CN104450632A - 一组可提高sod耐热温度和热稳定性的氨基酸序列及其应用 - Google Patents
一组可提高sod耐热温度和热稳定性的氨基酸序列及其应用 Download PDFInfo
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Abstract
本发明涉及一组可提高SOD耐热温度和热稳定性的氨基酸序列及其应用，它是一组来源于 Geobacillus 属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列。这组氨基酸序列具有以下特征：1）位于Fe/Mn-SOD蛋白的sodA功能域之前，序列长度为101-344个氨基酸，功能未知；2）其相互之间具有85-100%的同源性；3）均包含1或2个特殊的共有重复序列Geo-N-repeat。这组氨基酸序列对 Geobacillus 属的Fe/Mn-SOD的耐热温度和热稳定性具有决定性作用，可广泛应用于其它SOD（特别是常温SOD）的改造，显著提高其耐热温度和热稳定性。
Description
技术领域
本发明涉及一组可提高SOD耐热温度和热稳定性的氨基酸序列及其应用。
背景技术
超氧化物歧化酶（Superoxide dismutase，简称SOD），是唯一能够特异性清除自由基O2·ˉ的抗氧化金属酶，是生物体防御氧毒性的关键。该酶广泛存在于自然界的生物体内，自1969年从牛红细胞发现并正式命名以来，科学家已从细菌、真菌、原生动物、藻类、昆虫、鱼类、植物和哺乳动物等生物体内都分离得到了SOD。由于SOD的特殊功效，其在医药、日用化工、食品、农业以及环保等领域具有广泛的应用价值。目前，SOD临床应用主要集中在抗炎症方面（以类风湿以及放射治疗后引起的炎症病人为主），此外对某些自身免疫性疾病（如红斑狼疮、皮肌炎）、肺气肿、抗癌和氧中毒等都有一定疗效；在食品工业主要用作食品添加剂和重要的功能性基料；在化妆品行业里主要用作抗炎、抗衰老的重要功能性成分。
基于金属辅基不同，该酶可分为Cu/Zn-SOD、Mn-SOD、Fe-SOD、Ni-SOD四种类型。Mn-SOD与Fe-SOD主要存在于原核生物中，二者序列及结构同源性很高，进化上相近；而Cu/Zn-SOD存在于真核生物中，属于进化上的另一个分支。目前已开发的SOD产品绝大部分都是Cu/Zn-SOD，最早是从动物的血、肝中分离提取的，近年来植物来源的SOD也有了大量相关报道。微生物来源的SOD，尤其嗜热菌中分离的SOD由于具有耐高温、稳定性好的特点，使其在化工应用中比常温酶具有更好的适用性，而越来越受到更多关注。嗜热SOD具有极高的热稳定性、耐受物理、化学变性剂的优良特性，在工农业生产中具有巨大的应用价值，主要来源与自然界分离，原料受限，难以满足工业化需要。目前对SOD进行生产加工以提高其热稳定性的方法主要有基因工程方法、研究SOD模拟物、化学修饰、酶固定化等，但普遍存在改造手段技术繁琐，操作困难，适应性差，且其效果并不太明显等弊端和局限性，这些问题已严重影响到了嗜热SOD的工业化进程。本专利涉及的一组可提高SOD耐热温度和热稳定性的氨基酸序列为实现SOD的耐热性改造提供了一种全新思路和方法，该方法操作简便、可行性强、适应性好，可实现传统工业用SOD的升级换代，具有重要的应用价值和前景。
发明内容
本发明的一个目的是提供一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，这13个N端氨基酸序列具有以下特征：（1）位于Fe/Mn-SOD蛋白的sodA功能域之前，序列长度为101-344个氨基酸，不能独立行使SOD的功能；（2）其相互之间具有85-100%的同源性；（3）都包含特殊的共有重复序列Geo-N-repeat（图2），其中9个N端序列含有2个重复序列，另外4个N端序列含有1个重复序列。
本发明的另一目的是提供一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，这一组N端氨基酸序列对Geobacillus属的Fe/Mn-SOD的耐热温度和热稳定性具有决定性作用，除去这一组N端氨基酸序列后的Geobacillus属的Fe/Mn-SOD耐热温度和热稳定性大幅降低（实施例1所示）。
本发明的另一目的是提供一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，这组N端氨基酸序列可广泛应用于其它SOD（不仅限于SOD），特别是常温SOD的耐热温度和热稳定性改造。通过一定方法，将这段N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端，可以显著提高SOD的耐热温度和热稳定性（实施例2所示）。
本发明的另一目的是提供一种能表达重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组质粒。
本发明的再一目的是提供一种能产生上述重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组菌。
本发明的再一目的是提供了SEQ ID NO:1-13氨基酸序列在提高SOD的耐热温度、提高SOD的热稳定性方面的应用。
为了实现上述目的，本发明采用如下技术方案：
本发明提供一组来源于 Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，如SEQ ID NO:1-13所示。
上述一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，其特征在于：（1）位于Fe/Mn-SOD蛋白的sodA功能域之前，序列长度为101-344个氨基酸；（2）其相互之间具有85-100%的同源性；（3）都包含特殊的共有重复序列Geo-N-repeat（图2），其中SEQ ID NO:1-9的9个N端序列都含有2个重复序列，SEQ ID NO:10-13的4个N端序列都含有1个重复序列。
上述一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，其具有与SEQ ID NO:1-13所示的氨基酸序列至少70%的同源性。
上述一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，其具有SEQ ID NO:1-13所示的氨基酸序列中缺失、替换、或插入的多个氨基酸序列为2-100个。
上述一组来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，其特征在于，这组N端氨基酸序列可广泛应用于其它SOD（不仅限于SOD），特别是常温SOD的耐热温度和热稳定性改造。通过一定方法，将这段N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端，可以显著提高SOD的耐热温度和热稳定性。
本发明提供的SEQ ID NO:1-13氨基酸序列如下：
Geobacillus thermodenitrificans NG80-2 SEQ ID NO:1
MDDQTLFAQYAAEVNEWGEQVKQVLELRGASIDGASTLLQFIAEHDGKWTEEAVRELTRLVDDVYAAALRHYAIEAAEWGKQVEHALSMRGAAEDIGLSSLLARIEEHGDEWTEEEIHELQLLVDDVYARAIRLVEPLSDGQEEDLTRQEEVSALPEQEGGNREQMSKGTERSGEHKGDSEQEPVVAAERAEPFIASSTDSPDGEQLHEGDTMDEEWRHNADMTDKERLPEEGVTDGERQRAVS
Geobacillus thermoleovorans CCB_US3_UF5 SEQ ID NO:2
MRLDKETVWCSRRFAKAACLFQKKGGADPKREYVLGQPDFFERFIYGSFADPLQGSITAILFFLAVFSYDDCPRSSMYERPGIWVNADKNDFPMTAYDMANKTGGGFYQMDDQVLFAQYAARVNEWGNQVKETLALRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAADREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSPTDAADGEPDQADNVTDGKRRWVDADDGGEPRQQVAPGR
Geobacillus sp. G11MC16 SEQ ID NO:3
MDDQALFAQYAAEVNEWGEQVKQVLELRGASIDGASTLLQFIAEHDGEWTEEAVRELTRLVDDVYAAALRHYAIEAAEWGKQVEHALSMRGAAEDIGLSSLLARIEEHGDEWTEEEIHELQLLVDDVYARAIRLVEPLSDGQEEDLTRQEEVSALPEQEGGNGEQMSEGTERSGEHKGDSEQEPVVAAERAEPFIASSTDSPDGEQLHEGDTMDEEWRHNADMTDKERLTEEGVTDGERQRAVS
Geobacillus sp. C56-T3 SEQ ID NO:4
MDDQVLFAQYAARVNEWGNQVKETLALRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAAEREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSLPDIADGEPGQADNVTDGKRRWVDADDGGEPRQQAAPGR
Geobacillus sp. Y412MC52 SEQ ID NO:5
MDDQVLFAQYAARVNEWGNQVKETLALRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAAEREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSLPDIADGEPGQADNVTDGKRRWVDADDGGEPRQQVAPGR
Geobacillus sp. GHH01 SEQ ID NO:6
MDDQVLFAQYAARVNEWGNQVKETLALRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAAEREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSLPDIADGEPGQADNVTDGKRRWVDADDGGEPRQQAAPGR
Geobacillus sp. Y412MC61 SEQ ID NO:7
MDDQVLFAQYAARVNEWGNQVKETLALRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAAEREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSLPDIADGEPGQADNVTDGKRRWVDADDGGEPRQQVAPGR
Geobacillus kaustophilus HTA426 SEQ ID NO:8
MRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAADREEEATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSPTDAADGEPDQADNVTDGKRRWVDADDGGEPRQQVAPGR
Geobacillus sp. POT5 SEQ ID NO:9
LRGASTDGASSLLEFIAEHDGEWTEEAVRELQRLADDVYVGALRQYVMEAAAWGRQVEQALSARRMAEDVGLSSLLAYIDGHGDEWTEEAIYELQRLVDDVYTRAVRLADSSAADREEGATQEQVEGESVSPELESENKENEDGWLDTSGTAERVEDAKEPAFMAELSDSPTDAADGEPDQVDNVTDGKRRWVDADDGGEPRQQVAPGR
Geobacillus sp. WCH70 SEQ ID NO:10
MNEQERIQQYVAEVKEWGKQVEQILLQRGEDGGDCRVDSLLSYIEHHGDAWTEDAIYELQRMVDEVYEKALVFQQNGQSAIRQEESGTEERQQTSIGQEENGIEERQQTAVRQEESGTEERQQTASEQEEESEAEERQQTYVAAGR
Geobacillus thermoglucosidans TNO-09.020 SEQ ID NO:1 1
MSEQELFQRYVKQVSEWGAQVGQMLPRRDDGTVHHDIAALLSYIDRHDGEWTETEIYDLQRMADAVYEKAAAVSANGTLADESRETSEEEARRQTYITAGR
Geobacillus thermoglucosidasius C56-YS93 SEQ ID NO:12
MSEQELFQRYVKQVSEWGAQVGQMLPRRDDGTVHHDIAALLSYIDRHDGEWTETEIYDLQRMADAVYEKAAAVSANGTLADESRETSEEEARRQTYITAGR
Geobacillus sp. Y4.1MC1 SEQ ID NO:13
MSEQELFQRYVKQVSKWGAQVGQMLPRRDDGTVHRDIAALLSYIDRHDGEWTETEIYDLQRMADAVYEKAAAVSANGTLADESRETSEEEARRQTYITAGR
一种表达上述的超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组质粒，该质粒至少包括SEQ ID NO:1-13所示的基因。
上述表达重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组质粒的载体为pET-28a(+)（实验室常用载体）。
一种产生上述的重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组菌，该重组菌导入了超氧化物歧化酶。
上述产生重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组菌为大肠杆菌。
上述产生重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的重组菌的大肠杆菌为大肠杆菌BL21菌株（保藏号H1566）。
上述的重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）应用于催化超氧阴离子自由基，发生歧化反应生成氧气和双氧水。
对本发明的重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）基因所表达的酶分子的氨基酸进行一个或多个氨基酸替换、插入或缺失所得到的蛋白质也能达到本发明的目的。因而本发明还包括与SEQ ID NO: 1-13所示的氨基酸序列具有至少70%的同源性，优选具有至少90%的同源性，但同时具有重组超氧化物歧化酶活性的蛋白质。上面使用的术语“多个”可以是小于100的数目，优选为小于10的数目。
本发明提出的上述重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）的性能不同于已知的超氧化物歧化酶，将这段N段序列添加到其它SOD的N端或sodA功能域的N端，可以提高其它SOD的耐热温度和热稳定性，可高效催化超氧阴离子自由基(O2·ˉ)发生歧化反应生成氧气O2和双氧水H2O2。
上述的重组超氧化物歧化酶（N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端）改造后的重组超氧化物歧化酶主要应用于医药、卫生保健、食品或化妆品加工。
本发明公开的一组可提高SOD耐热温度和热稳定性的氨基酸序列所具有的积极效果在于：
（1）阐明了一种提高SOD耐热温度和热稳定性的新方法。利用添加本专利中氨基酸序列的基因重组方法进行常温SOD的热稳定性改造和高效表达，具有重要应用价值，也为其它耐高温工业酶的改造提供新思路。
（2）通过添加本专利中氨基酸序列所获得的SOD酶是一种耐高温酶，可在高温条件下保持极好的稳定性，克服了中温酶（20℃~50℃）及低温酶（2℃~20℃）在应用过程中出现的化学性质不稳定现象，有利于其在食品、化妆品、药品及保健品等领域的工业应用。
（3）通过添加本专利中氨基酸序列提高SOD耐热温度和热稳定性的方法操作简单，成本低廉，重复性好，具有重要的工业应用前景和实际意义。
附图说明
图2 为13个Geobacillus属的重复序列Geo-N-repeat；其中 Repeat1和 Repeat2分别表示重复序列1和重复序列2；在Repeat1和 Repeat2中，字母的大小表示氨基酸所占比例，空缺处用字母“B” 表示。
具体实施方式
下面通过具体实施例并结合附图对本发明作进一步的详细说明。以下各实施例仅仅是用于说明而不是限制本发明。需要特别说明的是实施例中所用到的试剂均由市售，嗜热脱氮芽胞杆菌NG80-2（CGMCC No. 1228）已保藏在国家菌种保藏中心。
实施例1
构建编码NG80-2的Fe/Mn-SOD全序列基因（sod-GTNG_2215）的克隆，并且构建编码SOD-GTNG_2215的结构域sodA的DNA序列（sodA-GTNG_2215）的克隆，并且测定表达蛋白的最适反应温度及热稳定性。
1. 嗜热脱氮芽胞杆菌NG80-2（CGMCC No. 1228）总DNA的提取
在本实施例中，采用从中国天津大港油田官69-8区块油井地层水分离获得的嗜热脱氮芽胞杆菌NG80-2（Geobacillus thermodenitrificans该菌株已保藏在中国微生物菌种保藏委员会普通微生物中心，其保藏号为CGMCC No.1228），取其过夜培养的新鲜培养物3mL，离心收集菌体，菌体悬于250μL 50mM Tris缓冲液中（pH8.0），加入10μL 0.4M EDTA（pH8.0），混匀后37℃保温20min，之后加入30μL 20mg/L溶菌酶，混匀后37℃再保温20min，再加入5μL 20mg/L蛋白酶K，温柔混匀后，再加入20μL 10%SDS，50℃保温至溶液澄清，分别用等体积酚:氯仿:异戊醇抽提两次，氯仿:异戊醇抽提一次，最后一次的上清溶液，加入2.5倍体积预冷的无水乙醇，回收DNA，用70%乙醇洗，沉淀溶于100μL TE缓冲液（pH8.0，10mM Tris，1 mM EDTA），加入10mg/L RNase 2μL，65℃保温30min，分别用酚:氯仿:异戊醇、氯仿:异戊醇各抽提一次，上清液加入2.5倍体积预冷的无水乙醇，回收DNA，用70%乙醇洗，真空干燥，沉淀溶于50μL TE缓冲液。DNA溶液的紫外分光光度计测定结果为A260/A280=1.95，A260=0.73。
2. 超氧化物歧化酶基因的克隆和筛选
2.1扩增NG80-2的Fe/Mn-SOD全序列基因（sod-GTNG_2215），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCCATATGGACGACCAAACGTTGTTTGC 3'
下游引物：5' CCCAAGCTTTTAAAATGGTTGCCAACGCA 3'
2.2扩增NG80-2的Fe/Mn-SOD的结构域sodA的DNA序列（sodA-GTNG_2215），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCCATATGCCTGGCAAGCATGTGCTGCC 3'
下游引物：5' CCCAAGCTTTTAAAATGGTTGCCAACGCA 3'
上述两组PCR产物纯化后都用NdeI和HindIII双酶切，分别与经同样限制型内切酶酶解并切胶回收的质粒pET-28a(+)连接，转化感受态大肠杆菌DH5α（本实验室保存）后，涂于含50μg/mL Kan（卡拉霉素）的LB固体培养基上。37℃培养16～18小时，挑取单克隆菌落鉴定，插入有sod-GTNG_2215编码的DNA序列的pET-28a(+)质粒为重组质粒pLW01，含有该质粒的重组大肠杆菌DH5α为DH01。插入有sodA-GTNG_2215编码的序列的pET-28a(+)质粒为重组质粒pLW02，含有该质粒的重组大肠杆菌DH5α为DH02。采用Sanger双脱氧法对此DNA片段进行了测序，测序结果显示插入的DNA序列正确。然后将重组质粒pLW01和pLW02分别转化入大肠杆菌BL21中，此大肠杆菌BL21分别命名为BL01和BL02。
3. 重组超氧化物歧化酶的纯化和特性
将上述重组菌BL01和BL02单克隆分别接入20mL含50μg/mL Kan的LB培养基中，37℃，180rpm/min培养12小时，然后将培养物按1%（V/V）接种量接入200mL含50μg/mL Kan的LB培养基（共2个摇瓶），37℃，220rpm/min培养A600为0.6时，加入IPTG至终浓度为0.1 mM, 37℃, 180rpm/min诱导3小时。离心收集菌体，悬于50 mM Tris-Cl（pH8.0）缓冲液中，利用超声波破碎细胞，离心上清液为重组超氧化物歧化酶的粗提液。此上清液经螯合琼脂糖凝胶（Chelating Sepharose）镍亲合柱层析纯化，得到的酶制剂在SDS-PAGE上显示一条带。理论上推算SOD-GTNG_2215和 SODA-GTNG_2215的分子量分别为54.0kD和26.6kD，与SDS-PAGE检测结果一致。
4. 重组超氧化物歧化酶（SOD）活性测定
3mL反应混合液中14.5 mM L-甲硫氨酸加入2.7mL，30μL EDTA-Na2加入10ul，2.25 mM NBT加入100uL，60mM核黄素加入100μL，PBS加入90μL，加入10μL的样品酶液。各试剂加完后充分混匀，取1管置于暗处，560nm比色时调零。另取1管不加蛋白酶，用磷酸钠缓冲液代替作为空白对照。其余几管待测样品置于一定温度光强为4000Lux条件下光照15min，然后立刻避光终止反应。在560nm波长处比色时，用置于黑暗处的样品液调零，测定各样品管光吸收并记录结果。在一定测定条件下将NBT光还原反应抑制到对照的50%时的酶量作为一个酶活力单位（U）
4.1 最适酶活性温度
将纯化后超氧化物歧化酶（SOD），分别在不同温度条件下（20℃，30℃，40℃，50℃,60℃，70℃，80℃），测定超氧化物歧化酶的活性，将所得最高的酶活力定义为100％，分别计算各个温度条件下超氧化物歧化酶的剩余酶活性（采用相对酶活性来表示，即在不同温度条件下的剩余的酶活性占酶活性最大值的百分比）。结果表明（见图1），SOD-GTNG_2215在20-70℃内，随着温度的升高，酶活性逐渐提高，在70℃时酶活性最高，温度继续升高后酶活性大幅降低。SODA-GTNG_2215在30℃时酶活性最高，随着温度继续升高，酶活性继续降低。
4.2 SOD的热稳定性测定
将纯化的超氧化物歧化酶（SOD），分别置于不同温度条件下（20℃，30℃，40℃，50℃，60℃，70℃，80℃），保温一定时间（10min，20min，30min，40min，50min，60min）后，将其迅速冷却至酶的最适温度，然后测定剩余的酶活性。将最高的酶活力定义为100%，分别计算不同温度条件下超氧化物歧化酶的剩余酶活性与最高酶活性的比值。结果表明，SODA-GTNG_2215在20℃条件下酶活性稳定，即使保温60min，酶活性也没有明显变化。但当温度超过40℃后，其热稳定性大幅下降，酶活性残留低于20%，说明其已不具嗜热性，热稳定性差。SOD-GTNG_2215在<70℃时保持较好的热稳定性，即使70℃保温60min，酶活性仍保留了超过70%。在80℃时加热10min后酶活性下降到52.41%，但是直到加热60min酶活性仍保持在40%左右，热稳定性良好。
结论：当SOD-GTNG_2215去除N端序列后，其耐热温度大幅下降（最适反应温度由70℃下降至30℃），并且热稳定性显著变差。这说明N端序列对SOD-GTNG_2215的耐热温度和热稳定性具有决定性作用。
实施例2
构建编码B. subtilis BSn5的Mn-SOD全序列基因（sod-BSn5）的克隆，并且构建编码SOD-BSn5的结构域sodA的DNA序列（sodA-BSn5）的克隆，最后还要构建编码重组SOD（SOD-GTNG_2215的N端序列和B. subtilis BSn5的SODA重组结合成重组SOD）全序列基因（sod-combinant）的克隆。并且测定表达蛋白的酶活性及热稳定性。
1. B. subtilis BSn5总DNA的提取
在本实施例中，取其过夜培养的新鲜培养物3mL，离心收集菌体，菌体悬于250μL 50 mM Tris缓冲液中（pH8.0），加入10μL 0.4M EDTA（pH8.0），混匀后37℃保温20min，之后加入30μL 20mg/L溶菌酶，混匀后37℃再保温20min，再加入5μL 20mg/L蛋白酶K，温柔混匀后，再加入20μL 10%SDS，50℃保温至溶液澄清，分别用等体积酚:氯仿:异戊醇抽提两次，氯仿:异戊醇抽提一次，最后一次的上清溶液，加入2.5倍体积预冷的无水乙醇，回收DNA，用70%乙醇洗，沉淀溶于100μL TE缓冲液（pH8.0，10mM Tris，1mM EDTA），加入10mg/L RNase 2μL，65℃保温30min，分别用酚:氯仿:异戊醇、氯仿:异戊醇各抽提一次，上清液加入2.5倍体积预冷的无水乙醇，回收DNA，用70%乙醇洗，真空干燥，沉淀溶于50μL TE缓冲液。DNA溶液的紫外分光光度计测定结果为A260/A280=1.96，A260=0.72。
2. 超氧化物歧化酶（SOD）基因的克隆和筛选
2.1 扩增BSn5的Mn-SOD全序列基因（sod-BSn5），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCATGAAACGTGAATCTTATCAAACG 3'
下游引物：5' CCGCTCGAGTTAATAGAGCTTCCAAACGACTTC 3'
2.2 扩增BSn5的Mn-SOD的结构域sodA的DNA序列（sodA -BSn5），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCCATATGAAACAcGTGCTGCCAAAGCT 3'
下游引物：5' CGCGGATCCTTAATAGAGCTTCCAAACGACTTC 3'
2.3扩增重组SOD的DNA序列（sod-combinant）
2.3.1 扩增NG80-2 SOD的N端序列基因（sod_N-GTNG_2215），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCCATATGGACGACCAAACGTTGTTTGC 3'
下游引物：5' GCACATGTTTCGAAACCGCC 3'
2.3.2 扩增BSn5 SOD的C端序列基因（sod_C-BSn5），取前面所述的总DNA溶液0.5μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGCGGTTTCGAAACATGTGC 3'
下游引物：5' CGCGGATCCTTAATAGAGTTTCCAAACGACTTC 3'
2.3.3 扩增重组SOD的DNA序列（sod-combinant），sod_N-GTNG_2215和sod_C-BSn5各取0.25μL（约10ng）作为模板，以下列寡核苷酸序列作为引物，并按下述设定的PCR循环参数进行25个循环PCR。
设定的PCR循环参数如下：
95℃，3min；95℃，30s；55℃，45s；72℃，2min；72℃，10min；4℃，2hr
上游引物：5' GGAATTCCATATG GACGACCAAACGTTGTTTGC 3'
下游引物：5' CGCGGATCCTTAATAGAGcTTCCAAACGACTTC 3'
sod-BSn5的PCR产物纯化后用EcoRI/ XhoI双酶切，sodA-BSn5和sod-combinant的PCR产物纯化后用NdeI/ BamH双酶切，以上酶切产物分别与经同样限制型内切酶酶解并切胶回收的质粒pET-28a(+)连接，转化感受态大肠杆菌DH5α（本实验室保存）后，涂于含50μg/mL Kan（卡拉霉素）的LB固体培养基上。37℃培养16～18小时，挑取单克隆菌落鉴定，插入有sod-BSn5编码的DNA序列的pET-28a(+)质粒为重组质粒pLW03，含有该质粒的重组大肠杆菌DH5α为DH03。插入有sodS-BSn5编码的DNA序列的pET-28a(+)质粒为重组质粒pLW04，含有该质粒的重组大肠杆菌DH5α为DH104。插入有sod-combinant编码的DNA序列的pET-28a(+)质粒为重组质粒pLW05，含有该质粒的重组大肠杆菌DH5α为DH05。采用Sanger双脱氧法对此DNA片段进行了测序，测序结果显示插入的DNA序列正确。将上述重组质粒pLW03、pLW04和 pLW05分别转化入大肠杆菌BL21中，此大肠杆菌BL21分别命名为BL03、BL04和BL05。
3. 重组超氧化物歧化酶的纯化和特性
将上述重组菌BL03、BL04和BL05单克隆分别接入20mL含50μg/mL Kan的LB培养基中，37℃，180rpm/min培养12小时，然后将培养物按1%（V/V）接种量接入200mL含50μg/mL Kan的LB培养基（共2个摇瓶），37℃，220rpm/min培养A600为0.6时， BL03加入IPTG至终浓度为0.05mM, 25℃, 180rpm/min诱导3小时。BL04加入IPTG至终浓度为0.05mM, 25℃, 180rpm/min诱导3小时。BL05加入IPTG至终浓度为0.1mM, 30℃, 180rpm/min诱导3小时。诱导完后离心收集菌体，悬于50mMTris-Cl（pH8.0）缓冲液中，利用超声波破碎细胞，离心上清液为重组超氧化物歧化酶的粗提液。此上清液经螯合琼脂糖凝胶（Chelating Sepharose）镍亲合柱层析纯化，得到的酶制剂在SDS-PAGE上显示一条带。理论上推算SOD-BSn5、SODA-BSn5 和 SOD-combinant的分子量分别为37.28099 kD、26.28290 kD和53.61853 kD，与SDS-PAGE检测结果一致。
4. 重组超氧化物歧化酶活性测定
3mL反应混合液中14.5 mM L-甲硫氨酸加入2.7mL，30μL EDTA-Na2加入10μL，2.25 mM NBT加入100μL，60μM核黄素加入100μL，PBS加入90μL，加入10μL的样品酶液。各试剂加完后充分混匀，取1管置于暗处，560nm比色时调零。另取1管不加蛋白酶，用磷酸钠缓冲液代替作为空白对照。其余几管待测样品置于一定温度光强为4000Lux条件下光照15min，然后立刻避光终止反应。在560nm波长处比色时，用置于黑暗处的样品液调零，测定各样品管光吸收并记录结果。在一定测定条件下将NBT光还原反应抑制到对照的50%时的酶量作为一个酶活力单位（U）
4.1 最适酶活性温度
将纯化后超氧化物歧化酶，分别在不同温度条件下（20℃，30℃，40℃，50℃,60℃，70℃，80℃），测定超氧化物歧化酶的活性，将所得最高的酶活力定义为100％，分别计算各个温度条件下超氧化物歧化酶的剩余酶活性（采用相对酶活性来表示，即在不同温度条件下的剩余的酶活性占酶活性最大值的百分比）。结果表明（见图1），BSn5 SOD在37℃左右酶活性最高，随着温度继续升高，酶活性大幅降低。BSn5 sodA在30℃时酶活性最高，随着温度继续升高，酶活性大幅降低。SOD-combinant在55℃左右时酶活性最高，随着温度继续升高，酶活性继续降低，但是在80℃仍保留一定酶活性，可见SOD-combinant的耐热温度明显提高。
4.2 SOD的热稳定性测定
将纯化的超氧化物歧化酶，分别置于不同温度条件下（20℃，30℃，40℃，50℃，60℃，70℃，80℃），保温一定时间（10min，20min，30min，40min，50min，60min）后，将其迅速冷却至酶的最适温度，然后测定剩余的酶活性。将最高的酶活力定义为100%，分别计算不同温度条件下超氧化物歧化酶的剩余酶活性与最高酶活性的比值。结果表明，SOD-BSn5、SODA-BSn5和SOD-combinant在20℃条件下酶活性稳定，即使保温60min，酶活性也没有明显变化。Bsn5-sodA 在30℃条件下保温60min酶活性下降39.18%。BSn5-SOD、BSn5-sodA在40℃条件下热稳定性大幅下降，不具嗜热性，热稳定性差。SOD-combinant在小于50℃时保持较好的热稳定性，在60℃加热60min，酶活性仍保留了超过60%，热稳定性好。
结论：N端氨基酸序列添加到常温SOD（SODA-BSn5）的N端，可以显著提高常温SOD的耐热温度（SODA-BSn5的最适反应温度由30℃提高至50-60℃）和热稳定性。
实施例3
实际应用：
由于SOD的特殊功效，其在医药、日用化工、食品、农业以及环保等领域具有广泛的应用价值。目前，SOD临床应用主要集中在抗炎症方面（以类风湿以及放射治疗后引起的炎症病人为主），此外对某些自身免疫性疾病（如红斑狼疮、皮肌炎）、肺气肿、抗癌和氧中毒等都有一定疗效；在食品工业主要用作食品添加剂和重要的功能性基料；在化妆品行业里主要用作抗炎、抗衰老的重要功能性成分。
虽然本发明已以较佳实施例披露如上，然其并非用以限定本发明，任何所属技术领域的技术人员，在不脱离本发明的精神和范围内，可做些许的更动与改进，因此本发明的保护范围当视权利要求所界定者为准。
SEQUENCE LISTING
<110> 南开大学
<120> 一组可提高SOD耐热温度和热稳定性的氨基酸序列及其应用
<160> 13
<170> PatentIn version 3.5
<210> 1
<211> 244
<212> PRT
<213> Geobacillus thermodenitrificans NG80-2
<400> 1
Met Asp Asp Gln Thr Leu Phe Ala Gln Tyr Ala Ala Glu Val Asn Glu
1 5 10 15
Trp Gly Glu Gln Val Lys Gln Val Leu Glu Leu Arg Gly Ala Ser Ile
20 25 30
Asp Gly Ala Ser Thr Leu Leu Gln Phe Ile Ala Glu His Asp Gly Lys
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Thr Arg Leu Val Asp Asp Val
50 55 60
Tyr Ala Ala Ala Leu Arg His Tyr Ala Ile Glu Ala Ala Glu Trp Gly
65 70 75 80
Lys Gln Val Glu His Ala Leu Ser Met Arg Gly Ala Ala Glu Asp Ile
85 90 95
Gly Leu Ser Ser Leu Leu Ala Arg Ile Glu Glu His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Glu Ile His Glu Leu Gln Leu Leu Val Asp Asp Val Tyr
115 120 125
Ala Arg Ala Ile Arg Leu Val Glu Pro Leu Ser Asp Gly Gln Glu Glu
130 135 140
Asp Leu Thr Arg Gln Glu Glu Val Ser Ala Leu Pro Glu Gln Glu Gly
145 150 155 160
Gly Asn Arg Glu Gln Met Ser Lys Gly Thr Glu Arg Ser Gly Glu His
165 170 175
Lys Gly Asp Ser Glu Gln Glu Pro Val Val Ala Ala Glu Arg Ala Glu
180 185 190
Pro Phe Ile Ala Ser Ser Thr Asp Ser Pro Asp Gly Glu Gln Leu His
195 200 205
Glu Gly Asp Thr Met Asp Glu Glu Trp Arg His Asn Ala Asp Met Thr
210 215 220
Asp Lys Glu Arg Leu Pro Glu Glu Gly Val Thr Asp Gly Glu Arg Gln
225 230 235 240
Arg Ala Val Ser
<210> 2
<211> 344
<212> PRT
<213> Geobacillus thermoleovorans CCB_US3_UF5
<400> 2
Met Arg Leu Asp Lys Glu Thr Val Trp Cys Ser Arg Arg Phe Ala Lys
1 5 10 15
Ala Ala Cys Leu Phe Gln Lys Lys Gly Gly Ala Asp Pro Lys Arg Glu
20 25 30
Tyr Val Leu Gly Gln Pro Asp Phe Phe Glu Arg Phe Ile Tyr Gly Ser
35 40 45
Phe Ala Asp Pro Leu Gln Gly Ser Ile Thr Ala Ile Leu Phe Phe Leu
50 55 60
Ala Val Phe Ser Tyr Asp Asp Cys Pro Arg Ser Ser Met Tyr Glu Arg
65 70 75 80
Pro Gly Ile Trp Val Asn Ala Asp Lys Asn Asp Phe Pro Met Thr Ala
85 90 95
Tyr Asp Met Ala Asn Lys Thr Gly Gly Gly Phe Tyr Gln Met Asp Asp
100 105 110
Gln Val Leu Phe Ala Gln Tyr Ala Ala Arg Val Asn Glu Trp Gly Asn
115 120 125
Gln Val Lys Glu Thr Leu Ala Leu Arg Gly Ala Ser Thr Asp Gly Ala
130 135 140
Ser Ser Leu Leu Glu Phe Ile Ala Glu His Asp Gly Glu Trp Thr Glu
145 150 155 160
Glu Ala Val Arg Glu Leu Gln Arg Leu Ala Asp Asp Val Tyr Val Gly
165 170 175
Ala Leu Arg Gln Tyr Val Met Glu Ala Ala Ala Trp Gly Arg Gln Val
180 185 190
Glu Gln Ala Leu Ser Ala Arg Arg Met Ala Glu Asp Val Gly Leu Ser
195 200 205
Ser Leu Leu Ala Tyr Ile Asp Gly His Gly Asp Glu Trp Thr Glu Glu
210 215 220
Ala Ile Tyr Glu Leu Gln Arg Leu Val Asp Asp Val Tyr Thr Arg Ala
225 230 235 240
Val Arg Leu Ala Asp Ser Ser Ala Ala Asp Arg Glu Glu Glu Ala Thr
245 250 255
Gln Glu Gln Val Glu Gly Glu Ser Val Ser Pro Glu Leu Glu Ser Glu
260 265 270
Asn Lys Glu Asn Glu Asp Gly Trp Leu Asp Thr Ser Gly Thr Ala Glu
275 280 285
Arg Val Glu Asp Ala Lys Glu Pro Ala Phe Met Ala Glu Leu Ser Asp
290 295 300
Ser Pro Thr Asp Ala Ala Asp Gly Glu Pro Asp Gln Ala Asp Asn Val
305 310 315 320
Thr Asp Gly Lys Arg Arg Trp Val Asp Ala Asp Asp Gly Gly Glu Pro
325 330 335
Arg Gln Gln Val Ala Pro Gly Arg
340
<210> 3
<211> 244
<212> PRT
<213> Geobacillus sp. G11MC16
<400> 3
Met Asp Asp Gln Ala Leu Phe Ala Gln Tyr Ala Ala Glu Val Asn Glu
1 5 10 15
Trp Gly Glu Gln Val Lys Gln Val Leu Glu Leu Arg Gly Ala Ser Ile
20 25 30
Asp Gly Ala Ser Thr Leu Leu Gln Phe Ile Ala Glu His Asp Gly Glu
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Thr Arg Leu Val Asp Asp Val
50 55 60
Tyr Ala Ala Ala Leu Arg His Tyr Ala Ile Glu Ala Ala Glu Trp Gly
65 70 75 80
Lys Gln Val Glu His Ala Leu Ser Met Arg Gly Ala Ala Glu Asp Ile
85 90 95
Gly Leu Ser Ser Leu Leu Ala Arg Ile Glu Glu His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Glu Ile His Glu Leu Gln Leu Leu Val Asp Asp Val Tyr
115 120 125
Ala Arg Ala Ile Arg Leu Val Glu Pro Leu Ser Asp Gly Gln Glu Glu
130 135 140
Asp Leu Thr Arg Gln Glu Glu Val Ser Ala Leu Pro Glu Gln Glu Gly
145 150 155 160
Gly Asn Gly Glu Gln Met Ser Glu Gly Thr Glu Arg Ser Gly Glu His
165 170 175
Lys Gly Asp Ser Glu Gln Glu Pro Val Val Ala Ala Glu Arg Ala Glu
180 185 190
Pro Phe Ile Ala Ser Ser Thr Asp Ser Pro Asp Gly Glu Gln Leu His
195 200 205
Glu Gly Asp Thr Met Asp Glu Glu Trp Arg His Asn Ala Asp Met Thr
210 215 220
Asp Lys Glu Arg Leu Thr Glu Glu Gly Val Thr Asp Gly Glu Arg Gln
225 230 235 240
Arg Ala Val Ser
<210> 4
<211> 235
<212> PRT
<213> Geobacillus sp. C56-T3
<400> 4
Met Asp Asp Gln Val Leu Phe Ala Gln Tyr Ala Ala Arg Val Asn Glu
1 5 10 15
Trp Gly Asn Gln Val Lys Glu Thr Leu Ala Leu Arg Gly Ala Ser Thr
20 25 30
Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile Ala Glu His Asp Gly Glu
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Gln Arg Leu Ala Asp Asp Val
50 55 60
Tyr Val Gly Ala Leu Arg Gln Tyr Val Met Glu Ala Ala Ala Trp Gly
65 70 75 80
Arg Gln Val Glu Gln Ala Leu Ser Ala Arg Arg Met Ala Glu Asp Val
85 90 95
Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp Gly His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg Leu Val Asp Asp Val Tyr
115 120 125
Thr Arg Ala Val Arg Leu Ala Asp Ser Ser Ala Ala Glu Arg Glu Glu
130 135 140
Glu Ala Thr Gln Glu Gln Val Glu Gly Glu Ser Val Ser Pro Glu Leu
145 150 155 160
Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly Trp Leu Asp Thr Ser Gly
165 170 175
Thr Ala Glu Arg Val Glu Asp Ala Lys Glu Pro Ala Phe Met Ala Glu
180 185 190
Leu Ser Asp Ser Leu Pro Asp Ile Ala Asp Gly Glu Pro Gly Gln Ala
195 200 205
Asp Asn Val Thr Asp Gly Lys Arg Arg Trp Val Asp Ala Asp Asp Gly
210 215 220
Gly Glu Pro Arg Gln Gln Ala Ala Pro Gly Arg
225 230 235
<210> 5
<211> 235
<212> PRT
<213> Geobacillus sp. Y412MC52
<400> 5
Met Asp Asp Gln Val Leu Phe Ala Gln Tyr Ala Ala Arg Val Asn Glu
1 5 10 15
Trp Gly Asn Gln Val Lys Glu Thr Leu Ala Leu Arg Gly Ala Ser Thr
20 25 30
Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile Ala Glu His Asp Gly Glu
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Gln Arg Leu Ala Asp Asp Val
50 55 60
Tyr Val Gly Ala Leu Arg Gln Tyr Val Met Glu Ala Ala Ala Trp Gly
65 70 75 80
Arg Gln Val Glu Gln Ala Leu Ser Ala Arg Arg Met Ala Glu Asp Val
85 90 95
Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp Gly His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg Leu Val Asp Asp Val Tyr
115 120 125
Thr Arg Ala Val Arg Leu Ala Asp Ser Ser Ala Ala Glu Arg Glu Glu
130 135 140
Glu Ala Thr Gln Glu Gln Val Glu Gly Glu Ser Val Ser Pro Glu Leu
145 150 155 160
Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly Trp Leu Asp Thr Ser Gly
165 170 175
Thr Ala Glu Arg Val Glu Asp Ala Lys Glu Pro Ala Phe Met Ala Glu
180 185 190
Leu Ser Asp Ser Leu Pro Asp Ile Ala Asp Gly Glu Pro Gly Gln Ala
195 200 205
Asp Asn Val Thr Asp Gly Lys Arg Arg Trp Val Asp Ala Asp Asp Gly
210 215 220
Gly Glu Pro Arg Gln Gln Val Ala Pro Gly Arg
225 230 235
<210> 6
<211> 235
<212> PRT
<213> Geobacillus sp. GHH01
<400> 6
Met Asp Asp Gln Val Leu Phe Ala Gln Tyr Ala Ala Arg Val Asn Glu
1 5 10 15
Trp Gly Asn Gln Val Lys Glu Thr Leu Ala Leu Arg Gly Ala Ser Thr
20 25 30
Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile Ala Glu His Asp Gly Glu
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Gln Arg Leu Ala Asp Asp Val
50 55 60
Tyr Val Gly Ala Leu Arg Gln Tyr Val Met Glu Ala Ala Ala Trp Gly
65 70 75 80
Arg Gln Val Glu Gln Ala Leu Ser Ala Arg Arg Met Ala Glu Asp Val
85 90 95
Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp Gly His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg Leu Val Asp Asp Val Tyr
115 120 125
Thr Arg Ala Val Arg Leu Ala Asp Ser Ser Ala Ala Glu Arg Glu Glu
130 135 140
Glu Ala Thr Gln Glu Gln Val Glu Gly Glu Ser Val Ser Pro Glu Leu
145 150 155 160
Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly Trp Leu Asp Thr Ser Gly
165 170 175
Thr Ala Glu Arg Val Glu Asp Ala Lys Glu Pro Ala Phe Met Ala Glu
180 185 190
Leu Ser Asp Ser Leu Pro Asp Ile Ala Asp Gly Glu Pro Gly Gln Ala
195 200 205
Asp Asn Val Thr Asp Gly Lys Arg Arg Trp Val Asp Ala Asp Asp Gly
210 215 220
Gly Glu Pro Arg Gln Gln Ala Ala Pro Gly Arg
225 230 235
<210> 7
<211> 235
<212> PRT
<213> Geobacillus sp. Y412MC61
<400> 7
Met Asp Asp Gln Val Leu Phe Ala Gln Tyr Ala Ala Arg Val Asn Glu
1 5 10 15
Trp Gly Asn Gln Val Lys Glu Thr Leu Ala Leu Arg Gly Ala Ser Thr
20 25 30
Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile Ala Glu His Asp Gly Glu
35 40 45
Trp Thr Glu Glu Ala Val Arg Glu Leu Gln Arg Leu Ala Asp Asp Val
50 55 60
Tyr Val Gly Ala Leu Arg Gln Tyr Val Met Glu Ala Ala Ala Trp Gly
65 70 75 80
Arg Gln Val Glu Gln Ala Leu Ser Ala Arg Arg Met Ala Glu Asp Val
85 90 95
Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp Gly His Gly Asp Glu Trp
100 105 110
Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg Leu Val Asp Asp Val Tyr
115 120 125
Thr Arg Ala Val Arg Leu Ala Asp Ser Ser Ala Ala Glu Arg Glu Glu
130 135 140
Glu Ala Thr Gln Glu Gln Val Glu Gly Glu Ser Val Ser Pro Glu Leu
145 150 155 160
Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly Trp Leu Asp Thr Ser Gly
165 170 175
Thr Ala Glu Arg Val Glu Asp Ala Lys Glu Pro Ala Phe Met Ala Glu
180 185 190
Leu Ser Asp Ser Leu Pro Asp Ile Ala Asp Gly Glu Pro Gly Gln Ala
195 200 205
Asp Asn Val Thr Asp Gly Lys Arg Arg Trp Val Asp Ala Asp Asp Gly
210 215 220
Gly Glu Pro Arg Gln Gln Val Ala Pro Gly Arg
225 230 235
<210> 8
<211> 209
<212> PRT
<213> Geobacillus kaustophilus HTA426
<400> 8
Met Arg Gly Ala Ser Thr Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile
1 5 10 15
Ala Glu His Asp Gly Glu Trp Thr Glu Glu Ala Val Arg Glu Leu Gln
20 25 30
Arg Leu Ala Asp Asp Val Tyr Val Gly Ala Leu Arg Gln Tyr Val Met
35 40 45
Glu Ala Ala Ala Trp Gly Arg Gln Val Glu Gln Ala Leu Ser Ala Arg
50 55 60
Arg Met Ala Glu Asp Val Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp
65 70 75 80
Gly His Gly Asp Glu Trp Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg
85 90 95
Leu Val Asp Asp Val Tyr Thr Arg Ala Val Arg Leu Ala Asp Ser Ser
100 105 110
Ala Ala Asp Arg Glu Glu Glu Ala Thr Gln Glu Gln Val Glu Gly Glu
115 120 125
Ser Val Ser Pro Glu Leu Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly
130 135 140
Trp Leu Asp Thr Ser Gly Thr Ala Glu Arg Val Glu Asp Ala Lys Glu
145 150 155 160
Pro Ala Phe Met Ala Glu Leu Ser Asp Ser Pro Thr Asp Ala Ala Asp
165 170 175
Gly Glu Pro Asp Gln Ala Asp Asn Val Thr Asp Gly Lys Arg Arg Trp
180 185 190
Val Asp Ala Asp Asp Gly Gly Glu Pro Arg Gln Gln Val Ala Pro Gly
195 200 205
Arg
<210> 9
<211> 209
<212> PRT
<213> Geobacillus sp. POT5
<400> 9
Leu Arg Gly Ala Ser Thr Asp Gly Ala Ser Ser Leu Leu Glu Phe Ile
1 5 10 15
Ala Glu His Asp Gly Glu Trp Thr Glu Glu Ala Val Arg Glu Leu Gln
20 25 30
Arg Leu Ala Asp Asp Val Tyr Val Gly Ala Leu Arg Gln Tyr Val Met
35 40 45
Glu Ala Ala Ala Trp Gly Arg Gln Val Glu Gln Ala Leu Ser Ala Arg
50 55 60
Arg Met Ala Glu Asp Val Gly Leu Ser Ser Leu Leu Ala Tyr Ile Asp
65 70 75 80
Gly His Gly Asp Glu Trp Thr Glu Glu Ala Ile Tyr Glu Leu Gln Arg
85 90 95
Leu Val Asp Asp Val Tyr Thr Arg Ala Val Arg Leu Ala Asp Ser Ser
100 105 110
Ala Ala Asp Arg Glu Glu Gly Ala Thr Gln Glu Gln Val Glu Gly Glu
115 120 125
Ser Val Ser Pro Glu Leu Glu Ser Glu Asn Lys Glu Asn Glu Asp Gly
130 135 140
Trp Leu Asp Thr Ser Gly Thr Ala Glu Arg Val Glu Asp Ala Lys Glu
145 150 155 160
Pro Ala Phe Met Ala Glu Leu Ser Asp Ser Pro Thr Asp Ala Ala Asp
165 170 175
Gly Glu Pro Asp Gln Val Asp Asn Val Thr Asp Gly Lys Arg Arg Trp
180 185 190
Val Asp Ala Asp Asp Gly Gly Glu Pro Arg Gln Gln Val Ala Pro Gly
195 200 205
Arg
<210> 10
<211> 146
<212> PRT
<213> Geobacillus sp. WCH70
<400> 10
Met Asn Glu Gln Glu Arg Ile Gln Gln Tyr Val Ala Glu Val Lys Glu
1 5 10 15
Trp Gly Lys Gln Val Glu Gln Ile Leu Leu Gln Arg Gly Glu Asp Gly
20 25 30
Gly Asp Cys Arg Val Asp Ser Leu Leu Ser Tyr Ile Glu His His Gly
35 40 45
Asp Ala Trp Thr Glu Asp Ala Ile Tyr Glu Leu Gln Arg Met Val Asp
50 55 60
Glu Val Tyr Glu Lys Ala Leu Val Phe Gln Gln Asn Gly Gln Ser Ala
65 70 75 80
Ile Arg Gln Glu Glu Ser Gly Thr Glu Glu Arg Gln Gln Thr Ser Ile
85 90 95
Gly Gln Glu Glu Asn Gly Ile Glu Glu Arg Gln Gln Thr Ala Val Arg
100 105 110
Gln Glu Glu Ser Gly Thr Glu Glu Arg Gln Gln Thr Ala Ser Glu Gln
115 120 125
Glu Glu Glu Ser Glu Ala Glu Glu Arg Gln Gln Thr Tyr Val Ala Ala
130 135 140
Gly Arg
145
<210> 11
<211> 101
<212> PRT
<213> Geobacillus thermoglucosidans TNO-09.020
<400> 11
Met Ser Glu Gln Glu Leu Phe Gln Arg Tyr Val Lys Gln Val Ser Glu
1 5 10 15
Trp Gly Ala Gln Val Gly Gln Met Leu Pro Arg Arg Asp Asp Gly Thr
20 25 30
Val His His Asp Ile Ala Ala Leu Leu Ser Tyr Ile Asp Arg His Asp
35 40 45
Gly Glu Trp Thr Glu Thr Glu Ile Tyr Asp Leu Gln Arg Met Ala Asp
50 55 60
Ala Val Tyr Glu Lys Ala Ala Ala Val Ser Ala Asn Gly Thr Leu Ala
65 70 75 80
Asp Glu Ser Arg Glu Thr Ser Glu Glu Glu Ala Arg Arg Gln Thr Tyr
85 90 95
Ile Thr Ala Gly Arg
100
<210> 12
<211> 101
<212> PRT
<213> Geobacillus thermoglucosidasius C56-YS93
<400> 12
Met Ser Glu Gln Glu Leu Phe Gln Arg Tyr Val Lys Gln Val Ser Glu
1 5 10 15
Trp Gly Ala Gln Val Gly Gln Met Leu Pro Arg Arg Asp Asp Gly Thr
20 25 30
Val His His Asp Ile Ala Ala Leu Leu Ser Tyr Ile Asp Arg His Asp
35 40 45
Gly Glu Trp Thr Glu Thr Glu Ile Tyr Asp Leu Gln Arg Met Ala Asp
50 55 60
Ala Val Tyr Glu Lys Ala Ala Ala Val Ser Ala Asn Gly Thr Leu Ala
65 70 75 80
Asp Glu Ser Arg Glu Thr Ser Glu Glu Glu Ala Arg Arg Gln Thr Tyr
85 90 95
Ile Thr Ala Gly Arg
100
<210> 13
<211> 101
<212> PRT
<213> Geobacillus sp. Y4.1MC1
<400> 13
Met Ser Glu Gln Glu Leu Phe Gln Arg Tyr Val Lys Gln Val Ser Lys
1 5 10 15
Trp Gly Ala Gln Val Gly Gln Met Leu Pro Arg Arg Asp Asp Gly Thr
20 25 30
Val His Arg Asp Ile Ala Ala Leu Leu Ser Tyr Ile Asp Arg His Asp
35 40 45
Gly Glu Trp Thr Glu Thr Glu Ile Tyr Asp Leu Gln Arg Met Ala Asp
50 55 60
Ala Val Tyr Glu Lys Ala Ala Ala Val Ser Ala Asn Gly Thr Leu Ala
65 70 75 80
Asp Glu Ser Arg Glu Thr Ser Glu Glu Glu Ala Arg Arg Gln Thr Tyr
85 90 95
Ile Thr Ala Gly Arg
100
Claims (6)
1.一组可提高SOD耐热温度和热稳定性的氨基酸序列，其特征在于它是来源于Geobacillus属的13个特殊嗜热Fe/Mn-SOD的N端氨基酸序列，如SEQ ID NO:1-13所示。
2.权利要求1所述的一组可提高SOD耐热温度和热稳定性的氨基酸序列，其特征在于：
（1）这组N端氨基酸序列来源于Geobacillus属的13个菌株，其中，SEQ ID NO:1来源于Geobacillus thermodenitrificans NG80-2；SEQ ID NO:2来源于Geobacillus thermoleovorans CCB_US3_UF5；SEQ ID NO:3来源于Geobacillus sp. G11MC16； SEQ ID NO:4来源于Geobacillus sp. C56-T3；SEQ ID NO:5来源于Geobacillus sp. Y412MC52；SEQ ID NO:6来源于Geobacillus sp. GHH01；SEQ ID NO:7来源于Geobacillus sp. Y412MC61；SEQ ID NO:8来源于Geobacillus kaustophilus HTA426；SEQ ID NO:9来源于Geobacillus sp. POT5；SEQ ID NO:10来源于Geobacillus sp. WCH70；SEQ ID NO:11来源于Geobacillus thermoglucosidansTNO-09.020；SEQ ID NO:12来源于Geobacillus thermoglucosidasius C56-YS93；SEQ ID NO:13来源于Geobacillus sp. Y4.1MC1；
（2）这组N端氨基酸序列位于Fe/Mn-SOD蛋白的sodA功能域之前，序列长度分别为244个氨基酸（SEQ ID NO: 1）、344个氨基酸（SEQ ID NO:2）、244个氨基酸（SEQ ID NO:3）、235个氨基酸（SEQ ID NO:4-7）、209个氨基酸（SEQ ID NO:8-9）、146个氨基酸（SEQ ID NO:10）、101个氨基酸（SEQ ID NO:11-13）；
（3）这组N端氨基酸序列相互之间具有85-100%的同源性；
（4）这组N端氨基酸序列都包含特殊的共有重复序列Geo-N-repeat（图2），其中SEQ ID NO:1-9的9个N端序列都含有2个重复序列，SEQ ID NO:10-13的4个N端序列都含有1个重复序列。
3.权利要求1所述的一组可提高SOD耐热温度和热稳定性的氨基酸序列，其中所述N端多肽序列具有与SEQ ID NO:1-13所示的氨基酸序列至少70%的同源性；SEQ ID NO: 1-13所示的氨基酸序列中缺失、替换或插入一个或多个氨基酸后的氨基酸序列，并且具有该序列的蛋白质有对Geobacillus属的Fe/Mn-SOD的耐热温度和热稳定性具有决定性作用。
4.根据权利要求1至3中任一项所述的一组可提高SOD耐热温度和热稳定性的氨基酸序列，其特征在于，这组N端氨基酸序列可广泛应用于其它SOD，特别是常温SOD的耐热温度和热稳定性改造；通过一定方法，将这段N端氨基酸序列添加到其它SOD的N端或sodA功能域的N端。
5.根据权利要求1至3中任一项所述的一组可提高SOD耐热温度和热稳定性的氨基酸序列，其特征在于将编码N端氨基酸序列的核苷酸与编码其它SOD或sodA功能域的核苷酸连接后经过克隆表达重组SOD，可显著提高SOD的耐热温度和热稳定性。
6.权利要求1所述的SEQ ID NO:1-13氨基酸序列在提高SOD的耐热温度、热稳定性方面的应用。
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104911155A (zh) * | 2015-07-03 | 2015-09-16 | 南开大学 | 采用基因工程改造的耐热抗逆sod及其编码基因和应用 |
| CN104946606A (zh) * | 2015-07-03 | 2015-09-30 | 南开大学 | 一种基因工程改造的耐热抗逆sod及其编码基因与应用 |
| CN104946606B (zh) * | 2015-07-03 | 2018-11-02 | 南开大学 | 一种基因工程改造的耐热抗逆sod及其编码基因与应用 |
| CN104911155B (zh) * | 2015-07-03 | 2018-11-02 | 南开大学 | 采用基因工程改造的耐热抗逆sod及其编码基因和应用 |
| CN106916833A (zh) * | 2017-03-09 | 2017-07-04 | 曲阜师范大学 | 一种锰超氧化物歧化酶基因Mn‑SOD及其应用 |
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| CN110195044A (zh) * | 2019-06-26 | 2019-09-03 | 南开大学 | 一组可提高sod活性和稳定性的氨基酸序列及其应用 |
| CN110195044B (zh) * | 2019-06-26 | 2024-04-30 | 南开大学 | 一组可提高sod活性和稳定性的氨基酸序列及其应用 |
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