CN115109760A - 单胺氧化酶及其在制备药物中间体中的应用 - Google Patents
单胺氧化酶及其在制备药物中间体中的应用 Download PDFInfo
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- CN115109760A CN115109760A CN202210346741.XA CN202210346741A CN115109760A CN 115109760 A CN115109760 A CN 115109760A CN 202210346741 A CN202210346741 A CN 202210346741A CN 115109760 A CN115109760 A CN 115109760A
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- azabicyclo
- dimethyl
- hexane
- monoamine oxidase
- gly
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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- C12N9/0012—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7)
- C12N9/0014—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4)
- C12N9/0022—Oxidoreductases (1.) acting on nitrogen containing compounds as donors (1.4, 1.5, 1.6, 1.7) acting on the CH-NH2 group of donors (1.4) with oxygen as acceptor (1.4.3)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
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- C12N15/70—Vectors or expression systems specially adapted for E. coli
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种单胺氧化酶及其在制备药物中间体中的应用。所述单胺氧化酶具有如SEQ ID No:2或SEQ ID No:4所示的氨基酸序列。本发明的单胺氧化酶用于制备药物例如波普瑞韦(Boceprevir)和奈玛特韦(Nirmatrelvir)中间体,酶活更高,反应效率更高,如反应时间更短,进而提高了生产效率,从而降低了生产成本。
Description
技术领域
本发明涉及生物工程技术领域,具体地涉及一种单胺氧化酶在制备药物例如波普瑞韦(Boceprevir)和奈玛特韦(Nirmatrelvir)中间体中的应用。
背景技术
波普瑞韦(Boceprevir),化学名为(1R,2S,5S)-N-(4-氨基-1-环丁基-3,4- 二氧代丁烷-2-基)-2-[(2S)-2-(叔丁胺基甲酰胺基)-3,3-二甲基丁酰基]-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-甲酰胺,是由美国Schering公司研发的 HCVNS3/4A蛋白酶抑制剂,2011年5月经美国FDA批准上市,临床用于治疗慢性丙型肝炎,商品名为Victrelis。
帕罗韦德(Paxlovid)其中的组成成分奈玛特韦的结构式如下:
其中,(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯或其盐是波普瑞韦和奈玛特韦的重要中间体。其结构式如下:
CN102131813B公开了制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯或其盐的方法,其先采用单胺氧化酶催化6,6-二甲基-3-氮杂二环[3.1.0]己烷氧化制得(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯,再经亚硫酸氢钠加成得到(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸钠化合物,再经NaCN处理得到(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷- 2-腈化合物,再经水解,酯化得到(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯。反应路线如下:
其中单胺氧化酶采用来源于野生型黑曲霉和野生型米曲霉的单胺氧化酶或其突变体。来自黑曲霉的野生型单胺氧化酶的催化反应中,有20%的胺转化为亚胺中间体,而来自米曲霉的野生型单胺氧化酶催化反应中,40%的胺转化为亚胺中间体。进而对野生型酶进行改造,获得突变体,突变体的酶活更好,其中SEQ ID NO:12的酶活最高。
为了获得高产率,光学纯度高的产品,单胺氧化酶至关重要,因此有必要筛选出更高活性,更高催化效率的单胺氧化酶。
发明内容
本发明所要解决的技术问题是为了克服现有技术中将6,6-二甲基-3-氮杂二环[3.1.0]己烷氧化制得(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的单胺氧化酶酶活低,反应效率不高等缺陷,提供了一种单胺氧化酶及其在制备药物例如波普瑞韦(Boceprevir)和奈玛特韦(Nirmatrelvir)中间体中的应用。将本发明的单胺氧化酶用于制备波普瑞韦或奈玛特韦中间体,酶活更高,反应效率更高,如反应时间更短,进而提高了生产效率,从而降低了生产成本。
为解决上述技术问题,本发明的第一方面提供了一种单胺氧化酶,所述的单胺氧化酶具有如SEQ ID No:2或SEQ ID No:4所示的氨基酸序列。
本发明的第二方面提供了一种分离的核酸,所述的核酸编码如第一方面所述的单胺氧化酶。
本发明的一些实施方案中,所述的核酸的序列如SEQ ID No:3或SEQ ID No:5所示。
本发明的第三方面提供了一种重组表达载体,其包含如第二方面所述的核酸。
所述重组表达载体的骨架可为本领域常规,在本发明一具体实施方案中,所述重组表达载体的骨架为质粒pET28a。
本发明的第四方面提供了一种转化体,其包含如第二方面所述的核酸或如第三方面所述的重组表达载体。
本发明的一具体实施方案中,所述转化体的宿主细胞为埃希氏大肠杆菌(Escherichia coli)例如E.coli BL21(DE3)。
本发明的第五方面提供了一种制备单胺氧化酶的方法,其包括发酵培养如第四方面所述的转化体,使表达所述单胺氧化酶。
优选地,所述方法还包括利用所述转化体发酵生产获得的菌泥制备菌粉,和/或,利用所述转化体发酵生产获得的菌泥破碎后的上清进一步纯化的步骤。
本发明的第六方面提供了一种制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的方法,所述方法包括步骤:在选自辅因子FAD、FMN、NAD 和NADP的一种或多种和氧的存在下,在第一方面所述的单胺氧化酶或本发明的第五方面的方法制备的单胺氧化酶的存在下,将底物6,6-二甲基-3-氮杂二环[3.1.0]己烷进行氧化制得(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯。
所述辅因子优选地为FAD。
所述的氧化反应会产生过氧化氢,过氧化氢是能够灭活单胺氧化酶的强氧化剂。因此本发明的一些实施方案中,所述方法还包括加入过氧化氢酶催化过氧化氢的步骤。
本发明的一些实施方案中,所述底物的浓度为10~100g/L;
所述单胺氧化酶与底物的质量比为:1:1~1:5,例如1:2;
所述氧化的pH为7.2~7.4;所述pH优选为7.3;
所述氧化的温度为20~25℃,所述温度优选为23℃。
本发明的第七方面提供了一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐的方法,所述方法包括根据第六方面所述的方法制备 (1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的步骤,并且包括将(1R,5S) -6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯和亚硫酸氢盐进行加成反应的步骤;
本发明的一个实施方案中,所述亚硫酸氢盐优选为亚硫酸氢钠。
本发明的第八方面提供了一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈的方法,所述方法包括:
(a)采用如第七方面所述方法生产(1R,2S,5S)-6,6-二甲基-3-氮杂双环 [3.1.0]己烷-2-磺酸盐的步骤,并且包括将(1R,2S,5S)-6,6-二甲基-3-氮杂双环 [3.1.0]己烷-2-磺酸盐与氰化物接触的步骤;或
(b)采用本发明第六方面所述的方法制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的步骤,并且包括将(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0] 己-2-烯与氰化物接触反应的步骤;或者采用由第七方面所述的方法制备 (1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐,再加入碱例如NaOH,反应产物与氰化物接触的步骤。
所述氰化物可为本领域常规,本发明的一些实施方案中,所述氰化物为 NaCN或者三甲基氰硅烷。
本发明的第九方面提供了一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸的方法,所述方法包括采用如第八方面所述方法生产(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈的步骤,并且包括将 (1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈进行水解制得酸的步骤。
本发明的第十方面提供了一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环 [3.1.]己烷-2-羧酸酯或其盐的方法,所述方法包含采用第九方面所述方法制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸的步骤,并且包括将 (1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸与醇接触进行酯化的步骤。
所述醇为本领域常规,如甲醇或乙醇。本发明一实施方案中,所述醇为甲醇。
本发明的第十一方面提供了如第一方面所述的单胺氧化酶在制备 (1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2- 腈、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.]己烷-2-羧酸酯或其盐中的应用。
在符合本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
将本发明的单胺氧化酶用于制备波普瑞韦或奈玛特韦中间体,酶活更高,反应效率更高,进而提高了生产效率,从而降低了生产成本。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
本发明中的实验方法如无特别说明均为常规方法,基因克隆操作具体可参考J.萨姆布鲁克等编的《分子克隆实验指南》。
实施例中使用的生物材料和试剂如下表1所示:
表1生物材料和试剂
实施例中的基因合成、引物合成与基因测序工作由上海生工生物工程有限公司完成。
实施例3和4中原料转化率通过分析气相色谱检测,检测条件如下:
色谱柱:HP-5(30m*0.32mm,0.25μm);
进样口:250℃;检测器:280℃;升温程序:以初始温度70℃保持5min,以10℃每分钟的速率升温至280℃,保持6min;柱流量(载气N2):1mL/min;分流比:25:1;运行时间:27min;进样体积:0.5μL;空气:300mL/min;氢气:30mL/min;氮气:25mL/min。
产物化合物6经过碱处理后,通过高效液相色谱进行手性分析,具体的分析方法如下:
色谱柱:Daicel Chiralpak AD-H(4.6mm*250mm,5μm);流动相:正庚烷:乙醇:DEA=98:2:0.1;检测波长:220nm;流速:0.6ml/min;柱温:25℃;进样体积:10μl;运行时间:40min。
实施例1基因工程菌的构建与表达
根据表2所示的单胺氧化酶基因,均由生工生物工程(上海)股份有限公司(上海市松江区香闵路698号)全基因合成,所用酶切位点为Nde I、 Hind III,克隆至pET28a载体,获得含有目标酶基因的重组质粒,使得N端带有His标签,以便于后期筛选过程中的蛋白纯化。
表2单胺氧化酶列表
酶编号 | 核苷酸序列 | 氨基酸序列 |
1 | SEQ ID No:5 | CN102131813B SEQ ID No:12 |
2 | SEQ ID No:1 | SEQ ID No:2 |
3 | SEQ ID No:3 | SEQ ID No:4 |
将已经构建好的重组质粒转入表达宿主E.coli BL21(DE3),涂布在含50 μg/mL的卡那抗性LB平板上,37℃倒置培养16h,挑取单菌落接种至含50 μg/mL卡那霉素的5mL LB液体培养基中,37℃220rpm培养,OD600至0.6- 0.8时得种子液,再将种子液以1%接种量接种至含50μg/mL卡那霉素的TB 液体培养基中,37℃220rpm培养,OD600至0.3-0.4时,添加终浓度0.1mM 的IPTG于25℃220rpm诱导16h,4000rpm离心20min,弃去上清,收集湿菌体,-20℃冰箱保存,备用。
实施例2单胺氧化酶的制备
取实施例1所制备的湿菌体5g,悬浮于50mL 50mM pH 7.0的PBS缓冲液中,4℃600Bar均质破碎,将所得破碎液于12000rpm离心5min,去除沉淀,所得上清即为单胺氧化酶的粗酶液,用Bradford法蛋白定量试剂盒测定蛋白浓度。
将上述所得粗酶液分别用Ni柱纯化,所得酶液即为目标酶的纯酶液。用Bradford法蛋白定量试剂盒检测蛋白浓度,取部分酶液,统一将所得的纯化蛋白用50mM pH 7.0的PBS稀释至终浓度25mg/mL,剩余纯酶于-80℃冰箱保存,备用。
实施例3单胺氧化酶的生物催化活力比较
称0.5g底物6,6-二甲基-3-氮杂双环[3.1.0]己烷,加75mL水,用H3PO4调pH 7.5变澄清,加过氧化氢酶1mL,再加入实施例2制得的单胺氧化酶纯酶酶液1mL,补水至终体积100mL,25℃搅拌,通气(速率为2L/min)。反应体系用20%的Na2CO3调控pH 7.2-7.4。反应30min,测转化率,结果如表3所示。
表3不同来源的单胺氧化酶的催化转化率
酶编号 | 30min转化率 |
1 | 5% |
2 | 15% |
3 | 13% |
实施例4(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的制备
按照实施例1的方式发酵生产菌泥,用20mM pH8.0的磷酸钾缓冲液重悬均质,冷冻干燥,制成酶粉。
向100mL烧瓶中添加25mL 100mM pH3.0磷酸钾缓冲液和330μL底物,得到均匀的溶液。用浓H3PO4将pH调节至大约7.5。向经pH调节的溶液中添加60μL过氧化氢酶悬浮液(SigmaAldrich;目录号C3515)和在pH8.0 的磷酸钾缓冲液中的150mg CN102131813B中SEQ IDNo:12,本发明中SEQ ID No:2或SEQ ID No:4的单胺氧化酶粉末。搅拌200r/min,空气流速40m3/h,10%氢氧化钠水溶液控pH7.3,23℃下反应12小时。用10N NaOH将pH增至大约14来淬灭反应,取样分析转化率。
酶编号 | 12小时转化率 |
1 | 75% |
2 | 98% |
3 | 99% |
实施例5(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.]己烷-2-羧酸甲酯的制备
5.1(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸钠(化合物3)合成
将酶液500g,过氧化氢分解酶5g,消泡剂3g,加入发酵罐,升温至23℃,搅拌200r/min,通入空气0.016m3/h,将底物溶液(62.5g NaHSO3溶于250g 水中,缓慢加入50g化合物1配成底物溶液),在5h内滴加至发酵罐,10%氢氧化钠水溶液控pH7.3,流加完毕继续反应0.5h至原料转化完,GC检测收率95%,反应液降温至10度,加硅藻土板框压滤,滤液超滤得化合物3 水溶液900g备用。
5.2(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈(化合物4)的合成
5.2.1将化合物3水溶液900g,甲基叔丁基醚250g加入反应瓶,降温至 10度,1.5h内流加NaCN(97.4g,30%)至反应中,保温2h,静置分层,水相用甲基叔丁基醚100g萃取,有机相合并用100g饱和食盐水洗,浓缩至 250g备用;
5.2.2向化合物3水溶液900g中加入900g甲基叔丁基醚,降温至10度,缓慢加入15%的氢氧化钠溶液300g,搅拌0.5h静置分出有机相,向有机相缓慢加入三甲基氰硅烷68.12g,保温1h,有机相用5%的氢氧化钠水溶液 100g洗涤,浓缩至250g备用;
5.3(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸(化合物5)的合成
将250g化合物4溶液在1h内滴加到6M的盐酸300g中,加热50度保温5h,减压浓缩至干,用含水5%的四氢呋喃300g打浆,抽滤得到60g白色固体化合物5。
5.4(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸甲酯盐酸盐(化合物 6)合成
将60g化合物5加入到甲醇300g中,降温至10度,缓慢滴加氯化亚砜 55.7g,升温至60度保温2h,减压浓缩至干,降温至0度,加100g MeOH溶解,滴加甲基叔丁基醚600g,保温2h,抽滤烘干得50g白色固体化合物6。经手性HPLC检测,未检测到2R立体异构体。
SEQUENCE LISTING
<110> 弈柯莱生物科技(上海)股份有限公司
<120> 单胺氧化酶及其在制备药物中间体中的应用
<130> P22012050C
<160> 5
<170> PatentIn version 3.5
<210> 1
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 单胺氧化酶2基因
<400> 1
atgacctctc gtgacggtta ccagtggacc ccgaaaaccg gtctgaccca gggtgttccg 60
tctctgggtg ctatctctcc gccgaccaac atcgaagaca ccgacaaaga cggtccgtgg 120
gacgttatcg ttatcggtgg tggttactgc ggtctgaccg ctacccgtga cctgaccgtt 180
gctggtttca aaaccctgct gctggaagct cgtgaccgta tcggtggtcg ttcttggtct 240
tctaacatcg acggttaccc gtacgaaatg ggtggtacct gggttcactg gcaccagtct 300
cacgtttggc gtgaaatcac ccgttacaaa atgcagaacg ctctgtctcc gtctttcaac 360
ttctctcgtg gtgttaacca cttccagctg cgtaccaacc cgaccacctc tacctacatg 420
acccacgaag ctgaagacga actgctgcgt tctgctctgc acaaattcac caacgttgac 480
ggtaccaacg gtcgtaccgt tctgccgttc ccgcacgaca tgttctacgt tccggaattc 540
cgtaaatacg acgaaatgtc ttacgctgaa cgtatcgacc agatccgtga cgaactgtct 600
ctgaacgaac gttcttctct ggaagctttc atcctgctgt gctctggtgg taccctggaa 660
aactcttctt tcggtgaatt cctgcactgg tgggctatgt ctggttacac ctaccagggt 720
tgcatggact gcctgatctc ttacaaattc accgacggtc agtctgcttt cgctcgtaaa 780
ttctgggaag aagctgttgg taccggtcgt ctgggttacg ttttcggttg cccggttcgt 840
tctgttgtta acggtaacgg tggtaacggt gttcgtgtta ccgctcgtga cggtcgtgaa 900
ttcgttgcta aacgtgttgt ttgcaccatc ccgctgaacg ttctgtcttc tgttcacttc 960
tctccgccgc tgtctccgca gcgtatggct gctgctaaca tcggtcacgt taaccagtgc 1020
gttaaagttc acgctgaagt ttcttgcccg gacatgcgtt cttggtctgg tatctcttac 1080
ccgttcaaca aactggctta cgctatcggt gacggtacca ccccggctgg taacacccac 1140
atcgtttgcc tgggtggtgc tcacaaccac atccagccgg aagaagacgt tgaagctacc 1200
aaaatggctg ttgaaaacat gtctccgggt aacatggaca tcaaacgtct ggttttccac 1260
aactggtgca aagacgaatt cgctaaaggt gcttggttct tcgctccgcc gcagctgctg 1320
tctaaatctc tggacgaact gcgttgccgt cacggtaacg ttctgttcgc taactctgac 1380
tgggctctgg gttggcgtgg tttcatcgac ggtgctatcg aagaaggtac ccgtgctgct 1440
gttaccgtta tcgaagaact gcgtccggct ccggctgttc gttctcacct g 1491
<210> 2
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> 单胺氧化酶2
<400> 2
Met Thr Ser Arg Asp Gly Tyr Gln Trp Thr Pro Lys Thr Gly Leu Thr
1 5 10 15
Gln Gly Val Pro Ser Leu Gly Ala Ile Ser Pro Pro Thr Asn Ile Glu
20 25 30
Asp Thr Asp Lys Asp Gly Pro Trp Asp Val Ile Val Ile Gly Gly Gly
35 40 45
Tyr Cys Gly Leu Thr Ala Thr Arg Asp Leu Thr Val Ala Gly Phe Lys
50 55 60
Thr Leu Leu Leu Glu Ala Arg Asp Arg Ile Gly Gly Arg Ser Trp Ser
65 70 75 80
Ser Asn Ile Asp Gly Tyr Pro Tyr Glu Met Gly Gly Thr Trp Val His
85 90 95
Trp His Gln Ser His Val Trp Arg Glu Ile Thr Arg Tyr Lys Met Gln
100 105 110
Asn Ala Leu Ser Pro Ser Phe Asn Phe Ser Arg Gly Val Asn His Phe
115 120 125
Gln Leu Arg Thr Asn Pro Thr Thr Ser Thr Tyr Met Thr His Glu Ala
130 135 140
Glu Asp Glu Leu Leu Arg Ser Ala Leu His Lys Phe Thr Asn Val Asp
145 150 155 160
Gly Thr Asn Gly Arg Thr Val Leu Pro Phe Pro His Asp Met Phe Tyr
165 170 175
Val Pro Glu Phe Arg Lys Tyr Asp Glu Met Ser Tyr Ala Glu Arg Ile
180 185 190
Asp Gln Ile Arg Asp Glu Leu Ser Leu Asn Glu Arg Ser Ser Leu Glu
195 200 205
Ala Phe Ile Leu Leu Cys Ser Gly Gly Thr Leu Glu Asn Ser Ser Phe
210 215 220
Gly Glu Phe Leu His Trp Trp Ala Met Ser Gly Tyr Thr Tyr Gln Gly
225 230 235 240
Cys Met Asp Cys Leu Ile Ser Tyr Lys Phe Thr Asp Gly Gln Ser Ala
245 250 255
Phe Ala Arg Lys Phe Trp Glu Glu Ala Val Gly Thr Gly Arg Leu Gly
260 265 270
Tyr Val Phe Gly Cys Pro Val Arg Ser Val Val Asn Gly Asn Gly Gly
275 280 285
Asn Gly Val Arg Val Thr Ala Arg Asp Gly Arg Glu Phe Val Ala Lys
290 295 300
Arg Val Val Cys Thr Ile Pro Leu Asn Val Leu Ser Ser Val His Phe
305 310 315 320
Ser Pro Pro Leu Ser Pro Gln Arg Met Ala Ala Ala Asn Ile Gly His
325 330 335
Val Asn Gln Cys Val Lys Val His Ala Glu Val Ser Cys Pro Asp Met
340 345 350
Arg Ser Trp Ser Gly Ile Ser Tyr Pro Phe Asn Lys Leu Ala Tyr Ala
355 360 365
Ile Gly Asp Gly Thr Thr Pro Ala Gly Asn Thr His Ile Val Cys Leu
370 375 380
Gly Gly Ala His Asn His Ile Gln Pro Glu Glu Asp Val Glu Ala Thr
385 390 395 400
Lys Met Ala Val Glu Asn Met Ser Pro Gly Asn Met Asp Ile Lys Arg
405 410 415
Leu Val Phe His Asn Trp Cys Lys Asp Glu Phe Ala Lys Gly Ala Trp
420 425 430
Phe Phe Ala Pro Pro Gln Leu Leu Ser Lys Ser Leu Asp Glu Leu Arg
435 440 445
Cys Arg His Gly Asn Val Leu Phe Ala Asn Ser Asp Trp Ala Leu Gly
450 455 460
Trp Arg Gly Phe Ile Asp Gly Ala Ile Glu Glu Gly Thr Arg Ala Ala
465 470 475 480
Val Thr Val Ile Glu Glu Leu Arg Pro Ala Pro Ala Val Arg Ser His
485 490 495
Leu
<210> 3
<211> 1491
<212> DNA
<213> Artificial Sequence
<220>
<223> 单胺氧化酶3基因
<400> 3
atgacctctc gtgacggtta ccagtggacc ccggaaaccg gtctgaccca gggtgttccg 60
tctctgggtg ttatctctcc gccgaccaac atcaaagacg aagacaaaga cggtccgtgg 120
gacgttatcg ttatcggtgg tggttactgc ggtctgaccg ctacccgtga cctgaccgtt 180
gctggtttca aaaccctgct gctggaagct cgtgaccgta tcggtggtcg ttcttggtct 240
tctaacatcg acggttaccc gtacgaaatg ggtggtacct gggttcactg gcaccagtct 300
cacgtttggc gtgaaatcac ccgttacaaa atgcacaacg ctctgtctcc gtctttcaac 360
ttctctcgtg gtgttaacca cttccagctg cgtaccaacc cgacctcttc tacctacatg 420
acccacgaag ctgaagacga actgctgcgt tctgctctgc acaaattcac caacgttgac 480
ggtaccaacg gtcgtaccgt tctgccgttc ccgcacgaca tgttctacgt tccggaattc 540
cgtaaatacg acgaaatgtc ttacgctgaa cgtatcgaac agatcaaaga cgaactgtct 600
ctgaacgaac gttcttctct ggaagctttc atcctgctgt gctctggtgg tcgtatggaa 660
aactcttctt tcggtgaatt cctgcactgg tgggctatgt ctggttacac ctaccagggt 720
tgcatggact gcctgatctc ttacaaattc accgaaggtc agtctgcttt cgctcgtcgt 780
ttctgggaag aagctatggg taccggtcgt ctgggttacg ttttcgaatg cccggttcgt 840
tctgttgttg acgaaaaagg tggtcgtggt gttcgtgtta ccgctcgtga cggtcgtgaa 900
ttcgttgcta aacgtgttgt ttgcaccatc ccgctgaacg ttctgtcttc tgttcacttc 960
tctccgccgc tgtctccgca gcgtatggct gctgctaaca tcggtcacgt taaccagtgc 1020
gttaaagttc acgctgaagt ttcttgcccg gacatgcgtt cttggtctgg tatctcttac 1080
ccgttcaaca aactggctta cgctatcggt gacggtacca ccccggctgg taacacccac 1140
atcgtttgcc tgggtggtgc tcacaaccac atccagccgg aagaagacgt tgaagctacc 1200
aaaatggctg ttgaaaacat gtctccgggt aacatggaca tcaaacgtct ggttttccac 1260
aactggtgca aagacgaatt cgctaaaggt gcttggttct tcgctccgcc gcagctgctg 1320
tctaaatctc tggacgaact gcgttgccgt cacggtaacg ttctgttcgc taactctgac 1380
tgggctctgg gttggcgtgg tttcatcgac ggtgctatcg aagaaggtac ccgtgctgct 1440
gttaccgtta tcgaagaact gcgtccggct ccggctgttc gttctcacct g 1491
<210> 4
<211> 497
<212> PRT
<213> Artificial Sequence
<220>
<223> 单胺氧化酶3
<400> 4
Met Thr Ser Arg Asp Gly Tyr Gln Trp Thr Pro Glu Thr Gly Leu Thr
1 5 10 15
Gln Gly Val Pro Ser Leu Gly Val Ile Ser Pro Pro Thr Asn Ile Lys
20 25 30
Asp Glu Asp Lys Asp Gly Pro Trp Asp Val Ile Val Ile Gly Gly Gly
35 40 45
Tyr Cys Gly Leu Thr Ala Thr Arg Asp Leu Thr Val Ala Gly Phe Lys
50 55 60
Thr Leu Leu Leu Glu Ala Arg Asp Arg Ile Gly Gly Arg Ser Trp Ser
65 70 75 80
Ser Asn Ile Asp Gly Tyr Pro Tyr Glu Met Gly Gly Thr Trp Val His
85 90 95
Trp His Gln Ser His Val Trp Arg Glu Ile Thr Arg Tyr Lys Met His
100 105 110
Asn Ala Leu Ser Pro Ser Phe Asn Phe Ser Arg Gly Val Asn His Phe
115 120 125
Gln Leu Arg Thr Asn Pro Thr Ser Ser Thr Tyr Met Thr His Glu Ala
130 135 140
Glu Asp Glu Leu Leu Arg Ser Ala Leu His Lys Phe Thr Asn Val Asp
145 150 155 160
Gly Thr Asn Gly Arg Thr Val Leu Pro Phe Pro His Asp Met Phe Tyr
165 170 175
Val Pro Glu Phe Arg Lys Tyr Asp Glu Met Ser Tyr Ala Glu Arg Ile
180 185 190
Glu Gln Ile Lys Asp Glu Leu Ser Leu Asn Glu Arg Ser Ser Leu Glu
195 200 205
Ala Phe Ile Leu Leu Cys Ser Gly Gly Arg Met Glu Asn Ser Ser Phe
210 215 220
Gly Glu Phe Leu His Trp Trp Ala Met Ser Gly Tyr Thr Tyr Gln Gly
225 230 235 240
Cys Met Asp Cys Leu Ile Ser Tyr Lys Phe Thr Glu Gly Gln Ser Ala
245 250 255
Phe Ala Arg Arg Phe Trp Glu Glu Ala Met Gly Thr Gly Arg Leu Gly
260 265 270
Tyr Val Phe Glu Cys Pro Val Arg Ser Val Val Asp Glu Lys Gly Gly
275 280 285
Arg Gly Val Arg Val Thr Ala Arg Asp Gly Arg Glu Phe Val Ala Lys
290 295 300
Arg Val Val Cys Thr Ile Pro Leu Asn Val Leu Ser Ser Val His Phe
305 310 315 320
Ser Pro Pro Leu Ser Pro Gln Arg Met Ala Ala Ala Asn Ile Gly His
325 330 335
Val Asn Gln Cys Val Lys Val His Ala Glu Val Ser Cys Pro Asp Met
340 345 350
Arg Ser Trp Ser Gly Ile Ser Tyr Pro Phe Asn Lys Leu Ala Tyr Ala
355 360 365
Ile Gly Asp Gly Thr Thr Pro Ala Gly Asn Thr His Ile Val Cys Leu
370 375 380
Gly Gly Ala His Asn His Ile Gln Pro Glu Glu Asp Val Glu Ala Thr
385 390 395 400
Lys Met Ala Val Glu Asn Met Ser Pro Gly Asn Met Asp Ile Lys Arg
405 410 415
Leu Val Phe His Asn Trp Cys Lys Asp Glu Phe Ala Lys Gly Ala Trp
420 425 430
Phe Phe Ala Pro Pro Gln Leu Leu Ser Lys Ser Leu Asp Glu Leu Arg
435 440 445
Cys Arg His Gly Asn Val Leu Phe Ala Asn Ser Asp Trp Ala Leu Gly
450 455 460
Trp Arg Gly Phe Ile Asp Gly Ala Ile Glu Glu Gly Thr Arg Ala Ala
465 470 475 480
Val Thr Val Ile Glu Glu Leu Arg Pro Ala Pro Ala Val Arg Ser His
485 490 495
Leu
<210> 5
<211> 1485
<212> DNA
<213> Artificial Sequence
<220>
<223> 单胺氧化酶1基因
<400> 5
atgaccagcc gcgatggtta tcagtggacc ccggaaaccg gtctgaccca gggcgtgccg 60
agcctgggcg tgattagtcc gccgaccaat attgaagata ccgataaaga tggtccgtgg 120
gatgttattg ttattggtgg tggttattgt ggtctgaccg caacccgtga tctgaccgtt 180
gcgggtttta aaaccctgct gctggaagca cgtgatcgca ttggtggtcg tagctggagc 240
agcaatattg atggttatcc gtatgaaatg ggtggcacct gggtgcattg gcatcagtca 300
catgtgtggc gtgaaattac ccgttataaa atgcataatg cactgtcacc gagctttaat 360
tttagccgtg gtgttaatca ttttcagctg cgtaccaatc cgaccaccag cacctatatg 420
acccatgaag cagaagatga actgctgcgt agcgcactgc ataaatttac caatgttgat 480
ggcaccaatg gtcgtaccgt tctgccgttt ccgcatgata tgttttatgt tccggaattt 540
cgtaaatatg atgaaatgag ctatagcgaa cgtattgatc agattcgtga tgaactgagc 600
ctgaatgaac gtagtagcct ggaagccttt attctgctgt gcagcggtgg caccctggaa 660
aattctagct ttggtgaatt tctgcattgg tgggcgatga gcggttatac ctatcagggt 720
tgtatggatt gtctgattag ctataaattt aaagatggtc agagcgcctt tgcccgtcgc 780
ttttgggaag aagcggcagg caccggtcgt ctgggctatg tttttggttg cccggttcgt 840
agcgtggtga atgaacgtga tgcggtgcgt gtgacagcgc gtgatggtcg tgaatttgcg 900
gcaaaacgtc tggtttgcac cattccgctg aatgttctga gtagcgttca tttttcaccg 960
ccgctgagcc cgcagcgcat ggccgcagcg aatattggtc atgtgaatca gtgtgttaaa 1020
gtgcatgcag aagttagctg cccggatatg cgtagttgga gcggtattag ttatccgttt 1080
aataaactgg cctatgccat tggtgatggt accaccccgg cgggtaatac ccatattgtg 1140
tgtctgggtg gtgcacataa tcatattcag ccggaagaag atgtggaagc caccaaaatg 1200
gcagttgaaa atatgagccc aggtaatatg gatattaaac gtctggtttt tcataattgg 1260
tgtaaagatg aatttgcgaa aggcgcatgg tttttcgccc cgccgcagct gctgagcaaa 1320
tcactggatg aactgcgttg tcgtcatggt aatgtgctgt ttgccaatag tgattgggca 1380
ctgggttggc gcggttttat tgatggcgcc attgaagaag gtacccgtgc agcggtgacc 1440
gtgattgaag aactgcgtcc ggccccggca gttcgtagcc atctg 1485
Claims (12)
1.一种单胺氧化酶,其特征在于,所述的单胺氧化酶具有如SEQ ID No:2或SEQ ID No:4所示的氨基酸序列。
2.一种分离的核酸,其特征在于,所述的核酸编码如权利要求1所述的单胺氧化酶;
较佳地,所述的核酸的序列如SEQ ID No:3或SEQ ID No:5所示。
3.一种重组表达载体,其特征在于,其包含如权利要求2所述的核酸;
较佳地,所述重组表达载体的骨架为质粒pET28a。
4.一种转化体,其特征在于,其包含如权利要求2所述的核酸或如权利要求3所述的重组表达载体;
较佳地,所述转化体的宿主细胞为埃希氏大肠杆菌(Escherichia coli),例如E.coliBL21(DE3)。
5.一种制备单胺氧化酶的方法,其特征在于,所述方法包括发酵培养如权利要求4所述的转化体,使表达所述单胺氧化酶;
较佳地,所述方法还包括利用所述转化体发酵生产获得的菌泥制备菌粉的步骤,和/或,
利用所述转化体发酵生产获得的菌泥破碎后的上清进一步纯化的步骤。
6.一种制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的方法,其特征在于,所述方法包括步骤:在选自辅因子FAD、FMN、NAD和NADP的一种或多种和氧的存在下,在如权利要求1所述的单胺氧化酶或权利要求5的方法所制备的单胺氧化酶的存在下,将底物即6,6-二甲基-3-氮杂二环[3.1.0]己烷进行氧化制得(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯;
较佳地,所述方法还包括加入过氧化氢酶催化所述氧化所产生的过氧化氢的步骤。
7.权利要求6所述的方法,其特征在于,所述底物的浓度为10~150g/L;
所述单胺氧化酶与底物的质量比为:1:1~1:5,例如1:2;
所述氧化的pH为7.2~7.4;所述pH优选为7.3;
所述氧化的温度为20~25℃,所述温度优选为23℃。
8.一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐的方法,其特征在于,所述方法包括根据权利要求6或7所述的方法制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的步骤,并且包括将(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯和亚硫酸氢盐进行加成反应的步骤;
所述亚硫酸氢盐优选为亚硫酸氢钠。
9.一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈的方法,其特征在于,所述方法包括:
(a)采用如权利要求8所述方法制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐的步骤,并且包括将(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐与氰化物接触的步骤;较佳地,所述氰化物为NaCN;或,
(b)采用如权利要求6-7任一项的所述的方法制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯的步骤,并将包括将(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯与氰化物接触反应的步骤;或者采用如权利要求8所述的方法制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐,再加入碱例如NaOH,反应产物与氰化物接触的步骤;较佳地,所述氰化物为三甲基氰硅烷。
10.一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸的方法,其特征在于,所述方法包括:
采用如权利要求9所述方法生产(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈的步骤,并且包括将(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈进行水解制得酸的步骤。
11.一种制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.]己烷-2-羧酸酯或其盐的方法,其特征在于,所述方法包括:
采用如权利要求10所述方法制备(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸的步骤,并且包括将(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸与醇接触进行酯化的步骤;
优选地,所述醇为甲醇或乙醇。
12.如权利要求1所述的单胺氧化酶在制备(1R,5S)-6,6-二甲基-3-氮杂二环[3.1.0]己-2-烯、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-磺酸盐、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-腈、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.0]己烷-2-羧酸、(1R,2S,5S)-6,6-二甲基-3-氮杂双环[3.1.]己烷-2-羧酸酯或其盐中的应用。
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