CN113980918B - 一种南极冰藻MAAs合成酶及其编码基因和应用 - Google Patents
一种南极冰藻MAAs合成酶及其编码基因和应用 Download PDFInfo
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- CN113980918B CN113980918B CN202111207603.5A CN202111207603A CN113980918B CN 113980918 B CN113980918 B CN 113980918B CN 202111207603 A CN202111207603 A CN 202111207603A CN 113980918 B CN113980918 B CN 113980918B
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- maas
- leu
- gly
- ala
- synthetase
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Abstract
本发明公开了一种南极冰藻MAAs合成酶及其编码基因和应用。所述南极冰藻MAAs合成酶包括MysA、MysB、MysC，其氨基酸序列分别如SEQ ID NO.7、SEQ ID NO.9、SEQ ID NO.11所示，其编码基因的核苷酸序列分别如SEQ ID NO.8、SEQ ID NO.10、SEQ ID NO.12所示。本发明经实验验证，将3种南极冰藻MAAs合成酶的编码基因同时克隆转化到重组菌株中，能够有效提高菌株在UVB辐射中的存活率，且能够用于生产MAAs及其中间体，而所产的MAAs具有修复由紫外辐射引起的细胞DNA损伤和角膜损伤的作用，具有广阔的应用价值。
Description
技术领域
本发明涉及生物学技术领域，具体涉及一种南极冰藻MAAs合成酶及其编码基因和应用。
背景技术
随着臭氧空洞问题的日益严重，尤其是南北两极臭氧空洞的出现、扩大，到达地球表面的紫外光辐射也越来越强烈。不断增强的紫外辐射会导致生物体内活性氧急剧增加，破坏蛋白质和DNA等大分子物质的结构，造成氧化损伤，进而导致水生和陆生生态系统中光合生物的生长受到抑制。与其他生物体一样，人类暴露在紫外线辐射下会造成损害，如短期内出现红斑“晒伤”，长期内会导致皮肤过早老化和皮肤癌，严重威胁身体健康。目前，使用防晒霜来防止紫外线辐射是较为有效措施，但市面上的防晒霜多为含有氧苯酮、邻氨基苯甲酸盐的化学防晒霜和含有二氧化钛、氧化锌的物理防晒霜，经常使用会导致过敏反应、光毒性和内分泌失调。此外，紫外线对角膜的损伤是一种常见的眼科损伤。角膜可吸收大量紫外线，对阻挡紫外线进入眼内、保护眼内其他组织免受紫外辐射损伤起到重要作用。因此，在化妆品和生物医药领域，迫切需要寻找一种能够保护人类皮肤和眼睛等其他器官免受太阳紫外线辐射的更安全、更好的天然活性成分。
南极地区拥有高盐、低温、干旱、强紫外辐射、季节性融冰和极昼/极夜更替等特殊环境条件。南极冰藻是生存在南极海水、海冰及冰川融水等极端环境中各类微藻的总称，在这种极端环境下，尤其是暴露在强紫外辐射的环境中，南极冰藻仍生长繁殖旺盛，这暗示着南极冰藻为适应强烈的紫外辐射，已经发展了某种光保护机制来在高水平的紫外线下生存。类菌胞素氨基酸（MAAs）是一种水溶性无色的次级代谢物，普遍存在于海洋红藻、蓝藻、浮游植物和海洋微生物中。MAAs能够吸收UV-A（315-400 nm）和UV-B（280-315 nm）范围内的光，而不产生自由基，因此MAAs介导了光保护机制。此外，通过清除活性氧自由基，MAAs发挥了抗氧化作用，抑制了单态氧诱导的损伤。
基于MAAs在海洋生物中的含量与外部环境中紫外辐射强度呈正相关性，MAAs对海洋生物的紫外光防护作用越来越引起人们的关注。MAAs合成酶在生物体内的含量极少，这使得直接从生物体中分离纯化MAAs合成酶并进行其结构、功能活性和作用机制研究极为困难。但随着基因克隆技术的发展，可以利用基因工程手段克隆南极冰藻MAAs合成酶基因，并将其转化到目的宿主中，完成MAAs的过量表达和纯化，并对其进行详细的研究。
发明内容
本发明为了解决现有技术中的缺陷和不足，提供了一种南极冰藻MAAs合成酶及其编码基因和应用。所述的南极冰藻MAAs合成酶经克隆转化后，具有提高菌株UVB辐射存活率的作用。
为实现上述发明目的，本发明采用以下技术方案予以实现：
本发明提供了一种南极冰藻MAAs合成酶，所述南极冰藻MAAs合成酶具有如下之一所示的氨基酸序列：
（1）如SEQ ID NO.7所示的氨基酸序列；
（2）如SEQ ID NO.9所示的氨基酸序列；
（3）如SEQ ID NO.11所示的氨基酸序列。
进一步的，所述南极冰藻MAAs合成酶为MysA、MysB、MysC；所述MysA的氨基酸序列如SEQ ID NO.7所示；所述MysB的氨基酸序列如SEQ ID NO.9所示；所述MysC的氨基酸序列如SEQ ID NO.11所示。
本发明还提供了所述的南极冰藻MAAs合成酶的编码基因，所述南极冰藻MAAs合成酶的编码基因具有如下之一所示的核苷酸序列：
（1）如SEQ ID NO.8所示的核苷酸序列；
（2）如SEQ ID NO.10所示的核苷酸序列；
（3）如SEQ ID NO.12所示的核苷酸序列；
（4）与SEQ ID NO.8所示的核苷酸序列、或与SEQ ID NO.10所示的核苷酸序列、或与SEQ ID NO.12所示的核苷酸序列具有95%以上同源性且编码南极冰藻MAAs合成酶活性功能的核苷酸序列。
进一步的，所述南极冰藻MAAs合成酶编码基因为MysA基因、MysB基因、MysC基因；所述MysA基因的核苷酸序列如SEQ ID NO.8所示，所述MysB基因的核苷酸序列如SEQ IDNO.10所示；所述MysC基因的核苷酸序列如SEQ ID NO.12所示。
本发明还提供了所述的南极冰藻MAAs合成酶编码基因的扩增引物，所述扩增引物的核苷酸序列如SEQ ID NO.1- SEQ ID NO.6所示。
进一步的，所述扩增引物为：
MysA扩增引物：
MysA-F：ATGTCGTTCCGCCCCAAACT；
MysA-R：GCAGAAGTGATTCAAAGTCTCCTCC；
MysB扩增引物：
MysB-F：ATGCAAGTGTCCCTGAAGGGA；
MysB-R：CCGTTTTCGGCACAAAGCAA；
MysC扩增引物：
MysC-F：ATGCCACTTGGTGGCACTTCC；
MysC-R：GCTGCCCCCGGCATCCT。
本发明还提供了含有所述的南极冰藻MAAs合成酶编码基因的重组菌株。
进一步的，所述重组菌株的制备步骤为：通过体外基因合成手段将MysA基因的C端添加6×his-tag，序列优化至大肠杆菌中，基因合成后亚克隆至pACYCDuet-1载体的MCS-1区，酶切位点选择NcoI-XhoI；MysB基因的C端添加WSHPQFEK（strep标签），序列优化至大肠杆菌中，基因合成后亚克隆至pACYCDuet-1载体的MCS-2区，酶切位点选择NdeI-XhoI；MysC基因的C端添加DYKDDDDK（flag标签），序列优化至大肠杆菌中，基因合成后亚克隆至pACYCDuet-1载体的MCS-2区；将上述得到的重组质粒共转化大肠杆菌DH5α，挑取白色的菌落培养、酶切鉴定，鉴定正确的质粒转化大肠杆菌BL21(DE3)，测序鉴定得到重组菌株DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC。
进一步的，所述重组菌株中还包括能够产生颜色变化的酶的基因、或发光化合物的基因、或具有抗生素标记物的基因。
本发明还提供了所述的南极冰藻MAAs合成酶在用于制备提高菌株UVB辐射适应性的制剂中的应用。
进一步的，所述菌株中同时含有编码南极冰藻MAAs合成酶MysA的核苷酸序列如SEQ ID NO.8所示的MysA基因、编码南极冰藻MAAs合成酶MysB的核苷酸序列如SEQ IDNO.10所示的MysB基因以及编码南极冰藻MAAs合成酶MysC的核苷酸序列如SEQ ID NO.12所示的MysC基因。
本发明还提供了所述的南极冰藻MAAs合成酶在用于制备生产MAAs的制剂中的应用。
进一步的，所述MAAs为Mycosporine-glycine，其两种中间体化合物为Desmethy1,4-deoxygadusol，4-Deoxygadusol。
本发明还提供了所述的MAAs在用于制备预防和/或降低紫外辐射损伤的化妆品中的应用。
本发明还提供了所述的MAAs在用于制备修复由紫外辐射引起的角膜损伤的药物或保健品中的应用。
本发明与现有技术相比，具有以下优点和有益效果：
本发明首次从南极真核藻类中发现了产MAAs的藻种——Chlamydomonas sp.ICE-L，并首次从该藻中得到了三种MAAs合成酶MysA、MysB、MysC，通过克隆MAAs合成酶基因MysA、MysB、MysC到表达载体中，然后将三种基因共转化到大肠杆菌中，不仅在体外成功诱导得到了同时表达MAAs合成酶MysA、MysB、MysC的重组菌株，且根据实验验证，同时含有MysA、MysB和MysC基因能够提高菌株在UVB辐射下的存活率，且只有经过MysA、MysB和MysC的三步酶催化后才能产生MAAs。由此本发明还通过重组菌株获得了MAAs及其中间体化合物，并对其结构进行解析，MAAs的结构为Mycosporine-glycine，中间体化合物结构为Desmethy1,4-deoxygadusol和4-Deoxygadusol，而MAAs及其中间体应用到化妆品、生物医药等相关领域，能够主动修复由紫外辐射引起的皮肤炎症、红斑和角膜损伤，缓解紫外线损伤造成的负面伤害，进而带来巨大的社会效益，意义重大。
附图说明
图1是合成蛋白酶MysA、MysB、MysC的表达鉴定结果，其中M为标准分子量，1为诱导前样品，2-6表示诱导后样品。
图2是MysA的氨基酸保守位点。
图3是MysB的氨基酸保守位点。
图4是南极冰藻MysA的空间结构预测。
图5是南极冰藻MysA的进化树分析。
图6是南极冰藻MAAs合成酶基因重组菌株活性检测结果；其中A：空质粒 DBL21(DE3)/pACYCDuet-1；B：重组菌株DBL21(DE3)/pACYCDuet-1/MysA；C：重组菌株DBL21(DE3)/pACYCDuet-1/MysB；D：重组菌株DBL21(DE3)/pACYCDuet-1/MysC；E：重组菌株DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC。
图7是南极冰藻MAAs合成酶基因重组菌株的MAAs产物的可见-紫外光谱图。
图8是MAAs的ESI(-)总离子流图阴离子质谱图。
图9是MAAs的ESI(+)总离子流图阳离子质谱图。
图10是MAAs及其中间体化合物的结构分子式。
图11是MAAs对紫外线照射后HCEC细胞迁移的影响；其中A：空白对照组；B：UVB辐射组；C：MAAs治疗组。
图12是MAAs对紫外线照射后小鼠角膜上皮损伤修复的影响；其中A：空白对照组；B：UVB辐射组；C：MAAs治疗组。
具体实施方式
结合以下具体实例对本发明的技术方案作进一步详细的说明。
下述实施例中，如无特殊说明，所使用的实验方法均为常规方法，所用材料、试剂等均可从生物或化学试剂公司购买。实施例中所使用的方法均为本领域常规操作，详见《分子克隆实验指南》。
实施例1.南极冰藻的培养和全基因组测序
南极冰藻基因组总测序量为43.76 G，覆盖深度为71.07 X，此外构建二代小片段和10X Genomic文库，采用illumina平台进行测序，利用南极冰藻基因组103.70 G测序数据，测序深度为168.43 X，并对南极冰藻基因组进行denovo组装，鉴定其藻种。
组装结果如下：contig 总长为532.13 Mbp，contig N50达到209.56 Kbp；scaffold 的总长为541.31 Mbp，scaffold N50达到 490.02 Kbp。经生物信息学鉴定其为南极冰藻Chlamydomonas sp. ICE-L。
实施例2. 南极冰藻Chlamydomonassp. ICE-L MAAs合成酶（MysA、MysB、MysC）cDNA序列的获得
1、提取南极冰藻总RNA
利用Invitrogen公司的Trizol试剂提取在4℃培养至对数期的南极冰藻Chlamydomonassp. ICE-L的RNA。试验按照Trizol试剂的提取流程说明进行操作，在整个过程中保证无RNase污染，将提取的RNA冻存于-80℃冰箱备用。
2、南极冰藻MAAs合成酶基因cDNA序列的获得
将提取得到的高质量RNA按照PrimeScript 1ststrand cDNA Synthesis Kit（TaKaRa）说明书进行操作反转录，合成cDNA。具体操作步骤如下：
（1）将下述体系混合均匀：
TemplateRNA 0.6 μL
Oligo dT Primer (50 μM) 1 μL
dNTP Mixture (10 mM each) 1 μL
RNase free dH2O 7 μL
Total 10 μL
（2）上述混合液震荡数秒后，于PCR仪中65 °C孵育5 min，立即置于冰上冷却，使RNA变性，提高效率。
（3）在上述的反应液中加入下述的反转录反应液后，缓慢混匀：
步骤（2）中的变性反应液 10 μL
5 × PrimeScript Buffer 4 μL
RNase Inhibitor (40 U/μL) 0.5 μL (20 U/μL)
PrimeScript RTase (200 U/μL) 1 μL (200 U/μL)
RNase free dH2O 4.5 μL
Total 10 μL
（4）上述混合液于PCR仪中46°C孵育45 min进行反转录反应；70°C热激15 min，使反转录酶变性失活；
（5）置于冰上冷却，最后将Chlamydomonassp. ICE-L的cDNA放于-20°C冰箱保存备用。
根据三步合成酶基因的基因序列设计表达引物，序列分别如下：
MysA表达引物：
MysA-F：ATGTCGTTCCGCCCCAAACT；
MysA-R：GCAGAAGTGATTCAAAGTCTCCTCC；
MysB表达引物：
MysB-F：ATGCAAGTGTCCCTGAAGGGA；
MysB-R：CCGTTTTCGGCACAAAGCAA；
MysC表达引物：
MysC-F：ATGCCACTTGGTGGCACTTCC；
MysC-R：GCTGCCCCCGGCATCCT。
PCR反应体系为：10×Buffer：2.0 μl；dNTP（10 mmol/L）：0.4 μl；rTap：0.2 μl；Primer R：1.0 μl；Primer F：1.0 μl；cDNA：1.0 μl；H2O：14.4 μl。
PCR反应条件为：95℃预变性3 min；95℃变性30 s，55℃退火1 min，72℃延伸2min，重复30个循环。PCR结束后用1%琼脂糖回收PCR产物。
将PCR产物连接到pMD18-T，转化E.coliDH5α，进行测序验证；利用NCBI在线工具（https://blast.ncbi.nlm.nih.gov/Blast.cgi）和BLAST程序将所得序列进行序列同源性比对和相似性分析；用DNAstar软件进行序列拼接，并在NCBI中比对，以确认获得目的基因为MAAs合成酶基因的完整编码区序列。
实施例3. 南极冰藻Chlamydomonas sp.ICE-L MAAs合成酶基因（MysA、MysB、MysC）表达载体的构建和大肠杆菌的异源表达
1、根据测序得到的MAAs合成酶基因完整序列设计引物：
MysA表达引物：
MysA-F：ATGTCGTTCCGCCCCAAACT；
MysA-R：GCAGAAGTGATTCAAAGTCTCCTCC；
MysB表达引物：
MysB-F：ATGCAAGTGTCCCTGAAGGGA；
MysB-R：CCGTTTTCGGCACAAAGCAA；
MysC表达引物：
MysC-F：ATGCCACTTGGTGGCACTTCC；
MysC-R：GCTGCCCCCGGCATCCT。
PCR反应条件为：95℃预变性10 min；95℃变性15 s，55℃退火1min，72℃延伸2min，重复30个循环。
2、利用PCR法通过上述引物将MysA的C端添加6×his-tag，序列优化至大肠杆菌中，将纯化好的目的片段用T4 DNA连接酶于16℃下连接16 h，亚克隆至pACYCDuet-1载体的MCS-1区，酶切位点选择NcoI-XhoI；MysB的C端添加WSHPQFEK（strep标签），序列优化至大肠杆菌中，基因合成后亚克隆至pACYCDuet-1载体的MCS-2区，酶切位点选择NdeI-XhoI；MysC的C端添加DYKDDDDK（flag标签），序列优化至大肠杆菌中，基因合成后亚克隆至pACYCDuet-1载体的MCS-2区。
MysA所用连接反应体系（总体系10μl）为：MysA3.5μl；pACYCDuet-1 4.5μl；连接酶1μl；连接缓冲液 1μl。
MysB、MysC的连接反应体系同上。
3、将连接好的重组质粒共转化大肠杆菌DH5α，步骤如下：
（1）取感受态细胞300 μL于1.5 mL离心管中，冰浴5 min；
（2）于每管中加入各5 μL连接过的重组质粒，轻轻旋转以混合内容物，冰浴30min；
（3）42℃热休克90 s，不要摇动试管；
（4）取10 mL无菌试管，每管加入800 μL LB液体培养基，冰浴；
（5）取转化后的细胞200 μL加入800 μL LB液体培养基中，37℃ 150 rpm振荡培养45 min；
（6）将100 μL转化的菌液涂布于平板表面，37℃培养倒置培养过夜。
4、挑取白色的菌落置于5 mL含氯霉素的LB液体培养基中，37℃振荡培养8-12 h，碱裂解法提取质粒以进行酶切鉴定；鉴定正确的质粒以相同方法转化大肠杆菌BL21(DE3)，测序鉴定得到重组菌株DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC。
实施例4. 南极冰藻Chlamydomonassp. ICE-L MAAs合成酶（MysA、MysB、MysC）的纯化和蛋白检测
1、将重组菌株DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC接种于5 mL含氯霉素的LB液体培养基中，37℃培养培养至菌体OD600为0.6-0.8，加入IPTG至终浓度为0.5 mM，培养4h后离心，8000 rmp离心10 min，收集菌体。
2、Ni琼脂糖亲和柱亲和层析：将金属螯合剂Ni琼脂糖装入层析柱，用1×Ni柱结合缓冲液平衡；将上清液上柱；一般用40 mM咪唑洗脱，得到目的蛋白，即所述南极冰藻MAAs合成酶MysA、MysB、MysC。
3、取上述诱导表达的DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC菌体和纯化的MAAs合成酶基因表达的蛋白质，分别与等体积的2×上样缓冲液混合，100℃水浴3-5 min。配制12%的SDS-PAGE分离胶和5%的浓缩胶，取20 μL加样于凝胶，在浓缩胶中100 V，分离胶中120 V，进行SDS-PAGE电泳。电泳结束，将凝胶转移至PVDF膜上，5%（M/V）脱脂奶粉浸泡PVDF膜进行封闭。采用His tag antibody、strep tag antibody、flag tag antibody进行一抗孵育，TBST洗涤PVDF膜并采用羊抗兔IgG-HRP进行二抗孵育，TBST洗涤PVDF膜，加入ECL化学发光液曝光并进行定量分析。
结果如图1所示：SDS-PAGE和Western blot结果说明，利用上述方法能够在体外成功诱导同时含南极冰藻Chlamydomonassp. ICE-L MAAs合成酶基因MysA、MysB、MysC的重组菌株，并共表达了MAAs合成酶MysA、MysB、MysC。
实施例5. 南极冰藻Chlamydomonas sp. ICE-L MAAs合成酶（MysA、MysB、MysC）蛋白序列分析
所述南极冰藻MAAs合成酶MysA的氨基酸序列如SEQ ID NO.7所示，编码MysA的基因MysA的核苷酸序列如SEQ ID NO.8所示；MysB的氨基酸序列如SEQ ID NO.9所示，编码MysB的基因MysB的核苷酸序列如SEQ ID NO.10所示；MysC的氨基酸序列如SEQ ID NO.11所示，编码MysC的基因MysC的核苷酸序列如SEQ ID NO.12所示。
获得的南极冰藻Chlamydomonas sp. ICE-L MAAs合成酶基因（MysA、MysB、MysC）的开放阅读框（ORF）长度分别为1371 bp、795 bp、684 bp，分别编码456、266、227个氨基酸残基，相对分子质量分别为49.51 KDa、29.71 KDa、24.56 KDa。将南极冰藻Chlamydomonas sp. ICE-L MAAs合成酶（MysA、MysB、MysC）的氨基酸序列在NCBI上进行同源性比对，并进行生物信息学分析。
结果如图2和图3所示，南极冰藻Chlamydomonas sp. ICE-LMysA的编码蛋白MysA属于DHQ_Fe-ADH超家族，有18个活性位点(active sites)和3个金属离子结合位点(metalbinding sites)，其二聚体界面[多肽结合位点]分布于序列的中间部分165-255位氨基酸。南极冰藻MysB的编码蛋白MysB属于YrrM超家族，有12个s -腺苷蛋氨酸结合位点(S-adenosylmethionine binding sites)，和3个金属离子结合位点 (metal bindingsites)，其二聚体界面[多肽结合位点]分布于序列的中间部分165-255位氨基酸。
以Actinidia chinensis的AcmysA为模板，构建南极冰藻的MysA空间结构，其identity为66.85%。如图4所示，MysA的空间结构是同二聚体，两条多肽链分别用链A和链B表示，具有2个Gly非共价结合配体（如图绿色球状部分），螺旋、折叠结构分别用红色和黄色表示，其他结构为蓝色表示。图5的系统发育树显示的是南极冰藻MysA聚到绿藻分枝。
实施例6. 南极冰藻Chlamydomonassp. ICE-L MAAs合成酶基因（MysA、MysB、MysC）重组菌株活性检测
构建表达菌株DBL21(DE3)/pACYCDuet-1（空质粒）、DBL21(DE3)/pACYCDuet-1/ MysA、DBL21(DE3)/pACYCDuet-1/MysB、DBL21(DE3)/pACYCDuet-1/MysC、DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC，并对上述表达菌株在UVB辐射下照射15 min，计数存活菌落数。具体步骤如下：
1、取20 μL构建好的重组菌株接种于含氯霉素抗生素的LB中活化，摇菌过夜。第二天进行二次活化，继续摇菌至OD600= 0.6-0.8，加入IPTG（0.5 mM），诱导4-6 h。
2、分别稀释菌液100倍，用枪混匀。
3、取每一种菌液进行涂板，每种菌液再分别取3个作为对照，不进行UVB辐射；涂布后平板静置半小时。
4、将每个菌液剩下的涂布平板的盖子放在一边，在UVB下照射，照射时间为15min，照射结束后立即盖上盖子，与对照组一起放入37 ℃培养过夜。
5、每个UVB辐射实验，独立重复3次。
结果如图6所示，对照组在无UVB辐射的情况下，菌落基本铺满平板。UVB辐射组中DBL21(DE3)/pACYCDuet-1、DBL21(DE3)/pACYCDuet-1/MysB、DBL21(DE3)/pACYCDuet-1/MysC没有菌落存活，而DBL21(DE3)/pACYCDuet-1/MysA只有几个菌落存活，相比之下DBL21(DE3)/pACYCDuet-1/MysA/MysB/MysC有较多菌落存活。结果表明，只含有MysA或MysB或MysC基因对菌株的UVB辐射下的存活率提升有限或没有作用；同时含有MysA、MysB和MysC基因才能够提高菌株在UVB辐射下的存活率。产生该现象的原因在于只有经过MysA、MysB和MysC的三步酶催化后才能产生MAAs，说明南极冰藻MAAs合成酶在生物体的UVB辐射适应方面发挥了一定作用。
实施例7. 南极冰藻Chlamydomonassp. ICE-L MAAs合成酶基因（MysA、MysB、MysC）重组菌株对MAAs的初步合成
以景天庚酮糖7-磷酸（sedoheptulose 7-phosphate, SH7P）为底物，培养南极冰藻MAAs合成酶基因重组菌株，对其提取物的进行可见-紫外吸收光谱。
结果如图7所示，在260-360 nm有明显两个吸收峰，这是MAAs化合物的特征吸收峰，推测可能是在南极冰藻MAAs合成酶基因重组菌株中的MysA、MysB和MysC酶的共同作用下将底物SH7P转化成了M-Gly产物。
实施例8. 南极冰藻Chlamydomonassp. ICE-L MAAs的提取纯化与结构鉴定
1、重组菌株中MAAs的提取与纯化
（1）一次活化：将500 μL菌株接种于100 mL LB (Chl+ 25 μg/mL)培养基中，37℃、160 rmp过夜活化；
（2）二次活化：将25 mL经一次活化好的菌株接种于250 mL LB (Chl+ 25 μg/mL)，37 ℃、160 rpm培养1.5 h；
（3）诱导表达：冷却到一定温度，OD = 0.5-0.6时加IPTG 500 μM，诱导19 h；
（4）细胞破碎：离心菌体（6,000 rpm × 15 min），用7 mL甲醇重悬，超声破碎；
（5）离心溶菌产物(13,300 rpm × 30 min)，将上清液转移到新的EP管中，弃沉淀，上清45℃蒸发干燥，去除甲醇；
（6）残渣用1.5 mL水重悬，离心（16,100 rpm × 10 min），上清经超滤离心管离心(13,300 rpm × 30 min)，过0.45 μm滤膜，于-80℃保存。
2、MAAs种类的检测与鉴定
（1）样品前处理方法
a. 取出超低温保存的生物材料样本，用研磨仪（MM 400，Retsch）研磨（30 Hz，1min）至粉末状；
b. 称取200 mg研磨后的样本，加入适量内标，用甲醇: 水: 甲酸 =15:4:1（v：v：v）进行提取；
c. 离心纯化富集后，氮吹干燥，后用100 μL 80%乙腈-水溶液复溶，过0.22 μmPTFE滤膜，离心后内插管上样，上样体积10μL，用于LC-MS/MS分析。
（2）色谱方法
色谱柱：Agilent C18（2.1mm × 100mm，3μm）；柱温：35℃，流速：0.3mL/min；进样量：10 μL；流动相洗脱梯度表1所示。
表1 流动相洗脱梯度
（3）质谱方法
模式：电喷雾离子源（electrospray ionization，ESI），温度 500℃，质谱电压4500 V，帘气（curtain gas，CUR）35 psi，碰撞诱导电离（collision-activateddissociation，CAD）参数设置为 medium。在QE-HF中，每个离子对是根据优化的去簇电压（declustering potential，DP）和碰撞能（collision energy，CE）进行扫描检测。
根据分子量大小结果比对MAAs数据库，所得到南极冰藻Chlamydomonassp. ICE-LMAAs种类见表2-3和图8-9，推测MAAs及其中间体化合物的结构为Mycosporine-glycine，Desmethy1,4-deoxygadusol和4-Deoxygadusol，其分子式如图10所示。
表2 阴离子质谱分析结果
表3 阳离子质谱分析结果
| Formula | △ppm | Molecular Weight（理论值） | Molecular Weight（实际值） | RT[min] | Compound Name | Type | λmax (nm) | Molecular Formula |
| C20H28O3 | -2.22 | 316.20384 | 316.20314 | 11.393 | Mycosporine-glycine-alanine | Imino-mycosporine | 333 | C13H20N2O7 |
| C18H32O7 | -2.1 | 360.2148 | 360.21405 | 13.934 | Mycosporine-glycine-aspartic acid | Imino-mycosporine | 333 | C14H20N2O9 |
实施例9. 南极冰藻Chlamydomonassp. ICE-L MAAs在化妆品领域的应用
利用细胞实验研究MAAs对紫外辐射引起DNA损伤的修复作用。实验分组为A：空白对照组（正常培养细胞）、B：UVB辐射组（以紫外线照射损伤细胞）、C：MAAs治疗组（以紫外线照射损伤细胞后在MAAs培养液中培养）。HCEC细胞培养至密度达到80%-90%时，以紫外线照射损伤UVB辐射组、MAAs治疗组的细胞。利用Transwell实验检测各组细胞的迁移情况。具体为：24孔无菌细胞培养板的每孔作为下室并加入各组相应的培养液，按细胞传代方法将含有5-6×104个细胞的235 μl细胞悬液分别加入Transwell上室，培养48-72 h后取出培养板，弃去培养液，结晶紫染色后用PBS洗净，倒置相差显微镜照相。
结果如图11所示，相较于空白对照组，UVB照射组HCEC细胞的迁移减少；相较于UVB照射组，MAAs治疗组的HCEC细胞的迁移增加，表明紫外辐射会抑制HECE细胞的迁移，而外源性MAAs可恢复细胞的迁移能力。因此，可以将南极冰藻MAAs添加到化妆品中，用来保护皮肤免受紫外线的损伤，改善皮肤的健康状况。
实施例10. 南极冰藻Chlamydomonassp. ICE-L MAAs在生物医药领域应用
利用C57BL/6小鼠建立角膜上皮损伤模型。UVB辐射组和MAAs治疗组的小鼠在15 WUV-B 灯管下辐照，距离20 cm，时间60 min，然后采取腹腔内注射麻醉，充分暴露眼球，盐酸丙美卡因滴眼液行表面麻醉。以直径2.5 mm角膜环钻轻压小鼠角膜，保证环钻位于角膜中央，按压力度以保证留下压痕又不致损伤基质为宜。以电动上皮刮刀刮除压痕以内小鼠角膜上皮。治疗组于术前即刻结膜下注射一定浓度的MAAs，于建模后72h采用荧光素钠行角膜上皮染色，观察全部小鼠角膜上皮的损伤修复程度。
结果如图12所示，与空白对照组相比，紫外线照射组小鼠角膜上皮缺损面积变大；与紫外线照射组相比，MAAs治疗组的小鼠角膜上皮缺损面积变小。表明紫外辐射导致小鼠角膜上皮细胞的损伤，而外源性MAAs可促进小鼠角膜上皮的损伤修复速度。
以上实施例仅用以说明本发明的技术方案，而非对其进行限制；尽管参照前述实施例对本发明进行了详细的说明，对于本领域的普通技术人员来说，依然可以对前述实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换；而这些修改或替换，并不使相应技术方案的本质脱离本发明所要求保护的技术方案的精神和范围。
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<110> 中国海洋大学、自然资源部第一海洋研究所
<120> 一种南极冰藻MAAs合成酶及其编码基因和应用
<160> 12
<170> SIPOSequenceListing 1.0
<210> 1
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 1
atgtcgttcc gccccaaact 20
<210> 2
<211> 25
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 2
gcagaagtga ttcaaagtct cctcc 25
<210> 3
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 3
atgcaagtgt ccctgaaggg a 21
<210> 4
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 4
ccgttttcgg cacaaagcaa 20
<210> 5
<211> 21
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 5
atgccacttg gtggcacttc c 21
<210> 6
<211> 17
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 6
gctgcccccg gcatcct 17
<210> 7
<211> 456
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 7
Met Ser Phe Arg Pro Lys Leu Arg Val Gly Gln Ala Val Ser Ser Lys
1 5 10 15
Ala Ser Leu Ile Lys Pro Ile Arg Ser Pro Leu Leu Ser Ser Leu Gly
20 25 30
Gly Asp Ser Leu Val Ser Pro Leu Gln Ser Ser Ala Leu Ser Ser Cys
35 40 45
Ser Thr Ala Thr Ser Ser Ile Val Gly Ser Ser Phe Ser Gly Val Asn
50 55 60
Arg Arg Ile Val Gln Arg Leu Arg Gln Glu Arg Arg Leu Ala Met Ala
65 70 75 80
Thr Pro Val Met Ala Val Ala Ser Pro Glu Arg Val Met Lys Thr Val
85 90 95
Asp Val Ser Leu Gly Asp Arg Ser Tyr Pro Ile Phe Ile Gly Asn Gln
100 105 110
Leu Leu Ala Glu Lys Gly Glu Leu Leu Arg Lys His Ile Lys Gly Lys
115 120 125
Arg Val Leu Ile Val Thr Asn Thr Thr Ile Ala Pro Leu Tyr Leu Asp
130 135 140
Gln Cys Val Gln Ala Leu Thr Ala Asp Gly Lys Ile Gln Val Asp Ser
145 150 155 160
Val Ile Leu Pro Asp Gly Glu Glu Tyr Lys Thr Met Glu Val Leu Gly
165 170 175
Lys Ile Trp Asp Lys Ala Leu Glu Cys Arg Leu Asp Arg Gly Ala Thr
180 185 190
Phe Leu Ala Leu Gly Gly Gly Val Ile Gly Asp Met Cys Gly Phe Ala
195 200 205
Ala Ser Cys Tyr Gln Arg Gly Val Asn Phe Val Gln Val Pro Thr Thr
210 215 220
Val Met Ala Gln Val Asp Ser Ser Val Gly Gly Lys Thr Gly Val Asn
225 230 235 240
His Ala Leu Gly Lys Asn Met Ile Gly Ala Phe Tyr Gln Pro Gln Cys
245 250 255
Val Leu Ile Asp Thr Asp Ser Leu Ala Thr Leu Pro Asp Arg Glu Leu
260 265 270
Ala Ser Gly Ile Ser Glu Ile Ile Lys Tyr Gly Leu Ile Arg Asp Pro
275 280 285
Lys Leu Phe Val Trp Leu Glu Glu Asn Met Glu Arg Leu Leu Ala Arg
290 295 300
Asp Thr Glu Ala Leu Ala Tyr Ala Val Glu Gln Ser Cys Ile Asn Lys
305 310 315 320
Ala Glu Val Val Ala Ala Asp Glu Arg Glu Thr Asn Asp Val Arg Ala
325 330 335
Thr Leu Asn Leu Gly His Thr Phe Gly His Ala Ile Glu Thr Gly Leu
340 345 350
Gly Tyr Gly Glu Trp Leu His Gly Glu Ala Val Ser Ala Gly Thr Cys
355 360 365
Met Ala Ala Asp Leu Ser Tyr Arg Leu Gly Trp Ile Asp Leu Asp Leu
370 375 380
Lys Glu Arg Thr Glu Lys Leu Leu Ile Arg Ala Lys Leu Pro Thr Thr
385 390 395 400
Val Pro Asp Thr Met Thr Pro Gln Ile Phe Arg Asp Leu Met Ser Val
405 410 415
Asp Lys Lys Val Ala Asp Gly Lys Leu Arg Leu Val Leu Leu Lys Gly
420 425 430
Glu Leu Gly Ser Cys Val Val Thr Gly Asp Phe Asp Pro Ala Lys Leu
435 440 445
Glu Glu Thr Leu Asn His Phe Cys
450 455
<210> 8
<211> 1371
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
atgtcgttcc gccccaaact gcgcgttgga caggctgtga gcagcaaagc gagcttgatt 60
aagcccatcc gatcccccct gttgagttct ctcggtggcg attccctcgt ctctcctctg 120
cagtccagcg cattgtcatc ttgctcaacc gcaacctcct ccatcgttgg gagctccttc 180
agtggggtca accgccgcat tgttcagcgc cttcgccagg agaggcgctt ggcgatggcc 240
acccctgtca tggctgtagc ctcccccgaa cgtgtgatga agacagtaga cgtgtccctg 300
ggggacagga gctatccaat tttcattggc aaccagcttc tggctgagaa gggcgagctt 360
ttgaggaagc acatcaaggg caagcgtgtc ctcatcgtca ccaacacaac catcgcgccc 420
ctgtacctgg accaatgcgt ccaggcactg acagcggatg gcaaaatcca agtcgacagc 480
gtcatcttgc ccgatggaga ggagtacaag acaatggagg tgctgggcaa gatttgggac 540
aaggccttgg agtgccgttt ggatagggga gccacgttct tggcgctggg aggaggggtg 600
ataggcgaca tgtgtggctt cgctgcctcc tgctaccagc gtggtgttaa cttcgtacag 660
gtgcccacca cagtgatggc acaggtggat tcctctgtgg gcggaaagac cggcgtcaac 720
catgctttgg gcaagaacat gatcggcgcc ttctaccagc ctcagtgtgt gttgattgac 780
actgactccc tggccactct gcctgaccgc gagctggcct ccggaatcag tgagattatc 840
aagtatggcc tcatcaggga ccccaagctg tttgtgtggt tggaggagaa catggagcgt 900
ctcctggcta gggacactga ggccctggct tatgctgtgg agcagtcctg catcaacaag 960
gctgaggttg ttgctgctga cgagcgcgag accaatgacg tccgagctac cttgaacctt 1020
ggtcacactt ttggacatgc gatcgagacc ggtctcggct atggagagtg gttgcatgga 1080
gaggctgtgt cagccggtac ttgcatggcc gctgatctgt cttaccgcct gggctggatc 1140
gatctggatc taaaggagcg cacggagaag ctgctgattc gcgccaaact ccccaccacc 1200
gtgccggaca ccatgactcc ccagatcttc cgcgacttga tgtcagtgga taagaaagtg 1260
gctgatggca agcttaggct ggttctgtta aagggagagc tgggaagctg tgtagtcacc 1320
ggtgactttg atcctgctaa gctggaggag actttgaatc acttctgcta g 1371
<210> 9
<211> 266
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 9
Met Gln Val Ser Leu Lys Gly Phe Pro Ser Lys Leu Thr Pro Asp Arg
1 5 10 15
Gln Ala Ala Arg Pro Arg Gly Arg Leu Leu Thr Trp Ala Gln Lys Pro
20 25 30
Glu Glu Leu Gly Ser Gly Leu Ala Pro Ile Phe Ser Asn Lys Val Pro
35 40 45
Val Val Met Asn Met Asn Pro Glu Leu Tyr Ser Tyr Leu Met Gln His
50 55 60
Thr Arg Glu Pro Gln Ile Leu Lys Asp Leu Lys Asp Glu Thr Ala Ser
65 70 75 80
Leu Met Glu Thr Gly Ser His Met Gln Ile Thr Pro Asp Gln Gly Gln
85 90 95
Phe Phe Ala Leu Met Val Glu Leu Leu Gly Val Lys Arg Ala Ile Glu
100 105 110
Val Gly Val Phe Thr Gly Tyr Ser Ser Leu Ala Val Ala Met Ala Leu
115 120 125
Pro Glu Asp Gly Leu Leu Val Ala Met Asp Lys Asp Asp Arg Ser Met
130 135 140
Thr Val Ala Arg Lys Tyr Trp Lys Glu Ala Gly Val Glu His Lys Val
145 150 155 160
Lys Glu Met Leu Gly Pro Gly Gln Asp Ser Leu Lys Gln Leu Ile Ala
165 170 175
Glu Gly Glu Ser Asn Thr Tyr Asp Phe Ala Phe Ile Asp Ala Asp Lys
180 185 190
Arg Ala Tyr Trp Ala Tyr Phe Glu Leu Leu Leu Glu Leu Val Arg Pro
195 200 205
Gly Gly Leu Ile Ile Ala Asp Asn Val Leu Phe Tyr Gly Lys Val Ala
210 215 220
Asp Pro Glu Val Asn Asp Lys Ala Thr Ile Ala Leu Arg Glu Phe Asn
225 230 235 240
Asp Arg Leu Leu Val Asp Glu Arg Ile Ser Leu Ser Thr Leu Pro Val
245 250 255
Gly Asp Gly Ile Ala Leu Cys Arg Lys Arg
260 265
<210> 10
<211> 795
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
atgcaagtgt ccctgaaggg atttccctcg aagctgacac ctgacaggca ggcagctcgg 60
ccaaggggaa gactgctgac atgggcccaa aagcctgagg agcttggttc aggactggca 120
cccatttttt caaataaggt tccagtggtg atgaatatga atcctgagct gtactcatac 180
ttgatgcaac atacaagaga gccacagatc ttaaaggacc tgaaggacga gacggcatcg 240
ctgatgggct ctcatatgca aatcacccct gaccagggcc aattctttgc gctgatggtt 300
gagcttttag gtgtcaagag agctattgaa gtcggtgtct tcactgggta ctcttcgctt 360
gctgtcgcaa tggcacttcc ggaagatgga ttgctggttg cgatggacaa ggatgacagg 420
tccatgactg ttgcccgaaa atattggaaa gaggcaggag ttgaacacaa agtgaaggag 480
atgttgggtc caggtcaaga ttctttgaag caactcatag cagaagggga atccaacacg 540
tacgactttg ctttcattga tgctgacaaa agagcctact gggcatattt tgaacttctg 600
ttggagcttg tccgccctgg tggtcttatc atcgctgaca atgtcctttt ctatggcaag 660
gtggcagatc ctgaggtgaa cgataaagct accattgctc tccgtgagtt caatgatcgc 720
ctattagtgg atgagcgtat ctcgctcagc actctcccag taggggatgg gattgctttg 780
tgccgaaaac ggtga 795
<210> 11
<211> 227
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 11
Met Pro Leu Gly Gly Thr Ser Ala Val Gly Gly Pro Ala Pro Thr Ala
1 5 10 15
Ala Arg Gln Gly Arg His Lys Gln Arg Tyr Gly Glu Gly Gly Glu Arg
20 25 30
Leu Val Ala Gly Cys Ile Pro Val Arg Met Thr Gly Gln Glu Asn Ser
35 40 45
Val Asp Asn Val Glu Val Leu Met Val Ser Ser Arg Gly Gly Lys Gly
50 55 60
Phe Cys Phe Pro Lys Gly Gly Trp Glu Asp Asp Glu Thr Val Glu Ala
65 70 75 80
Ala Ala Met Arg Glu Thr Val Glu Glu Ala Gly Val Arg Gly Glu Leu
85 90 95
Glu Glu Pro Ile Val Gly Thr Phe Pro Phe Gly Ser Lys His Met Gly
100 105 110
Thr Lys His Ala Asp Asp Thr Pro His Gly Gly Arg Cys Arg Ala His
115 120 125
Met Tyr Val Met His Val Leu Glu Val Leu Glu Val Trp Pro Glu Ser
130 135 140
Ser Glu Arg Gln Arg His Trp Leu Ser Val Ser Glu Ala Ser Leu Arg
145 150 155 160
Cys Lys His Glu Trp Met Arg Gln Ala Leu Gln Thr Trp Met Arg Arg
165 170 175
Lys Gly Trp Glu Lys His Ile Ile Pro Glu His Ser Cys Cys Ser Ser
180 185 190
Thr Pro Leu Ser Thr Thr Ser Thr Thr Thr Ser Val Asn Ala Ser Ser
195 200 205
Gly Ala Asn Asn Thr Ser Thr Pro Ala Ser Thr Pro Ala Gln Asp Ala
210 215 220
Gly Gly Ser
225
<210> 12
<211> 684
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
atgccacttg gtggcacttc cgctgtggga ggacctgcgc caacggccgc taggcagggc 60
aggcataaac agcgctacgg agagggaggc gagcggctag tagcaggctg tatcccggtc 120
cgaatgacag gccaagagaa ttcagtagac aatgtggagg tgctcatggt gtccagcaga 180
ggaggtaaag gtttctgttt ccccaagggg ggatgggaag atgacgaaac tgtggaagct 240
gcagccatgc gagaaactgt agaggaggct ggtgtaagag gtgaactaga agaacccatc 300
gtgggcactt tcccctttgg cagcaagcac atgggcacaa agcatgcaga cgacacaccc 360
cacggggggc gctgcagggc gcacatgtat gtaatgcacg tgctagaggt gttggaggtt 420
tggcctgaga gcagcgaacg ccaacggcac tggttgtctg tatcagaggc aagcttacga 480
tgtaaacatg aatggatgcg gcaggctttg caaacttgga tgaggagaaa gggttgggag 540
aagcatatca tccctgaaca tagctgctgc tcctccacac cccttagcac cacctccacc 600
accacaagtg tcaatgccag ctctggtgcc aacaatacgt caacaccagc aagcacaccg 660
gcccaggatg ccgggggcag ctag 684
Claims (4)
1.一种南极冰藻MAAs合成酶的编码基因组合，其特征在于，所述南极冰藻MAAs合成酶的编码基因组合中的基因的核苷酸序列分别如SEQ ID NO.8所示、如SEQ ID NO.10所示和如SEQ ID NO.12所示。
2.一种南极冰藻MAAs合成酶组合，其特征在于，所述南极冰藻MAAs合成酶组合中的酶是由权利要求1所述的南极冰藻MAAs合成酶的编码基因组合中的基因编码得到的。
3.含有权利要求1所述的南极冰藻MAAs合成酶的编码基因组合的重组菌株。
4.权利要求2所述的南极冰藻MAAs合成酶组合在用于制备生产MAAs的制剂中的应用，其特征在于，所述MAAs为Mycosporine-glycine，结构式为
。
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