CN112746066A - 一种l-赖氨酸脱羧酶突变体及其应用 - Google Patents
一种l-赖氨酸脱羧酶突变体及其应用 Download PDFInfo
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- CN112746066A CN112746066A CN202110097255.4A CN202110097255A CN112746066A CN 112746066 A CN112746066 A CN 112746066A CN 202110097255 A CN202110097255 A CN 202110097255A CN 112746066 A CN112746066 A CN 112746066A
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Abstract
本发明公开了一种L‑赖氨酸脱羧酶突变体及其应用，其氨基酸序列为SEQ ID NO:3，能够有效催化L‑赖氨酸的脱羧反应、但不催化D‑赖氨酸反应，从而通过外消旋体拆分法制备D‑赖氨酸，具有较好的工业化应用前景。
Description
技术领域
本发明属于基因工程和酶催化技术领域，具体地说，涉及一种L-赖氨酸脱羧酶(L-lysine decarboxylase，LdcA)突变体、及其在通过外消旋体拆分法制备D-赖氨酸中的用途。
背景技术
D-型氨基酸多为人工合成氨基酸，但在许多植物、微生物和高等植物中都有D-氨基酸的存在，它在医药、食品和新型农药方法有广泛的用途，科研人员在海洋嗜热菌中也鉴定到了D-赖氨酸合成途径的存在。D-赖氨酸(D-Lys)是合成促黄体生成素释放激素(LHRH)类似物和促性腺激素释放激素(GnRH)高活性类似物前体，口服或者静脉注射给药均可以降低肿瘤治疗中放射性肽的肾摄取。D-赖氨酸多聚物能够促进软管细胞和脑星形胶质细胞增殖，也是良好的药物载体。
目前国内外制备D-赖氨酸的方法有化学法、化学生物偶联法、生物酶法等。化学法的原理是，赖氨酸属于碱性氨基酸，可与手性酸生成非对映体盐，再通过非对映体盐的溶解度差异进行分离。例如，以L-赖氨酸盐酸盐为原料，用稀乙酸加水杨醛消旋得到DL-Lys，再以L-酒石酸为手性拆分剂化学拆分，并以无机钙盐进行分离纯化，最终D-Lys最高收率为34.6％。Takahashi等利用化学生物偶联法，以L-赖氨酸盐酸盐为原料，化学消旋得到质量浓度100g/L的DL-Lys反应液，再经加氧酶和脱氨酶生物降解L-Lys，混合反应液中剩余47g/L的D-Lys，结晶分离后D-Lys最终收率38％。还有报道利用化学法将L-Lys消旋后，再用蜂房哈夫尼菌(Hafnia alvei)AS1.1009菌株赖氨酸脱羧酶进行转化，30g DL-Lys经纯化回收后得到8.5g D-Lys，收率为28％。有文献报道利用氨基酸消旋酶和L-赖氨酸脱羧酶双酶级联催化法制备D-lys，从50g DL-赖氨酸中得到21gD-赖氨酸，收率42％，e.e.值为98％；还有文献报道构建表达赖氨酸消旋酶、L-赖氨酸单加氧酶和5-氨基戊酰胺氨基水解酶的基因工程大肠杆菌菌株，建立了一个两菌株耦合的全细胞生物转化系统，用于从L-赖氨酸生产D-赖氨酸，在最佳条件下，D-赖氨酸的最大值为53.5g/L，5-氨基戊酸的最大值为48.2g/L产率分别为47.4％和42.3％，D-赖氨酸e.e.值>99％。
目前，工业上生成D-lys主要是化学法和化学生物偶联法，因此DL-混旋赖氨酸中L-赖氨酸的生物转化成为关键步骤。
发明内容
本发明对源于铜绿假单胞菌(Pseudomonas aeruginosa)的L-赖氨酸脱羧酶(NC_002516.2)基因进行定向诱变，并通过高通量筛选，获得了一种酶活力和立体专一性更高、从而高效催化L-赖氨酸反应的突变酶。具体来说，本发明包括如下技术方案：
一种L-赖氨酸脱羧酶突变体，其氨基酸序列为SEQ ID NO:3：
MYKDLKFPVLIVHRDIKADTVAGERVRGIAHELEQDGFSILSTASSAEGRIVASTHHGLACILVAAEGAGENQRLLQDVVELIRVARVRAPQLPIFALGEQVTIENAPAESMADLHQLRGILYLFEDTVPFLARQVARAARNYLAGLLPPFFRALVEHTAQSNYSWHTPGHGGGVAYRKSPVGQAFHQFFGENTLRSDLSVSVPELGSLLDHTGPLAEAEDRAARNFGADHTFFVINGTSTANKIVWHSMVGREDLVLVDRNCHKSILHSIIMTGAIPLYLTPERNELGIIGSIPLSEFSKQSIAAKIAASPLARGREPKVKLAVVTNSTYDGLCYNAELIKQTLGDSVEVLHFDEAWYAYAAFHEFYDGRYGMGTSRSEEGPLVFATHSTHKMLAAFSQASMIHRQDGGTRKLDVARFNEAFMMHISTSPQYGIIASLDVASAMMEGPAGRSLIQETFDEALSFRRALANVRQNLDRNDWWFGVWQPEQVEGTDQVGTHDWVLEPSADWHGFGDIAEDYVLLDPIKVTLTTPGLSAGGKLSEQGIPAAIVSRFLWERGLVVEKTGLYSFLVLFSMGITKGKWSTLVTELLEFKRCYDANLPLLDVLPSVAQAGGKRYNGVGLRDLSDAMHASYRDNATAKAMKRMYTVLPEVAMRPSEAYDKLVRGEVEAVPIARLEGRIAAVMLVPYPPGIPLIMPGERFTEATRSILDYLEFARTFERAFPGFDSDVHGLQHQDGPSGRCYTVECIKE(SEQ ID NO:3)。
其为来源的L-赖氨酸脱羧酶SEQ ID NO:2(Gene ID 878596)第243位的P替换为S、第406位的V替换为R的突变体。
本发明的第二个方面在于提供编码上述L-赖氨酸脱羧酶突变体的基因。
本发明的第三个方面在于提供表达上述突变体SEQ ID NO:3的微生物，所述微生物选自大肠杆菌、毕赤酵母、枯草芽孢杆菌，优选大肠杆菌，更优选大肠杆菌BL21(DE3)。
通过上述微生物的发酵，可获得L-赖氨酸脱羧酶突变体。例如，在微生物发酵后，菌体用缓冲液重悬，超声破碎，离心，收集上清过柱层析，洗脱目的蛋白，即得L-赖氨酸脱羧酶突变体。
本发明的第四个方面在于提供一种生产D-赖氨酸的方法。
上述生产D-赖氨酸的外消旋体拆分反应体系可以为缓冲液体系比如磷酸盐缓冲液，pH5.0-9.0，优选pH6.0-8.0、pH6.5-7.5，例如为pH7.0。反应温度可以为20-40℃，例如25-38℃，优选28-38℃、最优选30-35℃。
上述反应体系中还添加有磷酸吡哆醛(PLP)，以便作为辅酶促进酶催化反应。
与来源的野生型L-赖氨酸脱羧酶SEQ ID NO:2相比，本发明获得的L-赖氨酸脱羧酶突变体SEQ ID NO:3具有更高的酶活力和更高的立体专一性，能够有效催化L-赖氨酸的脱羧反应、但不催化D-赖氨酸反应，从而通过外消旋体拆分法制备D-赖氨酸。在酶催化反应体系中D-赖氨酸产量能达到25.5g/L，e.e.值高达99.0以上，工业化应用前景广阔。
附图说明
图1为质粒pET28a的结构示意图，由浙江华睿生物技术有限公司研发中心惠赠。
图2为用于表达L-赖氨酸脱羧酶的重组质粒pET28a-LdcA的结构示意图。
具体实施方式
为了获得酶活力更高、立体选择性高的L-赖氨酸脱羧酶，本发明利用生物信息学技术对铜绿假单胞菌(Pseudomonas aeruginosa)来源的L-赖氨酸脱羧酶SEQ ID NO:2进行分析，判断其氨基酸序列中一些位点在酶的结构和功能方面起到关键作用。
MYKDLKFPVLIVHRDIKADTVAGERVRGIAHELEQDGFSILSTASSAEGRIVASTHHGLACILVAAEGAGENQRLLQDVVELIRVARVRAPQLPIFALGEQVTIENAPAESMADLHQLRGILYLFEDTVPFLARQVARAARNYLAGLLPPFFRALVEHTAQSNYSWHTPGHGGGVAYRKSPVGQAFHQFFGENTLRSDLSVSVPELGSLLDHTGPLAEAEDRAARNFGADHTFFVINGTSTANKIVWHSMVGREDLVLVDRNCHKSILHSIIMTGAIPLYLTPERNELGIIGPIPLSEFSKQSIAAKIAASPLARGREPKVKLAVVTNSTYDGLCYNAELIKQTLGDSVEVLHFDEAWYAYAAFHEFYDGRYGMGTSRSEEGPLVFATHSTHKMLAAFSQASMIHVQDGGTRKLDVARFNEAFMMHISTSPQYGIIASLDVASAMMEGPAGRSLIQETFDEALSFRRALANVRQNLDRNDWWFGVWQPEQVEGTDQVGTHDWVLEPSADWHGFGDIAEDYVLLDPIKVTLTTPGLSAGGKLSEQGIPAAIVSRFLWERGLVVEKTGLYSFLVLFSMGITKGKWSTLVTELLEFKRCYDANLPLLDVLPSVAQAGGKRYNGVGLRDLSDAMHASYRDNATAKAMKRMYTVLPEVAMRPSEAYDKLVRGEVEAVPIARLEGRIAAVMLVPYPPGIPLIMPGERFTEATRSILDYLEFARTFERAFPGFDSDVHGLQHQDGPSGRCYTVECIKE(SEQ ID NO:2)。
于是对L-赖氨酸脱羧酶编码基因(NC_002516.2中自5’-末端第1974821至1977076位核苷酸)进行密码子优化，得到密码子优化序列SEQ ID NO:1，然后在大肠杆菌中进行点突变。通过定点组合突变技术获得了一些酶活力提高的突变体，其中一个发生氨基酸替换(P243S,V406R)的突变体SEQ ID NO:3不仅酶活力比野生型L-赖氨酸脱羧酶SEQ ID NO:2有提高，而且意外的是，该突变体对于底物L-赖氨酸的立体专一性也有明显提高，几乎不催化D-构型的赖氨酸进行反应。这对于DL-赖氨酸外消旋体的拆分极为有利。
为表述方便起见，蛋白质的氨基酸缩写既可以使用英文三字母、也可以采用英文单字母，这是本领域技术人员熟知的，这些缩写列于下表1中：
表1、氨基酸中英文对照及缩写
| 丙氨酸 | Alanine | A或Ala | 脂肪族类 |
| 精氨酸 | Arginine | R或Arg | 碱性氨基酸类 |
| 天冬酰胺 | Asparagine | N或Asn | 酰胺类 |
| 天冬氨酸 | Aspartic acid | D或Asp | 酸性氨基酸类 |
| 半胱氨酸 | Cysteine | C或Cys | 含硫类 |
| 谷氨酰胺 | Glutamine | Q或Gln | 酰胺类 |
| 谷氨酸 | Glutamic acid | E或Glu | 酸性氨基酸类 |
| 甘氨酸 | Glycine | G或Gly | 脂肪族类 |
| 组氨酸 | Histidine | H或His | 碱性氨基酸类 |
| 异亮氨酸 | Isoleucine | I或Ile | 脂肪族类 |
| 亮氨酸 | Leucine | L或Leu | 脂肪族类 |
| 赖氨酸 | Lysine | K或Lys | 碱性氨基酸类 |
| 蛋氨酸 | Methionine | M或Met | 含硫类 |
| 苯丙氨酸 | Phenylalanine | F或Phe | 芳香族类 |
| 脯氨酸 | Proline | P或Pro | 亚氨基酸 |
| 丝氨酸 | Serine | S或Ser | 羟基类 |
| 苏氨酸 | Threonine | T或Thr | 羟基类 |
| 色氨酸 | Tryptophan | W或Trp | 芳香族类 |
| 酪氨酸 | Tyrosine | Y或Tyr | 芳香族类 |
| 缬氨酸 | Valine | V或Val | 脂肪族类 |
在本文中，为了与突变体SEQ ID NO:3相区别和表述方便起见，在本发明中可以将野生型L-赖氨酸脱羧酶称为“野生(型)L-赖氨酸脱羧酶”或者“野生(型)酶”，它们表示相同的意义，都是指原始L-赖氨酸脱羧酶的野生序列SEQ ID NO:2。
本发明的L-赖氨酸脱羧酶突变体的氨基酸数量有751个，序列明确，因此本领域技术人员很容易获得其编码基因、包含这些基因的表达盒和质粒、以及包含该质粒的转化体。
这些基因、表达盒、质粒、转化体可以通过本领域技术人员所熟知的基因工程构建方式获得。
上述转化体宿主可以使任何适合表达L-赖氨酸脱羧酶的微生物，包括细菌和真菌。优选微生物是枯草芽孢杆菌、毕赤酵母、酿酒酵母、或者大肠杆菌，优选大肠杆菌，更优选大肠杆菌BL21(DE3)。
为了在不同微生物中进行蛋白质SEQ ID NO:3的最佳表达，可以针对特定的微生物比如大肠杆菌、毕赤酵母、或者枯草芽孢杆菌进行密码子优化。密码子优化是可用于通过增加感兴趣基因的翻译效率使生物体中蛋白质表达最大化的一种技术。不同的生物体由于突变倾向和天然选择而通常示出对于编码相同氨基酸的一些密码子之一的特殊偏好性。例如，在生长快速的微生物如大肠杆菌中，优化密码子反映出其各自的基因组tRNA库的组成。因此，在生长快速的微生物中，氨基酸的低频率密码子可以被用于相同氨基酸的但高频率的密码子置换。因此，优化的DNA序列的表达在快速生长的微生物中得以改良。
当作为生物催化剂用于通过外消旋体拆分法生产D-赖氨酸时，本发明的L-赖氨酸脱羧酶呈现酶的形式、或者其表达微生物菌体的形式。上述酶的形式包括游离酶、固定化酶，包括纯化酶、载体固定的酶等。
以下结合具体实施例对本发明做进一步详细说明。应理解，以下实施例仅用于说明本发明而非用于限定本发明的范围。
本文中涉及到多种物质的添加量、含量及浓度，其中所述的百分含量，除特别说明外，皆指质量百分含量。
实施例
材料和方法
实施例中引物和基因合成、测序由南京金唯智生物技术有限公司完成。
实施例中的分子生物学实验包括质粒构建、酶切、感受态细胞、转化等主要参考《分子克隆实验指南》(第三版)，J.萨姆布鲁克，D.W.拉塞尔(美)编著，黄培堂等译，科学出版社，北京，2002)进行。必要时可以通过简单试验确定具体实验条件。
PCR扩增实验根据质粒或DNA模板供应商提供的反应条件或试剂盒说明书进行。必要时可以通过简单试验予以调整。
主要培养基：
LB液体培养基：10g/L胰蛋白胨，5g/L酵母提取物，10g/L氯化钠。(固体培养基另加20g/L琼脂粉。)
LBBL培养基：10g/L胰蛋白胨，5g/L酵母提取物，10g/L氯化钠，0.5％溴甲酚紫，0.5mM的IPTG。(固体培养基另加20g/L琼脂粉。)
质粒pET28a-LdcA质粒由洛阳华荣生物技术有限保存，任何单位和个人都可以获得该质粒及相关质粒和细菌用于验证本发明，但未经洛阳华荣生物技术有限允许不得用作其他用途，包括开发利用、科学研究和教学。
L-赖氨酸脱羧酶的酶活力测定方法参见乔长晟等，L-赖氨酸脱羧酶活力测定方法的研究.现代食品科技.2013，Vol.29，No.1，p189-192.。酶活定义为：在35℃下，在1min内能转化1μg L-赖氨酸的酶量为1个活力单位。
反映一种酶对特定底物比如L-赖氨酸的立体专一性高低的对映体比率E值的计算方法为下述公式：
E＝ln[(1-ξ)(1-ees)]/ln[(1-ξ)(1+ees)]算出对映体比率E值(式中ξ代表转化率)，用以表达酶的立体选择性。
实施例1：L-赖氨酸脱羧酶表达质粒pET28a-LdcA构建
对Pseudomonas aeruginosa来源的L-赖氨酸脱羧酶SEQ ID NO:2由南京金唯智生物技术有限公司进行密码子优化得到序列SEQ ID NO:1，进行全基因合成，并将其连入pET28a质粒XbaI和XhoI酶切位点，转入大肠杆菌DH5α菌株中。
菌株按常规方法培养后，提取质粒，测序验证正确，得到L-赖氨酸脱羧酶重组表达质粒pET28a-LdcA，质粒图谱见图2，备用。
将重组质粒pET28a-LdcA电转化大肠杆菌E.coli BL21(DE3)(Invitrogen公司)，涂LBBL平板，筛选阳性克隆，得到表达野生型L-赖氨酸脱羧酶SEQ ID NO:2的重组菌株，命名为BL21(DE3)-WT。
实施例2：LdcA突变体库构建及初步筛选
设计如下引物对LdcA-F和LdcA-R：
LdcA-F：ggatctcagtggtggtggtggtggtgctcgagtca；
LdcA-R：gaattgtgagcggataacaattcccctctagaatg。
以实施例1中构建的pET28a-LdcA质粒为模板，进行易错PCR，50μL易错PCR反应体系包括：10ng质粒模板pET24a-LdcA，LdcA-F和LdcA-R各50pmol，1×Taq buffer，0.2mMdGTP，0.2mM dATP，1mM dCTP，1mM dTTP，7mM MgCl2，(0mM、0.05mM、0.1mM、0.15mM、0.2mM)MnCl2，2.5个单位的Taq酶(fermentas公司)。
PCR反应条件为：95℃5min；94℃30s，55℃30s，72℃2min/kbp；30个循环；72℃10min。
胶回收2.2kb大小PCR片段(Axygen DNA凝胶回收试剂盒AP-GX-50)，以上述回收PCR片段作为大引物，用KOD-plus DNA聚合酶做MegaPrimer PCR：94℃5min，；98℃10s，60℃30s，68℃2min/kbp，25个循环；68℃10min。
Dpn I限制性内切酶(Thermo公司)消化质粒模板，电转化大肠杆菌E.coli BL21(DE3)(Invitrogen公司)，涂LBBL平板。构建LdcA突变体库。
实施例3：LdcA突变体库高通量筛选
在LBBL平板挑取深紫色转化子，接种到500μL含有50μg/mL卡那霉素的LB液体培养基的96孔深孔培养板中，培养过夜，然后取80μl过夜培养物，转接至800μl含有50μg/mL卡那霉素的LB液体培养基中，37℃培养3h后，加入终浓度0.5mM IPTG和30g/L外消旋DL-赖氨酸，降温至30℃，继续培养16h，4000rpm离心，取上清，HPLC检测D-赖氨酸含量。
HPLC检测方法：氨基酸手性柱Crownpak CR(+)(Daicel ChemicalIndustriesLtd.,Japan)；流动相：pH1.5高氯酸水溶液；检测波长：200nm，流速0.4ml/min；柱温：20℃。
挑选出降解L-赖氨酸能力强的350株转化子，以备进一步考察。
实施例4：突变体酶活性检测及突变位点鉴定
从LB平板挑取实施例3中获得的转化子，接种于装有30mL含有50μg/mL卡那霉素的LB液体培养基的250mL三角瓶中，置摇床180rpm，37℃培养过夜，加入终浓度0.5mM IPTG，降温至30℃，继续培养16h后，4000rpm离心，收集细胞。
对于实施例1中获得的重组菌株BL21(DE3)-WT，按同样的方法进行培养和细胞收集，作为对照菌株。
菌泥用0.05M磷酸盐缓冲液(pH7.0)稀释至OD600至大约5，超声破碎，按照10％v/v添加量加入到含50g/L DL-赖氨酸和100μM磷酸吡哆醛(PLP)的1.5ml反应体系中，30℃振荡5h，HPLC检测D-赖氨酸含量。
对照菌株的反应体系中残余D-赖氨酸产量为29.7g/L，e.e.值为86.2。同样反应条件下，其中一个转化子的反应体系中残余D-赖氨酸产量为25.5g/L，e.e.为99.1。
对该突变体菌株抽质粒测序，检测发现其L-赖氨酸脱羧酶SEQ ID NO:2发生了P243S,V406R突变(LdcAP243S,V406R)，对应的氨基酸序列为SEQ ID NO:3。
根据文献(乔长晟等，L-赖氨酸脱羧酶活力测定方法的研究.现代食品科技.2013，Vol.29，No.1，p189-192.)检测L-赖氨酸脱羧酶SEQ ID NO:2和其突变体SEQ ID NO:3的酶活，发现突变体SEQ ID NO:3的酶活力比野生酶提高了至少2倍。
另外野生酶SEQ ID NO:2催化L-赖氨酸进行脱羧反应的E值(对映体比率)为25；而突变体SEQ ID NO:3催化L-赖氨酸进行脱羧反应的E值为75，几乎不催化D-赖氨酸发生反应，表明对于L-赖氨酸的立体专一性(即立体选择性)更高。
实验结果表明，相对于野生L-赖氨酸脱羧酶SEQ ID NO:2，L-赖氨酸脱羧酶突变体SEQ ID NO:3的酶活力和立体专一性都有了明显提高，显示出较好的应用前景。
序列表
<110> 洛阳华荣生物技术有限公司
<120> 一种L-赖氨酸脱羧酶突变体及其应用
<130> SHPI2110012
<160> 3
<170> SIPOSequenceListing 1.0
<210> 1
<211> 2256
<212> DNA
<213> 人工序列()
<400> 1
atgtacaagg acctgaaatt cccggtactg atcgtacacc gtgacattaa agcagacacc 60
gtggcaggcg aacgcgttcg cggtatcgcg catgagctgg aacaagacgg tttctccatt 120
ctgtctaccg cctctagcgc tgaaggccgt attgtggctt ccacgcacca cggcctggcg 180
tgcatcctgg tcgctgcgga aggtgcgggt gaaaatcagc gcctgctgca agatgttgtc 240
gaactgattc gtgtagcacg cgttcgtgct ccgcagctgc cgatcttcgc gctgggcgaa 300
caggtaacca ttgaaaatgc cccggccgaa tctatggctg acctgcacca gctgcgtggt 360
atcctgtacc tgttcgaaga taccgttcct ttcctggcgc gtcaggtggc acgtgcagct 420
cgtaactacc tggctggcct gctgccgccg ttcttccgcg ctctggttga acacaccgct 480
cagagcaact actcttggca caccccgggt catggtggtg gtgtggccta tcgtaaatcc 540
ccagttggtc aagcattcca tcagtttttc ggcgaaaaca ctctgcgtag cgacctgtct 600
gtgtccgttc cggaactggg ctctctgctg gaccacaccg gtccgctggc tgaagccgaa 660
gaccgcgcgg cgcgtaactt cggtgccgac cacacgttct ttgtcatcaa cggcacttct 720
accgcgaaca aaatcgtgtg gcatagcatg gttggccgtg aagatctggt tctggtcgac 780
cgtaactgtc acaaatctat tctgcactct attatcatga ccggtgcaat cccgctgtac 840
ctgaccccgg aacgtaacga actgggtatc atcggtccga tccctctgtc cgaattctct 900
aaacagagca ttgctgccaa aattgcggca tctccgctgg cgcgtggtcg tgagccgaaa 960
gtgaaactgg cagtagtgac caacagcacg tatgacggcc tgtgctacaa cgctgagctg 1020
atcaaacaga ccctgggtga ctctgtggaa gttctgcact tcgatgaagc gtggtacgca 1080
tacgctgcct tccacgaatt ctacgatggc cgttacggca tgggcactag ccgtagcgaa 1140
gaaggcccac tggtattcgc cacgcactct actcacaaaa tgctggcggc cttttctcag 1200
gcttccatga tccacgtgca ggatggtggc actcgtaaac tggatgttgc gcgtttcaac 1260
gaagcgttta tgatgcacat ctccacttcc ccgcagtatg gtattatcgc ctctctggac 1320
gtggcttctg ctatgatgga aggccctgcg ggtcgttctc tgatccagga gaccttcgat 1380
gaagcgctgt ctttccgtcg cgccctggcg aacgtgcgcc agaacctgga tcgtaacgat 1440
tggtggttcg gcgtttggca gccggagcag gtggaaggta ccgaccaggt gggtacccac 1500
gattgggtgc tggaaccatc cgcggactgg cacggcttcg gtgacatcgc ggaggactac 1560
gtactgctgg atccgatcaa agtcactctg actaccccgg gcctgtctgc cggtggtaag 1620
ctgagcgaac aaggtattcc agcagcgatt gtaagccgtt tcctgtggga acgtggcctg 1680
gttgtggaaa aaaccggtct gtactccttc ctggttctgt tctctatggg tatcaccaaa 1740
ggcaagtggt ctaccctggt taccgaactg ctggaattta aacgttgcta tgacgcaaac 1800
ctgccgctgc tggacgtgct gccgtctgtc gctcaggcag gcggcaaacg ttacaatggc 1860
gtaggtctgc gcgatctgtc tgatgctatg catgcttctt atcgtgataa cgcgaccgct 1920
aaagcgatga aacgtatgta tactgttctg ccggaagttg caatgcgccc tagcgaagcg 1980
tacgataaac tggtgcgtgg cgaagttgaa gcagttccta ttgcccgcct ggaaggccgc 2040
atcgcagcag taatgctggt cccttatccg ccgggcatcc cgctgatcat gccgggcgaa 2100
cgttttactg aagcgacccg tagcattctg gactatctgg aattcgctcg caccttcgaa 2160
cgtgcttttc ctggtttcga cagcgatgtc cacggtctgc agcaccagga tggtccatct 2220
ggccgttgct acaccgtaga atgtattaag gaatga 2256
<210> 2
<211> 751
<212> PRT
<213> Pseudomonas aeruginosa
<400> 2
Met Tyr Lys Asp Leu Lys Phe Pro Val Leu Ile Val His Arg Asp Ile
1 5 10 15
Lys Ala Asp Thr Val Ala Gly Glu Arg Val Arg Gly Ile Ala His Glu
20 25 30
Leu Glu Gln Asp Gly Phe Ser Ile Leu Ser Thr Ala Ser Ser Ala Glu
35 40 45
Gly Arg Ile Val Ala Ser Thr His His Gly Leu Ala Cys Ile Leu Val
50 55 60
Ala Ala Glu Gly Ala Gly Glu Asn Gln Arg Leu Leu Gln Asp Val Val
65 70 75 80
Glu Leu Ile Arg Val Ala Arg Val Arg Ala Pro Gln Leu Pro Ile Phe
85 90 95
Ala Leu Gly Glu Gln Val Thr Ile Glu Asn Ala Pro Ala Glu Ser Met
100 105 110
Ala Asp Leu His Gln Leu Arg Gly Ile Leu Tyr Leu Phe Glu Asp Thr
115 120 125
Val Pro Phe Leu Ala Arg Gln Val Ala Arg Ala Ala Arg Asn Tyr Leu
130 135 140
Ala Gly Leu Leu Pro Pro Phe Phe Arg Ala Leu Val Glu His Thr Ala
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740 745 750
Claims (10)
1.一种L-赖氨酸脱羧酶突变体，其氨基酸序列为SEQ ID NO:3。
2.编码如权利要求1所述L-赖氨酸脱羧酶突变体的基因。
3.一种微生物，其表达如权利要求1所述的L-赖氨酸脱羧酶突变体。
4.如权利要求3所述的微生物，其特征在于，所述微生物选自大肠杆菌、毕赤酵母、枯草芽孢杆菌。
5.如权利要求3所述的微生物，其特征在于，所述微生物是大肠杆菌BL21(DE3)。
6.一种生产如权利要求1所述L-赖氨酸脱羧酶突变体的方法，其特征在于，通过如权利要求5所述微生物的发酵获得。
7.一种生产D-赖氨酸的方法，其特征在于，以外消旋体DL-赖氨酸为底物，使用如权利要求1所述的L-赖氨酸脱羧酶突变体、或者如权利要求3-5中任一项所述的微生物催化L-赖氨酸发生脱羧反应，得到未反应的D-赖氨酸。
8.如权利要求7所述的方法，其特征在于，反应体系为磷酸盐缓冲液，pH5.0-9.0。
9.如权利要求7所述的方法，其特征在于，反应温度为20-40℃。
10.如权利要求7所述的方法，其特征在于，反应体系中添加有磷酸吡哆醛(PLP)。
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