长2532个核苷酸，编码843个氨基酸，与Achromobacter
xylosoxidans A8青霉素酰化酶基因同源性为86%，氨基酸序列同源性为 85%。
本发明对该青霉素酰化酶粗酶进行了酶学性质的研究，实验证明该青霉素酰化酶对多种有机溶剂都具有良好的耐受性，并且耐受浓度高达40%（V/V）以上，在多元醇和疏水性有机溶剂中青霉素酰化酶的稳定性提高，半衰期延长；甲醇、DMSO处理24h，其酶活可维持在50%以上；该青霉素酰化酶的最适反应pH为8.0，在pH 5.0～8.5的范围具有较高的稳定性；其最佳反应温度为45℃，60℃处理2小时，其酶活还维持在70%以上，表明其具有良好的热稳定性。该酶最适反应底物是青霉素G。
本发明还提供青霉素酰化酶在合成β-内酰胺类抗生素中的应用。所述青霉素酰化酶在非水相体系中合成以6-青霉素烷酸为母核的β-内酰胺类抗生素。
所述的非水相酶催化反应是以6-氨基青霉烷酸（6-APA）和酰基供体为原料，在青霉素酰化酶的催化作用下进行缩合反应，形成以6-APA为母核的β-内酰胺类抗生素。所述的6-APA与酰基供体的摩尔比为1：1～1：3，其中6-APA的浓度为10～80mmol/L，酰基供体的浓度为10～240 mmol/L。所述的非水相体系为亲水性有机溶剂和水组成的混合溶剂，所述亲水性有机溶剂选自甲醇、丙三醇、乙二醇、聚乙二醇、1,2-丙二醇、1,4-丁二醇中的任意一种，其体积百分含量为5～80%。所述的酰基供体为羧酸及其甲酯、酰胺、酸酐等，所述羧酸可以为脂肪酸或芳香酸。
本发明的有益效果在于：木糖氧化无色杆菌（Achromobacter xylosoxidans）K18是青霉素酰化酶的高产菌。采用该菌株，以含有诱导剂的培养基进行发酵时，青霉素酰化酶的产量可达200U/L以上。木糖氧化无色杆菌（Achromobacter xylosoxidans）K18所产青霉素酰化酶耐高温、在酸性环境下能保持较高活力、底物特异性较高、有机溶剂耐受性强等优点。该青霉素酰化酶在非水相中成功催化合成β-内酰胺类抗生素，进一步证明该酶在有机溶剂催化反应所表现的优良性质，为后续研究非水相催化合成新型β-内酰胺类抗生素提供了有益前提。
附图说明
图1显示青霉素酰化酶K18的最适反应pH。
图2显示青霉素酰化酶K18的pH稳定性（在各pH条件下放置2h后的剩余酶活）。
图3显示青霉素酰化酶K18的最适反应温度。
图4显示青霉素酰化酶K18的温度稳定性（在各温度条件下放置2h后的剩余酶活）。
图5显示青霉素酰化酶K18的底物特异性。
图6显示40%有机溶剂对青霉素酰化酶K18的影响。所用有机溶剂为丙三醇（●）、乙二醇（▲）、聚乙二醇（▼）、1,4-丁二醇（×）、甲醇（▶）、叔丁醇（◀）、DMSO（
）、DMF（★）、正己烷（﹡）、二甲醚（◆）、对照（■）。
具体实施方式
实施例一
本实施例说明产青霉素酰化酶天然菌株的筛选程序。
初筛采用如下方法：以高浓度青霉素G为筛选压力从南京、苏州药厂周边土壤等样品中筛选获得耐高浓度青霉素微生物。具体筛选培养基的配方为：酵母膏5 g/L，蛋白胨 5 g/L，NaCl 2 g/L，苯乙酸2 g/L，青霉素 105～107U/ml ，pH
7.0，溶剂为水。培养温度为30℃，培养时间为24～48 h，摇床转速为180 rmp。此方法可筛选到大量耐高浓度青霉素微生物。
将初筛获得的菌株进行复筛，具体方法如下：用50mM磷酸缓冲液（pH7.5）配制浓度为2mg/ml的3-苯乙酰胺-6-硝基苯甲酸（缩写为NIPAB，下同）溶液，并加到透明的48孔板中。将初筛获得的菌株挑到48孔板中，以不加菌株的为空白对照，37℃反应，直接观察反应液的颜色变化。如果反应液变为黄色，说明孔中有青霉素酰化酶产生菌株。将青霉素酰化酶产生菌株接种到产酶发酵培养基，具体配方为：酵母膏5 g/L，蛋白胨 5 g/L，NaCl 2 g/L，苯乙酸2 g/L ，pH 7.0，溶剂为水。培养温度为30℃，培养时间为48 h，摇床转速为180 rmp。发酵结束后，取发酵液于8000 rpm、4℃离心10 min，弃上清，取菌体用与发酵液相同体积的50mM磷酸缓冲液（pH7.5）重悬，超声破碎细胞后，于12,000 rpm、4℃离心10 min，取上清为粗酶液。测定粗酶液的青霉素酰化酶活力，选取粗酶液活力最高的菌株作为产青霉素酰化酶菌株。通过上述方法，发明人获得了一株青霉素酰化酶产生菌株K18，采用产酶发酵培养基发酵培养后，青霉素酰化酶活力达到104.7U/L。
青霉素酰化酶活力检测方法（以NIPAB为底物）为：用50mM磷酸缓冲液（pH7.5）配制浓度为2mg/ml的NIPAB底物溶液。反应体系中先加入100µL酶液，再加入100µL底物溶液，在酶标仪中进行反应，反应温度为37℃，反应时间为4min，在405 nm波长下检测反应结束时生成的3-氨基-6-硝基苯甲酸（ANBA）的量。以煮沸灭活的酶液为空白对照。每1个单位（U）青霉素酰化酶定义为，在相应条件下，每分钟催化水解NIPAB分解产生1 µmol ANBA所需的酶量。
实施例二
本实施例说明青霉素酰化酶产生菌株K18的生物学性质、鉴定。
菌株K18的生物学性质：该菌株为革兰氏阴性菌株，无芽孢，菌落呈淡黄色，轻微隆起，圆形，边缘整齐，湿润、半透明、光滑；显微镜观察菌体为杆菌，0.5～1.2×0.5～2.6μm，专性好氧，最适生长温度为28℃～37℃。其生理生化特性表现在：过氧化氢酶反应、氧化酶反应、硝酸还原反应结果为阳性，明胶反应结果为阴性，有动力，氧化木糖产酸，可利用木糖、果糖、甘露糖等，不可利用海藻糖、甘露醇、阿拉伯糖。
经BIOLOG全自动细菌鉴定仪鉴定，菌株K18与Achromobacter属的Sim值为0.747。经16S rDNA序列分析，结果表明菌株K18与多株Achromobacter
xylosoxidans菌的同源性为99%。综合BIOLOG和16S rDNA分析结果，菌株K18鉴定为木糖氧化无色杆菌（Achromobacter
xylosoxidans），命名为木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18。
木糖氧化无色杆菌（Achromobacter xylosoxidans）K18，已经保藏。分类命名为Achromobacter
xylosoxidans K18保藏日期为2012年12月21日，保藏单位全称为中国典型培养物保藏中心，简称CCTCC，保藏单位地址：武汉大学，保藏登记号为：CCTCC
NO：M 2012541。
实施例三
本实施例说明木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18发酵产酶方法。
平板培养基配方：：酵母粉5 g/L，蛋白胨10
g/L，NaCl 10 g/L，琼脂1.8～2.0 g/L，pH 7.0，溶剂为水。
种子培养基配方：酵母粉5 g/L，蛋白胨10
g/L，NaCl 10 g/L，pH 7.0，溶剂为水。
种子液的制备：250 mL三角瓶中种子培养基的装液量为30 mL。刮取平板培养24 h的菌株K18，接入种子培养基中，摇床转速为180 rmp，培养温度为30℃，培养时间为8～10h，得到种子液。
方法1
产酶发酵培养基配方：甘油5 g/L，酵母粉7.5 g/L，NaCl 2 g/L，Triton X-100 0.25 mL/L，苯乙酸1g/L，pH 6.0，溶剂为水。
250
mL三角瓶中产酶发酵培养基的装液量30mL。将种子液接种产酶发酵培养基，接种量为5%（V/V），发酵温度28 ˚C，摇床转速150rpm，发酵时间为60h。
粗酶液（制备方法同实施例一）中青霉素酰化酶活力为222.3U/L。
方法2
产酶发酵培养基配方：甘油25 g/L，酵母粉15 g/L，NaCl 5g/L， Span-20 0.75 mL/L，苯乙酸4 g/L
培养基的pH7.2，溶剂为水。
250
mL三角瓶中产酶发酵培养的装液量50mL。将种子液接种产酶发酵培养基，接种量为5%（V/V），发酵温度30 ˚C，摇床转速200rpm，发酵时间为52h。
粗酶液（制备方法同实施例一）中青霉素酰化酶活力为233.6U/L。
方法3
产酶发酵培养基配方：甘油15 g/L，酵母粉12 g/L，NaCl 4 g/L， Span-20 0. 5 mL/L，苯甲酸2 g/L
培养基的pH6.5，溶剂为水。
250
mL三角瓶中产酶发酵培养的装液量40mL。将种子液接种产酶发酵培养基，接种量为5%（V/V），发酵温度29 ˚C，摇床转速180rpm，发酵时间为40h。
粗酶液（制备方法同实施例一）中青霉素酰化酶活力为210.9U/L。
方法4
产酶发酵培养基配方：甘油15 g/L，蛋白胨12 g/L，NaCl 4 g/L，Tween 80 0. 5 mL/L，4-羟基苯乙酸2 g/L 培养基的pH6.5，溶剂为水。
250
mL三角瓶中产酶发酵培养的装液量40mL。将种子液接种产酶发酵培养基，接种量为5%（V/V），发酵温度29 ˚C，摇床转速180rpm，发酵时间为40h。
粗酶液（制备方法同实施例一）中青霉素酰化酶活力为230.9U/L。
实施例四
本实验说明青霉素酰化酶粉的制备程序。
将木糖氧化无色杆菌（Achromobacter xylosoxidans）K18在产酶培养基中培养52 h后，发酵液在8,000 rpm、4℃离心20 min，弃上清，菌体重悬于0.025 M 磷酸缓冲液(pH 6.5)，采用高压匀质机（破碎压力为850～950Bar）进行细胞破碎，离心取上清为粗酶液。将粗酶液用30KD的超滤膜进行超滤，于-55℃条件下真空干燥，制得青霉素酰化酶粉。超滤后的粗酶液酶活力为1095U/L，青霉素酰化酶粉活力为30.6U/g。
将木糖氧化无色杆菌（Achromobacter xylosoxidans）K18所产青霉素酰化酶命名为青霉素酰化酶K18。
实施例五
本实施例说明木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18所产青霉素酰化酶K18编码基因的分离克隆程序。
采用酚－氯仿法抽提菌体总DNA。根据木糖氧化无色杆菌（Achromobacter
xylosoxidans）A8（NCBI Reference Sequence：NC_014640.1）的全基因测序结果进行分析，获得一个编码青霉素酰化酶的基因，根据该基因序列设计引物LU1和LD1。
LU1（SEQ ID NO:3）序列为:
GTTGCGACAAGTTGACCGCCTCT，
LD1（SEQ ID NO:4）序列为: CACCTCGCATCTGGACACCTTG。
以木糖氧化无色杆菌（Achromobacter xylosoxidans）K18总DNA为模板，以LU1和LD1为引物扩增青霉素酰化酶K18的CDS编码序列。将扩增到的3.0 kb的PCR片段连接到pMD18-T载体，进行序列测定和分析，青霉素酰化酶的基因序列如SEQ
ID NO：1所示，氨基酸序列如SEQ
ID NO：2所示。木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18与Achromobacter xylosoxidans A8青霉素酰化酶基因同源性为 86%，氨基酸序列同源性为85 %。
实施例六
用实施例四中超滤后的粗酶液进行下述实验，来检测青霉素酰化酶K18性质。
青霉素酰化酶K18最适反应pH和pH稳定性的检测：以不同pH缓冲液溶解的NIPAB为底物， pH7.5条件下的青霉素酰化酶活力为对照（100％），不同pH反应体系中的酶活如图1所示。本发明青霉素酰化酶的最适反应pH为8.0。以原始酶液的青霉素酰化酶活力为对照，检测该酶的pH稳定性（图2）。将青霉素酰化酶K18与不同pH的缓冲溶液按照体积比1:1进行混合，在30℃保温2 h后测残余酶活，实验表明该青霉素酰化酶在pH 5.0～8.5的范围内具有较高的稳定性，在pH 10.5的溶液中保温2h后，仍然保留最高活力的61%。
青霉素酰化酶K18最适反应温度和热稳定性的检测：最适反应温度的测定，在0.05
M Na2HPO4•12H2O-NaH2PO4•2H2O缓冲体系（pH
7.5）中进行，在不同的温度下以NIPAB为底物进行酶促反应。结果显示该酶的最适反应温度为45℃(图3)。热稳定性测定：青霉素酰化酶K18在30℃、40℃、50℃、60℃、70℃、80℃下处理2h以后，测定残留酶活。由图4可以看出该青霉素酰化酶具有较好的热稳定性，50℃以下处理 2 h 后活力基本不变，在60℃处理2 h后仍然保留最高活力的72%。
青霉素酰化酶K18底物特异性的检测：利用青霉素酰化酶能够催化水解β-内酰胺类抗生素生成6-APA或7-ADCA（7-氨基去乙酰氧基头孢烷酸）来检测青霉素酰化酶K18的底物特异性。将粗酶液与反应底物按照体积比1︰1进行混合，在30℃、转速180 rpm条件下反应，定时取样，采用HPLC进行检测。反应底物分别为氨苄青霉素，青霉素G，青霉素V，阿莫西林，头孢氨苄。 结果如图5，青霉素酰化酶K18对青霉素类抗生素有水解活力，而对头孢菌素类抗生素无水解能力，其中最适反应底物为青霉素G。
青霉素酰化酶K18的有机溶剂耐受性：向青霉素酰化酶K18中分别加入10种有机溶剂（按照实施三制备），其混合比例为酶液︰有机溶剂=3︰2（V/V），疏水有机溶剂组中对照不添加有机溶剂，亲水有机溶剂组中对照添加与溶剂等体积的缓冲液。30℃，150 rpm振荡，定时取样，以NIPAB为底物检测青霉素酰化酶活力。青霉素酰化酶K18具有良好的有机溶剂耐受性，其在乙二醇、甘油、聚乙二醇、1,4丁二醇、正己烷、二甲醚有机溶剂中半衰期有明显延长；甲醇、DMSO处理24h，其酶活可维持在50%以上（图6）。
实施例七
本实验说明青霉素酰化酶K18在非水相体系中催化合成β-内酰胺类抗生素的应用。
分别以pH6.5磷酸缓冲液、乙二醇-磷酸缓冲液、丙三醇-磷酸缓冲液、聚乙二醇-磷酸缓冲液、甲醇-磷酸缓冲液、1,2-丙二醇-磷酸缓冲液、1,4-丁二醇-磷酸缓冲液为反应介质。反应总体积为1mL，其中含有10mM 6-APA，20 mM
D-HPGM（对羟基苯甘氨酸甲酯），加入青霉素酰化酶K18酶粉（实施例四制备）33 mg，在15℃，转速180rpm条件下反应，定时取样。样品用溶剂（水︰甲醇︰乙酸=60︰35︰5（V/V））稀释适当倍数，采用HPLC进行检测。结果表明丙三醇-磷酸缓冲液为最佳反应介质，反应20h，阿莫西林的合成率可达50%。
结果表明青霉素酰化酶K18具有良好的合成阿莫西林的能力，表明该酶将来在合成新型β-内酰胺类抗生素中具有巨大的潜力，在生物制药工业中具有广阔的应用前景。
SEQUENCE LISTING
<110> 南京工业大学
<120> 青霉素酰化酶、其高产菌株及应用
<130> 20130411
<160> 4
<170> PatentIn version 3.3
<210> 1
<211> 2532
<212> DNA
<213> 木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18
<400> 1
atggcgcaac ccgtggcgca agccgcgggc caggagtccg cggccgtcgc
ggccccggcg 60
caaggcgccg ccggcaaggt cacgatccgg cgcgacgccc atggcatgcc
gcacgtctac 120
gctgacacgg tgtacggcat tttctacggc tacggttacg cggtggcgca
ggaccggctg 180
ttccagatgg agatggcgcg gcgcagcacc cagggccggg tggccgaagt
gctgggcgcg 240
tcgatggtgg cgttcgacaa atccatccgc ggcaattttt cgcccgaacg
catccagcgc 300
cagctggcgg cgctgccggc cgccgaccgc caggtgctgg acggctacgc
ggccggcatg 360
aacgcctggc tggcgcggat ccgcgcgcag ccggggcagt tgatgcccaa
ggaattcaac 420
gacctgggct tcgcgccggc cgactggacc gcctacgacg tggcgatgat
cttcatcggc 480
accatggcga accgcttctc tgacgccaac agcgagatcg acaacctggc
gctgctgacg 540
gcgctcaagg acaggcacgg cgaggccgag gccatgcgca tcttcaacca
gctgcgctgg 600
ctgacggaca gccgcgcgcc gaccacggtg ccgccccagg agggcagcta ccagccggcc
660
gtgttccagc cggaaggcgc ggaccagctg gcctacgcgc tgccgcgcta
cgacggcacg 720
ccgccgatgc tcgaacgcgt ggtgcgcgat ccggccacgc gcggcgtggt
cgatggcgcg 780
cccgccacgc tgcgggctcg actggccgag caatacgcgc aatcgggcca
gccgggcatc 840
gcaggcttcc cgaccaccag caacatgtgg atcgtgggcc gcgaccatgc
caaggatgcc 900
cgttcgatcc tgctgaacgg cccgcagttc ggctggtgga atccggccta
cacctacggc 960
atcggcctgc acggcgccgg cttcgacgtg gtcggcaaca cgccgttcgc
ctatccctcc 1020
atcctgttcg gccacaatgc gcacgtggcc tggggctcga ccgcgggctt
cggcgacgat 1080
gtcgacatct acgccgagaa gctcgatccg gccgaccgca accgttattt
ccacgacggc 1140
caatggaaga cgctggaaaa gcgcactgac ctgatcctgg tgaaggacgc
ggcgccggtg 1200
acgctggatg tgtaccgcag cgtgcatggc ctgatcgtca agttcgacga
cgcgcagcac 1260
gtggcctatg ccaaggcgcg cgcctgggag ggctttgaac tgcaatcgct
gatggcctgg 1320
acccgcaaga cgcaggcggc caactgggaa caatggaagg cgcaggcggc
gcgccacgcg 1380
ctgaccatca attggtacta cgccgacgac cgcggcaaca tcggctacgc
gcacacgggc 1440
ttctatccca ggcgccggcc gggccacgat ccgcgcctgc cggtgccggg
caccggcgaa 1500
atggactggc tgggcctgtt gccgttctcg accaatccgc aggtctacaa
cccgggccag 1560
gggttcatcg ccaactggaa caaccagccg atgcgcggct atccctccac
cgacctgttc 1620
gccatcgtct gggggcaggc cgaccgctat gccgagatcg agacgcgcct gaaggccatg
1680
accgccaacg gcggcaaggt cagcccgcaa cagatgtggg acctgatccg
caccaccagc 1740
tatgccgacg tcaaccgccg ccatttcctg ccgttcctgc aacgagcggt
gcaggggctg 1800
ccggccgacg atccgcgcgt gcggctggtg gcggggctgg ggggctggga
cggcatgatg 1860
accagcgagc gcgagccggg ctactacgac aacgccggcc cggcggtgat
ggacgcctgg 1920
ctgcgtgcga tgctcaagcg caccctggcc gacgagatgc cggccgactt
cttcaagtgg 1980
tacagcgcca ccgggtatcc gacgccgcag gcgcctgcca ctggttcgct
caacctgacc 2040
accggcgtga aggtgttgtt caacgccttg gcgggtccgg ctgccggggt
gccgcagcgg 2100
tatgacttct tcaatggcgc gcgcgccgac gatgtcatcc tggcggcgct
ggacgacgcg 2160
ctggcggcct tgcgccaggc ttatggcaag gatccggccg cgtggaagat
cccggcgccg 2220
ccgatggtgt tcgcgcccaa gaacttcctg ggcgtgccgc aggccgacgc
caaggcggtg 2280
ttgagctatc cggccacgca gaaccgcggc accgagaaca acatgacggt
gttcgacggc 2340
aggtcggtgc gcgcggtgga cgtggtggcg ccggggcaga gcggcttcgt
cgccccggac 2400
ggcacgccgt cgccgcacac ccgcgaccag ttcgacctgt acaacagctt
tggcagcaag 2460
cgggtgtggt tcacggcgga cgaggtgcgg cgcaacgcta cgtcggaaga
gacgttgcgc 2520
taccggcggt
aa
2532
<210> 2
<211> 843
<212> PRT
<213> 木糖氧化无色杆菌（Achromobacter
xylosoxidans）K18
<400> 2
Met Ala Gln Pro Val Ala Gln Ala Ala Gly Gln Glu Ser Ala Ala Val
1
5
10 15
Ala Ala Pro Ala Gln Gly Ala Ala Gly Lys Val Thr Ile Arg Arg Asp
20
25
30
Ala His Gly Met Pro His Val Tyr Ala Asp Thr Val Tyr Gly Ile Phe
35
40
45
Tyr Gly Tyr Gly Tyr Ala Val Ala Gln Asp Arg Leu Phe Gln Met Glu
50
55
60
Met Ala Arg Arg Ser Thr Gln Gly Arg Val Ala Glu Val Leu Gly Ala
65
70
75
80
Ser Met Val Ala Phe Asp Lys Ser Ile Arg Gly Asn Phe Ser Pro Glu
85
90
95
Arg Ile Gln Arg Gln Leu Ala Ala Leu Pro Ala Ala Asp
Arg Gln Val
100
105
110
Leu Asp Gly Tyr Ala Ala Gly Met Asn Ala Trp Leu Ala Arg Ile Arg
115
120
125
Ala Gln Pro Gly Gln Leu Met Pro Lys Glu Phe Asn Asp Leu Gly Phe
130
135
140
Ala Pro Ala Asp Trp Thr Ala Tyr Asp Val Ala Met Ile Phe Ile Gly
145
150
155
160
Thr Met Ala Asn Arg Phe Ser Asp Ala Asn Ser Glu Ile Asp Asn Leu
165
170
175
Ala Leu Leu Thr Ala Leu Lys Asp Arg His Gly Glu Ala Glu Ala Met
180
185
190
Arg Ile Phe Asn Gln Leu Arg Trp Leu Thr Asp Ser Arg
Ala Pro Thr
195
200
205
Thr Val Pro Pro Gln Glu Gly Ser Tyr Gln Pro Ala Val Phe Gln Pro
210
215
220
Glu Gly Ala Asp Gln Leu Ala Tyr Ala Leu Pro Arg Tyr Asp Gly Thr
225
230
235
240
Pro Pro Met Leu Glu Arg Val Val Arg Asp Pro Ala Thr Arg Gly Val
245
250
255
Val Asp Gly Ala Pro Ala Thr Leu Arg Ala Arg Leu Ala Glu Gln Tyr
260
265
270
Ala Gln Ser Gly Gln Pro Gly Ile Ala Gly Phe Pro Thr Thr Ser Asn
275
280
285
Met Trp Ile Val Gly Arg Asp His Ala Lys Asp Ala Arg Ser Ile Leu
290
295
300
Leu Asn Gly Pro Gln Phe Gly Trp Trp Asn Pro Ala Tyr Thr Tyr Gly
305
310
315
320
Ile Gly Leu His Gly Ala Gly Phe Asp Val Val Gly Asn Thr Pro Phe
325
330
335
Ala Tyr Pro Ser Ile Leu Phe Gly His Asn Ala His Val Ala Trp Gly
340
345
350
Ser Thr Ala Gly Phe Gly Asp Asp Val Asp Ile Tyr Ala Glu Lys Leu
355
360
365
Asp Pro Ala Asp Arg Asn Arg Tyr Phe His Asp Gly Gln Trp Lys Thr
370
375
380
Leu Glu Lys Arg Thr Asp Leu Ile Leu Val Lys Asp Ala Ala Pro Val
385
390
395
400
Thr Leu Asp Val Tyr Arg Ser Val His Gly Leu Ile Val Lys Phe Asp
405
410
415
Asp Ala Gln His Val Ala Tyr Ala Lys Ala Arg Ala Trp Glu Gly Phe
420
425
430
Glu Leu Gln Ser Leu Met Ala Trp Thr Arg Lys Thr Gln Ala Ala Asn
435
440
445
Trp Glu Gln Trp Lys Ala Gln Ala Ala Arg His Ala Leu Thr Ile Asn
450
455
460
Trp Tyr Tyr Ala Asp Asp Arg Gly Asn Ile Gly Tyr Ala His Thr Gly
465
470
475 480
Phe Tyr Pro Arg Arg Arg Pro Gly His Asp Pro Arg Leu Pro Val Pro
485
490
495
Gly Thr Gly Glu Met Asp Trp Leu Gly Leu Leu Pro Phe Ser Thr Asn
500
505
510
Pro Gln Val Tyr Asn Pro Gly Gln Gly Phe Ile Ala Asn Trp Asn Asn
515
520
525
Gln Pro Met Arg Gly Tyr Pro Ser Thr Asp Leu Phe Ala Ile Val Trp
530
535
540
Gly Gln Ala Asp Arg Tyr Ala Glu Ile Glu Thr Arg Leu Lys Ala Met
545
550
555
560
Thr Ala Asn Gly Gly Lys Val Ser Pro Gln Gln Met Trp Asp Leu Ile
565
570
575
Arg Thr Thr Ser Tyr Ala Asp Val Asn Arg Arg His Phe Leu Pro Phe
580
585
590
Leu Gln Arg Ala Val Gln Gly Leu Pro Ala Asp Asp Pro Arg Val Arg
595
600
605
Leu Val Ala Gly Leu Gly Gly Trp Asp Gly Met Met Thr Ser Glu Arg
610
615
620
Glu Pro Gly Tyr Tyr Asp Asn Ala Gly Pro Ala Val Met Asp Ala Trp
625
630
635
640
Leu Arg Ala Met Leu Lys Arg Thr Leu Ala Asp Glu Met Pro Ala Asp
645
650
655
Phe Phe Lys Trp Tyr Ser Ala Thr Gly Tyr Pro Thr Pro Gln Ala Pro
660
665
670
Ala Thr Gly Ser Leu Asn Leu Thr Thr Gly Val Lys Val Leu Phe Asn
675
680
685
Ala Leu Ala Gly Pro Ala Ala Gly Val Pro Gln Arg Tyr Asp Phe Phe
690
695
700
Asn Gly Ala Arg Ala Asp Asp Val Ile Leu Ala Ala Leu Asp Asp Ala
705
710
715
720
Leu Ala Ala Leu Arg Gln Ala Tyr Gly Lys Asp Pro Ala Ala Trp Lys
725
730
735
Ile Pro Ala Pro Pro Met Val Phe Ala Pro Lys Asn Phe Leu Gly Val
740
745
750
Pro Gln Ala Asp Ala Lys Ala Val Leu Ser Tyr Pro Ala Thr Gln Asn
755
760
765
Arg Gly Thr Glu Asn Asn Met Thr Val Phe Asp Gly Arg Ser Val Arg
770
775
780
Ala Val Asp Val Val Ala Pro Gly Gln Ser Gly Phe Val Ala Pro Asp
785
790
795
800
Gly Thr Pro Ser Pro His Thr Arg Asp Gln Phe Asp Leu Tyr Asn Ser
805
810
815
Phe Gly Ser Lys Arg Val Trp Phe Thr Ala Asp Glu Val Arg Arg Asn
820
825
830
Ala Thr Ser Glu Glu Thr Leu Arg Tyr Arg Arg
835
840
<210> 3
<211> 23
<212> DNA
<213> artificial
<220>
<223> LU1
<400> 3
gttgcgacaa gttgaccgcc
tct
23
<210> 4
<211> 22
<212> DNA
<213> artificial
<220>
<223> LD1
<400> 4
cacctcgcat ctggacacct
tg
22
Claims (10)
1.青霉素酰化酶高产菌株，其特征在于该菌株为木糖氧化无色杆菌（Achromobacter xylosoxidans）K18，保藏登记号为CCTCC
NO：M 2012541。
2.一种利用权利要求1所述菌株制备青霉素酰化酶的方法，其特征在于通过发酵木糖氧化无色杆菌（Achromobacter xylosoxidans）K18，得到青霉素酰化酶。
3.根据权利要求2所述制备青霉素酰化酶的方法，其特征在于：发酵木糖氧化无色杆菌（Achromobacter xylosoxidans）K18采用的培养基中含有诱导剂，所述诱导剂选自苯甲酸、苯乙酸、4-羟基苯乙酸、苯氧乙酸、苯丙酸和苯甘氨酸中的一种或两种以上。
4.根据权利要求3所述制备青霉素酰化酶的方法，其特征在于：所述培养基中诱导剂浓度为1-4 g/L。
5.根据权利要求4所述制备青霉素酰化酶的方法，其特征在于：所述培养基的碳源为甘油，氮源为酵母粉、蛋白胨或其混合物，表面活性剂为Span-20、Tween 80和Triton X-100中的一种或两种以上；所述培养基中碳源浓度为5～25 g/L，氮源浓度为7.5～15g/L，表面活性剂浓度为0.1～1 mL/L。
6.根据权利要求5所述制备青霉素酰化酶的方法，其特征在于：发酵培养条件为：发酵温度25～30˚C，摇床转速150～200 rpm，发酵时间40～60h。
7.一种权利要求1所述菌株产生的青霉素酰化酶，其氨基酸序列如SEQ ID NO：2所示。
8.编码权利要求7所述青霉素酰化酶的基因，其序列如SEQ ID NO：1所示。
9.权利要求7所述青霉素酰化酶在合成β-内酰胺类抗生素中的应用。
10.根据权利要求9所述青霉素酰化酶在合成β-内酰胺类抗生素中的应用，其特征在于所述青霉素酰化酶在非水相体系中合成以6-青霉素烷酸为母核的β-内酰胺类抗生素。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104789510A (zh) * | 2015-05-06 | 2015-07-22 | 南京工业大学 | 一种青霉素酰化酶、编码基因、产生菌株及其应用 |
| CN105274082A (zh) * | 2015-11-03 | 2016-01-27 | 湖南福来格生物技术有限公司 | 一种合成用青霉素g酰化酶突变体及其在制备阿莫西林中的应用 |
| CN105506050A (zh) * | 2016-01-21 | 2016-04-20 | 湖北凌晟药业有限公司 | 一种头孢菌素母核酶解反应的催化方法 |
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| CN101563459A (zh) * | 2007-01-31 | 2009-10-21 | 酵素生物技术有限公司 | 编码青霉素酰化酶的dna序列，携带该序列的新型重组dna结构及重组微生物 |
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| CN101563459A (zh) * | 2007-01-31 | 2009-10-21 | 酵素生物技术有限公司 | 编码青霉素酰化酶的dna序列，携带该序列的新型重组dna结构及重组微生物 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104789510A (zh) * | 2015-05-06 | 2015-07-22 | 南京工业大学 | 一种青霉素酰化酶、编码基因、产生菌株及其应用 |
| CN105274082A (zh) * | 2015-11-03 | 2016-01-27 | 湖南福来格生物技术有限公司 | 一种合成用青霉素g酰化酶突变体及其在制备阿莫西林中的应用 |
| CN105506050A (zh) * | 2016-01-21 | 2016-04-20 | 湖北凌晟药业有限公司 | 一种头孢菌素母核酶解反应的催化方法 |
| CN105506050B (zh) * | 2016-01-21 | 2018-12-25 | 湖北凌晟药业有限公司 | 一种头孢菌素母核酶解反应的催化方法 |
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