CN111500564B - 青霉素g酰化酶突变体及其在酶法合成头孢孟多中的应用 - Google Patents
青霉素g酰化酶突变体及其在酶法合成头孢孟多中的应用 Download PDFInfo
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- CN111500564B CN111500564B CN202010488868.6A CN202010488868A CN111500564B CN 111500564 B CN111500564 B CN 111500564B CN 202010488868 A CN202010488868 A CN 202010488868A CN 111500564 B CN111500564 B CN 111500564B
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- acylase
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Abstract
本发明涉及青霉素G酰化酶突变体及其在酶法合成头孢孟多中的应用。通过半理性设计的酶工程改造技术对木糖氧化无色杆菌(Achromobacter xylosoxidans)PX02来源的青霉素G酰化酶进行突变,获得了一种反应活性更高,反应速率更快,转化率更好的PGA突变体。该PGA突变体对产物的水解活性大大降低,在产率达到最大值后,几乎不水解产物,具有广阔的工业应用前景。
Description
技术领域
本发明属于生物制药技术领域,具体涉及一种木糖氧化无色杆菌来源青霉素G酰化酶突变体及在酶法合成头孢孟多中的应用。
背景技术
β-内酰胺类抗生素如头孢孟多属第二代头孢菌素高效医用药,杀菌力强,抗菌谱广其作用机制是通过抑制细菌的乙酰转肽酶而干扰细胞壁肽聚糖的合成,使细菌变成丝状或球状,最后溶解,对多种革兰氏阳性菌和革兰氏阴性菌均具有很强的杀灭作用。临床上主要用于治疗敏感细菌所致的呼吸道感染、胆道感染、腹腔感染、盆腔感染、尿路感染、皮肤软组织感染、骨和关节感染以及败血症等。
目前,国内企业已用化学法实现了大多数头孢类原料药的国产化,但酶法生产半合成头孢类抗生素尚未大规模产业化。与传统的化学法合成相比,酶法合成β-内酰胺类抗生素具有反应步骤少,废弃物产生少,有利于环境保护,生产成本降低,产品杂质少、易分离且质量优异等诸多优点。因此,β-内酰胺抗生素的酶法合成是21世纪β-内酰胺抗生素发展的趋势之一。
青霉素G酰化酶(penicillin G acylase,EC3.5.1.11)又称为青霉素酰胺酶或青霉素氨基水解酶,是一种N末端亲核丝氨酸水解酶。大部分酶具有水解特性已广泛应用于天然青霉素G的水解来获得β-内酰胺抗生素母核,然而只有少部分酶具有良好的酰化特性能够应用在β-内酰胺抗生素的合成中。
青霉素G酰化酶主要应用于抗生素工业中β-内酰胺抗生素中间体6-APA(6-氨基青霉烷酸)的生产和半合成β-内酰胺抗生素的合成。此外,它作为一种生物催化剂,还有其他许多潜在的应用,比如手性拆分、手性肽的合成、酯类化合物的水解等。因此,青霉素G酰化酶是工业上应用价值很高的酶。
在酶法制备半合成β-内酰胺类抗生素中,其主要在动力学控制下进行合成反应。在反应中必须提供活化的酰基供体,在合成体系中主要存在以下三个反应:(1)β-内酰胺抗生素产物的生成;(2)活化酰基供体的水解反应;(3)合成的抗生素的水解反应。最终转化率取决于这三个反应之间的平衡。
Srirangan K等(Biotechnology advances,2013,31(8):1319-1332)分析了青霉素酰化酶的水解机理可知,在青霉素G先脱掉6-APA后,苯乙酰基-酶中间体会受到H2O分子的亲核进攻,形成苯乙酸。由于整个过程是可逆的,所以在偏酸性低温条件下,可以用青霉素G酰化酶催化酰基供体R-MMA(扁桃酸甲酯)和β-内酰胺母核7-TMCA一步催化合成头孢孟多。Terreni等(Appl Microbiol Biotechnol,2007,77:579–587)固定化大肠杆菌(Escherichia coli)来源的青霉素G酰化酶,在母核7-TMCA浓度50mM,底物摩尔比R-MMA/7-TMCA=3:1,pH6.5,4℃的条件下催化合成头孢孟多,转化率71-76%。Ilona Estruch等(Enzyme and Microbial Technology,2008,42:121–129)固定化大肠杆菌(Escherichiacoli)来源的青霉素G酰化酶,在母核7-TMCA浓度50mM,底物摩尔比R-MMA/7-TMCA=3:1,pH6.5,4℃的条件下催化合成头孢孟多,转化率77%,合成水解比1.5。
国内外对生物催化研究越来越多,其中一个关键问题就是所用的酶往往不能满足实际工业化生产的需求。如本申请涉及的氨基酸序列如SEQ ID NO:2所示的野生型青霉素G酰化酶,虽然其能够催化缩合7-TMCA与扁桃酸甲酯合成头孢孟多,但是合成水解比较低,生成的副产物较多,从而转化率只有40%左右。
发明内容
本发明的第一个目的是提供一种高合成活性青霉素G酰化酶突变体。
为实现上述技术目的,本发明采用如下技术方案:
一种青霉素G酰化酶突变体,将SEQ ID NO:2所示青霉素G酰化酶氨基酸序列的第186位、187位、329位氨基酸残基中的一个或多个突变为另一种氨基酸残基,获取所述突变体。所述突变体可以是单点突变、两点组合突变或三点组合突变。
所述SEQ ID NO:2所示的野生青霉素G酰化酶来源于木糖氧化无色杆菌(Achromobacter xylosoxidans)PX02。该菌株已在申请人在先专利CN106399174A中公开,保藏号CCTCC NO:M2016392。
进一步的,所述第186位精氨酸突变为丙氨酸、天冬氨酸或赖氨酸,优选丙氨酸。第187位苯丙氨酸突变为异亮氨酸或缬氨酸,优选异亮氨酸。第329位苯丙氨酸突变为丙氨酸、甘氨酸、异亮氨酸、缬氨酸或丝氨酸;优选甘氨酸。
其中,优选的突变体为R186A/F187I、R186A/F329G、F187I/F329G或R186A/F187I/F329G;最优选R186A/F187I/F329G。
本发明的第二个目的是提供上述的突变型青霉素G酰化酶的制备方法,包括以下步骤:
a)将木糖氧化无色杆菌(Achromobacter xylosoxidans)PX02野生型青霉素G酰化酶核苷酸序列(SEQ ID NO:1)进行饱和突变、迭代饱和突变等步骤得到上述任一种青霉素G酰化酶的突变体的基因序列;
b)将突变体基因序列插入到质粒中得到表达载体;
c)将表达载体转化进入菌株中得到重组基因工程菌;
d)将重组基因工程菌用IPTG诱导进行发酵得到青霉素G酰化酶。
本发明涉及的突变型青霉素G酰化酶的制备方法,将产青霉素G酰化酶重组菌破碎、离心、收集获得酶液。
本发明的第三个目的是应用上述的突变型青霉素G酰化酶制备头孢孟多,并对催化条件进行优化,包括:
反应底物头孢甲肟中间体7-TMCA(7-氨基-3-(1-甲基-1H-四唑-5-硫代甲基)-8-氧代-5-硫杂-1-氮杂双环[4.2.0]辛-2-烯-2-羧酸)和侧链R-扁桃酸甲酯R-MMA浓度范围10mM-100mM;R-MMA与7-TMAC的摩尔比为1~1.5:1;优选1.3:1。
进一步的,反应体系中添加甘油;甘油添加浓度为0~50%(V/V),优选30%(V/V)。
进一步的,反应体温温度为5~30℃,优选20℃。
进一步的,反应体系初始pH为5.8~6.6℃,优选6.0。
本发明通过饱和突变、迭代饱和突变等半理性设计的酶工程改造技术对木糖氧化无色杆菌(Achromobacter xylosoxidans PX02)来源的PGA进行突变,提供了多种新的青霉素G酰化酶突变体(包括单点突变,两点组合突变和三点组合突变),相对野生酶提高了合成水解比,且缩短了反应时间。此外,本发明对催化条件进行优化,在最优条件下,三点组合突变体R186A/F187I/F329G在催化合成反应中使头孢孟多转化率从40%提高至85%以上,合成水解比从1.12提高至4.6。最重要的是对产物的水解活性大大降低,在产率达到最大值后,几乎不水解产物,具有广阔的工业应用前景。
附图说明
图1为实施例3的反应原理图。
图2为甘油添加量对酶法合成头孢孟多的影响。
图3为温度对酶法合成头孢孟多的影响。
图4为初始pH对酶法合成头孢孟多的影响。
图5为底物摩尔比对酶法合成头孢孟多的影响。
具体实施方式
实施例1
本实施例说明青霉素G酰化酶的定点突变方法。
将青霉素G酰化酶的如下三个位点进行单点突变、两点组合突变和三点组合突变:第186位精氨酸(R)突变为另外一种氨基酸残基选自下述的丙氨酸(A)、天冬氨酸(D)、或赖氨酸(L);第187位苯丙氨酸(F)突变为另外任意一种氨基酸残基(异亮氨酸(I)、缬氨酸(V));第329位苯丙氨酸(F)突变为另外一种氨基酸残基选自下述的丙氨酸(A)、甘氨酸(G)、异亮氨酸(I)、缬氨酸(V)、丝氨酸(S)。利用oligo7软件设计平末端引物,木糖氧化无色杆菌(Achromobacter xylosoxidans PX02)来源的野生型青霉素G酰化酶氨基酸序列(SEQIDNO.2)编码的基因序列(SEQ ID NO:1)为模板,然后进行PCR定点突变。
引物的碱基序列为:
PCR反应体系如下:
PCR循环过程:
1、预热:95℃,10min;
2、变性:95℃,30s;
3、退火:52℃,30s;
4、延伸:72℃,8min;
2~4循环30次
5、延伸:72℃,10min;冷却至4℃保存。
PCR产物回收,用琼脂糖凝胶电泳检测其是否定点突变完成。然后在50μL的体系里加入DpnI(1μL),37℃下保持3h,用以消化模板,冷却至4℃保存。
将上述突变后的质粒转化到大肠杆菌E.coli BL21(DE3)感受态细胞中,在含有卡那霉素的抗性平板上对阳性重组体进行筛选,挑选单克隆子,菌落PCR验证阳性的克隆子,经DNA测序验证后,即获得了对应的突变体。
实施例2
本实施例说明青霉素G酰化酶突变体的诱导表达与纯化。
1、青霉素G酰化酶突变体的诱导表达
(1)将实施例1所得的重组转化子,接种至含卡那霉素的LB培养基(蛋白胨10g/L,酵母粉5g/L,NaCl 10g/L,pH 6.5,37℃振荡培养12h,获得种子液。
(2)按2%(v/v)的接种量接入装有40mL LB培养基的250mL三角瓶中,置于37℃、180rpm摇床培养,当培养液OD600达到0.6时,加入终浓度为0.1mmol/L的IPTG作为诱导剂,16℃诱导24h。
(3)将培养液离心,收集细胞,并利用生理盐水洗涤两次,得静息细胞。将所得的静息细胞悬浮于pH8.0的缓冲液中,在冰浴中超声破碎,离心收集上清液,即为粗酶液。
2、青霉素G酰化酶突变体的纯化
蛋白纯化采用Ni+柱纯化:将收集到的野生型和突变体粗酶液过滤加入到Nisepharose 6Fast Flow(FF)填料,用10倍柱体积的缓冲A(10mM Tris-HCl pH 7.0,250mMNaCl,5mM咪唑)洗脱杂蛋白,再用缓冲B(10mM Tris-HCl pH 7.0,250mM NaCl,100mM咪唑)洗脱目的蛋白,将收集到的目的蛋白进行SDS-PAGE蛋白电泳。
实施例3
本实验说明青霉素G酰化酶突变体在合成头孢孟多中的应用。
本实施例采用的技术方案如图1所示。
由图1反应式可知,青霉素G酰化酶既能够缩合母核7-TMCA与侧链扁桃酸甲酯生成产物头孢孟多,又可以分解产物生成母核与扁桃酸,同时扁桃酸甲酯本身也会水解成扁桃酸。
反应体系:以pH 6.5磷酸缓冲液为反应介质。反应总体积为2mL,其中含有50mM7-TMCA,150mM R-MMA(R-扁桃酸甲酯),加入青霉素酰化酶突变体酶液(实施例1-2制备),在反应温度为25℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,催化结果如表1所示。
表1野生型青霉素酰化酶及其部分突变体在头孢孟多合成中转化率和合成水解比
青霉素酰化酶突变体具有良好的合成头孢孟多的能力,其中突变体R186A/F187I/F329G合成头孢孟多中具有巨大的潜力,在生物制药工业中具有广阔的应用前景。
实施例4
本实施例以突变体R186A/F187I/F329G为例,说明甘油溶剂添加量对酶法合成头孢孟多的影响。
反应体系:反应总体积为2mL,其中含有50mM的7-TMCA,150mM的R-MMA(R-扁桃酸甲酯),反应体系中添加甘油浓度分别为0%、10%、20%、30%、40%和50%的磷酸缓冲溶液,初始pH6.5,加入实施例2制备的青霉素酰化酶突变体酶液1.7×10-2U/mM 7-TMCA,在25℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,结果如图2。
实施例5
本实施例以突变体R186A/F187I/F329G为例,说明温度对酶法合成头孢孟多的影响。
反应体系:反应总体积为2mL,其中含有50mM的7-TMCA,150mM的R-MMA(R-扁桃酸甲酯),反应介质是添加甘油浓度30%的磷酸缓冲溶液,初始pH6.5,加入实施例二制备的青霉素酰化酶突变体酶液1.7×10-2U/mM 7-TMCA,设置反应温度分别为5℃、10℃、15℃、20℃、25℃和30℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,结果如图3。
实施例6
本实施例以突变体R186A/F187I/F329G为例,说明初始pH对酶法合成头孢孟多的影响。
反应体系:反应总体积为2mL,其中含有50mM的7-TMCA,150mM的R-MMA(R-扁桃酸甲酯),反应介质是添加甘油浓度30%的磷酸缓冲溶液,设置初始pH分别为5.8、6.0、6.2、6.4和6.6,加入实施例二制备的青霉素酰化酶突变体酶液量为1.7×10-2U/mM 7-TMCA,反应体系温度为20℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,结果如图4。
实施例7
本实施例以突变体R186A/F187I/F329G为例,说明底物摩尔比对酶法合成头孢孟多的影响。
反应体系:反应总体积为2mL,其中含有50mM的7-TMCA,R-MMA(扁桃酸甲酯)的浓度分别为50mM、55mM、60mM、65mM、70mM和75mM,反应介质是添加甘油浓度30%的磷酸缓冲溶液,初始pH为6.0,加入实施例二制备的青霉素酰化酶突变体酶液量为1.7×10-2U/mM 7-TMCA,反应温度为20℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,结果如图5。
实施例8
本实验说明青霉素G酰化酶突变体在优化后的催化条件下合成头孢孟多。
反应体系:反应总体积为2mL,其中含有50mM的7-TMCA,65mM的R-MMA(R-扁桃酸甲酯),反应介质是添加甘油浓度30%的磷酸缓冲溶液,反应体系初始pH为6.0,加入实施例二制备的青霉素酰化酶突变体酶液量为1.7×10-2U/mM 7-TMCA,反应温度为20℃,转速200rpm条件下反应5h,定时取样。样品用溶剂(水︰甲醇︰乙酸=60︰35︰5(V/V))稀释10倍,采用HPLC进行检测,各种突变体的催化结果如表2所示。优选的单点突变、双点突变和三点组合突变体的合成产率达40%~85%,体现了高效的合成能力。
表2优化后野生型青霉素酰化酶及其突变体在头孢孟多合成中转化率和合成水解比
序列表
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cagcccatgg tggcgttcga caagtccatc cggggaaatt tctcgccaga gcgcatccag 360
cgccagctcg cggcgttgcc ggcatcggag cgccagatcc tggacggcta cgcggccggc 420
atgaatgcct ggatcgcgcg ggtgcgcgcc gagcctggcg gactgatgcc caaggaattc 480
aacgacctgc gcttccagcc ggcggactgg acggcctacg acgtggcgat ggtgttcgtg 540
ggcaccatgg ccaaccgctt ctccgacgcc aatagcgaga tcgacaatct ggcgctgctg 600
accgcgctga aggacaagca cggcgatgag cgcgccatgc agatcttcaa ccagctgcgc 660
tggatgaccg acagccgcgc gcccaccacc gtgccggagg aagagggggt gtaccaaccg 720
gacgccgctc gtccttccgc caggctctcc tatgcgttgc cgcgctacga gggcacgccg 780
cccatgctgg aacgcgtggc gcgcgatccg caaacccgcg gtgtgctgga cgaagcgcct 840
gccgcggtgc cggcgcgact gctggcccag tttgcggaat cggggcaacc gggcatcgcc 900
ggctttccca cgaccagcaa catgtggatc gtgggccgcg accatgccaa ggacgcgcgc 960
gccatcctgc tgaacggacc gcagttcggc tggtggaacc cggcgtatac ctacgggatc 1020
ggcttgcacg gggccggatt cgacgtggtc ggcaatacgc cgtttgccta tcccagcatc 1080
ttgttcggcc acaatgcgca cgtgacctgg ggctcgactg ccggctttgg cgatgacgtg 1140
gacatctacg ccgaaaagct ggatcccaac gaccgcaccc gctatttcca tgatggcgtc 1200
tggaagacga tggaaaagcg caccgagctc atcgaggtga aggacgcgca gccggtggtg 1260
atggatgtct accgcaccgt gcacggcatc gtcacgaagt tcgacgacaa gcagcgcgtg 1320
gcctacgcca aggcgcgcgc ctgggagggc tatgagctgc aatcgctgat ggcctggacc 1380
cacaaggcgc agtcccgcaa ctgggaccag tggaaacagc aggccgcgcg ccacgccctg 1440
accatcaact ggtattacac ggacgacaag ggcaatatcg gctacgcgca tacggggttc 1500
taccccaaac gccgtccggg ccacgatccg cgcctgcccg tgcctggcac cggcgagatg 1560
gattgggacg gcatactgcc tttctcgacc aacccgcagg tgtacaaccc gcgccagggt 1620
tttatcgcca actggaacaa ccagcccatg cgcggctatc cctccaccga ccttttcgcc 1680
atcgtgtggg gccaggcgga tcgctatgcc gaaatcgaga cgcgcctgaa ggccatgaca 1740
gccaatggcg gcaaggtcag cgcgcaacag atgtgggacc tgatccgcac gaccagctat 1800
gccgacgtga accgccgcca tttcctgccg ttcctgcagc aggcggtgca agggctgccc 1860
gcggatgacg cgcgggcgcg gctggttgcc gggctggcat cgtgggacgg catgggtacc 1920
agcgacaagc aaccgggcta ctacgaccac acgggccccg cggtgatgga cgcctggctg 1980
cgcgccatgc tcaagcgcgc gctggccgac gagatgcccg ccgacttctt caagtggtac 2040
agcgccaccg gttatccgac gcaggcggcg cctgctaccg ggtcggtcaa cctgacggtg 2100
ggggtgaagg tgttgttcaa tgcgctggcg ggtcgcgatg cgggcgtgcc acagcagtac 2160
gatttcttca acggccaacg accccaggat gtaacgctgg cggccctgga cgacgcgctg 2220
gcggctttgc gcaaggccta tggcgaggat cccgcccagt ggcgcatacc tgcgcctccg 2280
atggtgttcg cgcccaagaa cttcctgggc gtgccgcagg cggacgacaa ggccgtgttg 2340
agcttcccgg ccacccagaa ccgcggcacc gagaacaaca tgacggtgtt cgatggcaag 2400
ggcgtgcgcg cggtggacgt ggtggcgccg ggacaaagcg gttttgtcgc cccggacggc 2460
accccgtcac cccacgcgcg cgaccagttc gacctttaca ccagtttcgg cagcaagcgg 2520
gtctggttca cggatgcgga agtgcgcgcc cacgctaagt cggtagagac gttgcgctac 2580
tga 2583
<210> 2
<211> 860
<212> PRT
<213> 青霉素G酰化酶(Penicillin G Acylase)
<400> 2
Met Lys Gln Gln Trp Leu Ser Ala Ala Ile Leu Ala Ala Cys Ala Ala
1 5 10 15
Val Gly Ala His Ala Gln Ala Gln Glu Ile Pro Gln Lys Thr Ser Pro
20 25 30
Gln Ala Gly Ala Ser Ala Arg Pro Ala Gly Ala Thr Ser Gly Gln Val
35 40 45
Thr Ile Arg Arg Asp Gly Tyr Gly Met Pro His Val Tyr Ala Asn Thr
50 55 60
Val Tyr Gly Ile Phe Tyr Gly Tyr Gly Tyr Ala Val Ala Gln Asp Arg
65 70 75 80
Pro Phe Gln Met Glu Met Ala Arg Arg Ser Thr Gln Gly Arg Val Ala
85 90 95
Glu Val Leu Gly Gln Pro Met Val Ala Phe Asp Lys Ser Ile Arg Gly
100 105 110
Asn Phe Ser Pro Glu Arg Ile Gln Arg Gln Leu Ala Ala Leu Pro Ala
115 120 125
Ser Glu Arg Gln Ile Leu Asp Gly Tyr Ala Ala Gly Met Asn Ala Trp
130 135 140
Ile Ala Arg Val Arg Ala Glu Pro Gly Gly Leu Met Pro Lys Glu Phe
145 150 155 160
Asn Asp Leu Arg Phe Gln Pro Ala Asp Trp Thr Ala Tyr Asp Val Ala
165 170 175
Met Val Phe Val Gly Thr Met Ala Asn Arg Phe Ser Asp Ala Asn Ser
180 185 190
Glu Ile Asp Asn Leu Ala Leu Leu Thr Ala Leu Lys Asp Lys His Gly
195 200 205
Asp Glu Arg Ala Met Gln Ile Phe Asn Gln Leu Arg Trp Met Thr Asp
210 215 220
Ser Arg Ala Pro Thr Thr Val Pro Glu Glu Glu Gly Val Tyr Gln Pro
225 230 235 240
Asp Ala Ala Arg Pro Ser Ala Arg Leu Ser Tyr Ala Leu Pro Arg Tyr
245 250 255
Glu Gly Thr Pro Pro Met Leu Glu Arg Val Ala Arg Asp Pro Gln Thr
260 265 270
Arg Gly Val Leu Asp Glu Ala Pro Ala Ala Val Pro Ala Arg Leu Leu
275 280 285
Ala Gln Phe Ala Glu Ser Gly Gln Pro Gly Ile Ala Gly Phe Pro Thr
290 295 300
Thr Ser Asn Met Trp Ile Val Gly Arg Asp His Ala Lys Asp Ala Arg
305 310 315 320
Ala Ile Leu Leu Asn Gly Pro Gln Phe Gly Trp Trp Asn Pro Ala Tyr
325 330 335
Thr Tyr Gly Ile Gly Leu His Gly Ala Gly Phe Asp Val Val Gly Asn
340 345 350
Thr Pro Phe Ala Tyr Pro Ser Ile Leu Phe Gly His Asn Ala His Val
355 360 365
Thr Trp Gly Ser Thr Ala Gly Phe Gly Asp Asp Val Asp Ile Tyr Ala
370 375 380
Glu Lys Leu Asp Pro Asn Asp Arg Thr Arg Tyr Phe His Asp Gly Val
385 390 395 400
Trp Lys Thr Met Glu Lys Arg Thr Glu Leu Ile Glu Val Lys Asp Ala
405 410 415
Gln Pro Val Val Met Asp Val Tyr Arg Thr Val His Gly Ile Val Thr
420 425 430
Lys Phe Asp Asp Lys Gln Arg Val Ala Tyr Ala Lys Ala Arg Ala Trp
435 440 445
Glu Gly Tyr Glu Leu Gln Ser Leu Met Ala Trp Thr His Lys Ala Gln
450 455 460
Ser Arg Asn Trp Asp Gln Trp Lys Gln Gln Ala Ala Arg His Ala Leu
465 470 475 480
Thr Ile Asn Trp Tyr Tyr Thr Asp Asp Lys Gly Asn Ile Gly Tyr Ala
485 490 495
His Thr Gly Phe Tyr Pro Lys Arg Arg Pro Gly His Asp Pro Arg Leu
500 505 510
Pro Val Pro Gly Thr Gly Glu Met Asp Trp Asp Gly Ile Leu Pro Phe
515 520 525
Ser Thr Asn Pro Gln Val Tyr Asn Pro Arg Gln Gly Phe Ile Ala Asn
530 535 540
Trp Asn Asn Gln Pro Met Arg Gly Tyr Pro Ser Thr Asp Leu Phe Ala
545 550 555 560
Ile Val Trp Gly Gln Ala Asp Arg Tyr Ala Glu Ile Glu Thr Arg Leu
565 570 575
Lys Ala Met Thr Ala Asn Gly Gly Lys Val Ser Ala Gln Gln Met Trp
580 585 590
Asp Leu Ile Arg Thr Thr Ser Tyr Ala Asp Val Asn Arg Arg His Phe
595 600 605
Leu Pro Phe Leu Gln Gln Ala Val Gln Gly Leu Pro Ala Asp Asp Ala
610 615 620
Arg Ala Arg Leu Val Ala Gly Leu Ala Ser Trp Asp Gly Met Gly Thr
625 630 635 640
Ser Asp Lys Gln Pro Gly Tyr Tyr Asp His Thr Gly Pro Ala Val Met
645 650 655
Asp Ala Trp Leu Arg Ala Met Leu Lys Arg Ala Leu Ala Asp Glu Met
660 665 670
Pro Ala Asp Phe Phe Lys Trp Tyr Ser Ala Thr Gly Tyr Pro Thr Gln
675 680 685
Ala Ala Pro Ala Thr Gly Ser Val Asn Leu Thr Val Gly Val Lys Val
690 695 700
Leu Phe Asn Ala Leu Ala Gly Arg Asp Ala Gly Val Pro Gln Gln Tyr
705 710 715 720
Asp Phe Phe Asn Gly Gln Arg Pro Gln Asp Val Thr Leu Ala Ala Leu
725 730 735
Asp Asp Ala Leu Ala Ala Leu Arg Lys Ala Tyr Gly Glu Asp Pro Ala
740 745 750
Gln Trp Arg Ile Pro Ala Pro Pro Met Val Phe Ala Pro Lys Asn Phe
755 760 765
Leu Gly Val Pro Gln Ala Asp Asp Lys Ala Val Leu Ser Phe Pro Ala
770 775 780
Thr Gln Asn Arg Gly Thr Glu Asn Asn Met Thr Val Phe Asp Gly Lys
785 790 795 800
Gly Val Arg Ala Val Asp Val Val Ala Pro Gly Gln Ser Gly Phe Val
805 810 815
Ala Pro Asp Gly Thr Pro Ser Pro His Ala Arg Asp Gln Phe Asp Leu
820 825 830
Tyr Thr Ser Phe Gly Ser Lys Arg Val Trp Phe Thr Asp Ala Glu Val
835 840 845
Arg Ala His Ala Lys Ser Val Glu Thr Leu Arg Tyr
850 855 860
Claims (14)
1.一种青霉素G酰化酶突变体,其特征在于,将SEQ ID NO:2所示青霉素G酰化酶氨基酸序列的第186位、187位、329位氨基酸残基中的一个或多个突变为另一种氨基酸残基,获取所述突变体;
所述第186位氨基酸残基突变为丙氨酸、天冬氨酸或赖氨酸;
所述第187位氨基酸残基突变为异亮氨酸或缬氨酸;
所述第329位氨基酸残基突变为丙氨酸、甘氨酸、异亮氨酸、缬氨酸或丝氨酸;
所述突变体不包含F329I、R186D/F329I、R186L/F329I、R186L/F329V、R186A/F329S。
2.根据权利要求1所述的青霉素G酰化酶突变体,其特征在于,所述第186位氨基酸残基突变为丙氨酸。
3.根据权利要求1所述的青霉素G酰化酶突变体,其特征在于,所述第187位氨基酸残基突变为异亮氨酸。
4.根据权利要求1所述的青霉素G酰化酶突变体,其特征在于,所述第329位氨基酸残基突变为甘氨酸。
5.根据权利要求1所述的青霉素G酰化酶突变体,其特征在于,所述突变体为R186A/F187I、R186A/F329G、F187I/F329G或R186A/F187I/F329G。
6.包含权利要求1-5任一项所述青霉素G酰化酶突变体基因的重组载体。
7.包含权利要求1-5任一项所述青霉素G酰化酶突变体基因的重组菌株。
8.权利要求1-5任一项所述青霉素G酰化酶突变体在酶法合成头孢孟多中的应用。
9.根据权利要求8所述的应用,其特征在于,反应底物头孢甲肟中间体7-TMCA和侧链R-扁桃酸甲酯R-MMA浓度范围10mM-100mM;R-MMA与7-TMAC的摩尔比为1~1.5:1。
10.根据权利要求9所述的应用,其特征在于,R-MMA与7-TMAC的摩尔比为1.3:1。
11.根据权利要求8所述的应用,其特征在于,反应体系中添加甘油;甘油添加浓度为≤50%(V/V)。
12.根据权利要求11所述的应用,其特征在于,甘油添加浓度为30%(V/V)。
13.根据权利要求8所述应用,其特征在于,反应体系温度为5~30℃;反应体系初始pH为5.8~6.6。
14.根据权利要求13所述应用,其特征在于,反应体系温度为20℃;反应体系初始pH为6.0。
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