Synthetic Biology Journal ›› 2020, Vol. 1 ›› Issue (6): 656-673.DOI: 10.12211/2096-8208.2020-050
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YUAN Yaomeng1, XING Xinhui1,2, ZHANG Chong1
Received:
2020-04-16
Revised:
2020-09-26
Online:
2021-01-15
Published:
2020-12-31
Contact:
ZHANG Chong
袁姚梦1, 邢新会1,2, 张翀1
通讯作者:
张翀
作者简介:
袁姚梦(1997—),女,博士研究生。主要研究方向为合成生物学、代谢工程。E-mail:2631825401@qq.com基金资助:
CLC Number:
YUAN Yaomeng, XING Xinhui, ZHANG Chong. Progress and prospective of engineering microbial cell factories: from random mutagenesis to customized design in genome scale[J]. Synthetic Biology Journal, 2020, 1(6): 656-673.
袁姚梦, 邢新会, 张翀. 微生物细胞工厂的设计构建:从诱变育种到全基因组定制化创制[J]. 合成生物学, 2020, 1(6): 656-673.
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分类 | 诱变技术/诱变剂 | 描述 | 参考文献 |
---|---|---|---|
物理诱变 | 电离辐射(X射线、γ射线等) | 引起DNA双链或单链断裂,实现DNA的删除或结构改变 | [ |
非电离辐射(紫外线) | 使嘧啶形成二聚体,实现GC的删除、移码突变以及GC→AT的转换 | [ | |
化学诱变 | 烷化剂(烷基磺酸盐、芥子气等) | 使DNA碱基发生烷化,导致DNA复制时发生配对错误 | [ |
碱基类似物 (嘧啶类似物、嘌呤类似物) | 与DNA碱基结构类似,在DNA复制时掺入并引发配对错误 | [ | |
移码诱变剂(原黄素、吖啶橙等) | 与DNA结合导致碱基增添或缺失 | [ | |
脱氨剂(亚硝酸) | 引起A、C、G碱基的脱氨,实现GC与AT的相互转换;引起DNA交联作用,引发突变 | [ | |
羟化剂(羟胺) | 引起胞嘧啶脱氨,实现GC→AT的转换 | [ | |
生物诱变 | 噬菌体、质粒和DNA转座子 | 通过碱基取代和DNA链断裂实现碱基的删除、重复和插入 | [ |
原生质体融合 | 将两个亲株的原生质体进行融合,形成杂合二倍体,使两个亲株发生基因组重组 | [ | |
DNA改组 | 对多个同源序列组成的文库进行随机片段化,再利用PCR使其发生随机的重组,实现多亲本的基因重组 | [ | |
基因组重排 | 先利用传统诱变手段获得多个表型改进的菌株,然后模拟DNA改组的反应条件,对原生质体进行多次递推式融合,实现正向突变的富集 | [ | |
复合诱变 | 结合多种诱变方式提高诱变效率 | [ | |
新型诱变技术 | 离子注入诱变 | 离子注入细胞导致DNA损伤,细胞修复损伤的过程中出现突变 | [ |
等离子体诱变 | 等离子体作用于细胞造成DNA损伤,细胞修复损伤的过程中出现突变 | [ |
Tab. 1 Summary of mutagenesis technologies
分类 | 诱变技术/诱变剂 | 描述 | 参考文献 |
---|---|---|---|
物理诱变 | 电离辐射(X射线、γ射线等) | 引起DNA双链或单链断裂,实现DNA的删除或结构改变 | [ |
非电离辐射(紫外线) | 使嘧啶形成二聚体,实现GC的删除、移码突变以及GC→AT的转换 | [ | |
化学诱变 | 烷化剂(烷基磺酸盐、芥子气等) | 使DNA碱基发生烷化,导致DNA复制时发生配对错误 | [ |
碱基类似物 (嘧啶类似物、嘌呤类似物) | 与DNA碱基结构类似,在DNA复制时掺入并引发配对错误 | [ | |
移码诱变剂(原黄素、吖啶橙等) | 与DNA结合导致碱基增添或缺失 | [ | |
脱氨剂(亚硝酸) | 引起A、C、G碱基的脱氨,实现GC与AT的相互转换;引起DNA交联作用,引发突变 | [ | |
羟化剂(羟胺) | 引起胞嘧啶脱氨,实现GC→AT的转换 | [ | |
生物诱变 | 噬菌体、质粒和DNA转座子 | 通过碱基取代和DNA链断裂实现碱基的删除、重复和插入 | [ |
原生质体融合 | 将两个亲株的原生质体进行融合,形成杂合二倍体,使两个亲株发生基因组重组 | [ | |
DNA改组 | 对多个同源序列组成的文库进行随机片段化,再利用PCR使其发生随机的重组,实现多亲本的基因重组 | [ | |
基因组重排 | 先利用传统诱变手段获得多个表型改进的菌株,然后模拟DNA改组的反应条件,对原生质体进行多次递推式融合,实现正向突变的富集 | [ | |
复合诱变 | 结合多种诱变方式提高诱变效率 | [ | |
新型诱变技术 | 离子注入诱变 | 离子注入细胞导致DNA损伤,细胞修复损伤的过程中出现突变 | [ |
等离子体诱变 | 等离子体作用于细胞造成DNA损伤,细胞修复损伤的过程中出现突变 | [ |
类别 | 分析方法 | 描述 | 参考文献 |
---|---|---|---|
动力学分析 | ODE&米氏方程 | 利用常微分方程(ODE)和米氏方程,能够描述胞内代谢物浓度随时间的变化趋势,从而建立代谢网络的动力学模型 | [ |
代谢控制分析(MCA) | MCA可用于估算动力学模型中各个通量的控制系数,从而确定代谢途径中需要过表达的目标基因,增加通过途径的通量 | [ | |
代谢网络分析 | 代谢通量分析(MFA) | MFA根据胞内代谢物的质量平衡确定线性方程组并求解,能够计算特定培养条件下细胞内的实际代谢通量分布。MFA需要依赖大量实验数据来增加可测量通量的数量,从而计算出不可测量通量向量 | [ |
通量平衡分析(FBA) | FBA可用于确定细胞代谢网络中每个反应的最佳通量,该方法基于凸分析,通过对系统施加最大化(最小化)的目标函数来确定代谢通量矢量 | [ | |
代谢途径分析(MPA) | MPA可用于识别代谢网络中存在的所有代谢通量向量,该方法仅以化学计量学和反应热力学为约束条件,不需要动力学参数进行计算(例如基元模式分析) | [ | |
整合了热力学的代谢网络分析 | 网络嵌入的热力学分析(NET) | 以热力学第二定律为依据,可用于检测代谢组学数据和假定的通量方向是否符合热力学一致性 | [ |
基于热力学的代谢通量分析(TMFA) | TMFA同时使用热力学方向性约束和质量守恒约束计算代谢通量分布 | [ | |
计算机应变优化算法 | 基于约束的重构与分析(COBRA) | COBRA采用基因组规模的计算机模拟,可用于代谢途径预测和优化,从而改善生产速率和产量 | [ |
最小化代谢调节(MOMA) | MOMA用于使野生型菌株和缺失突变体之间代谢通量分布的差别最小化,能够预测基因操作对代谢网络的影响 | [ | |
开/关最小化调节(ROOM) | 与MOMA的优化目标相同 | [ | |
OptKnock | 以产品产率为优化目标的基因敲除分析工具 | [ | |
生化网络集成计算浏览器(BNICE) | 使用广义酶反应规则发现新代谢途径的计算工具 | [ |
Tab. 2 Analytical methods for metabolic network design
类别 | 分析方法 | 描述 | 参考文献 |
---|---|---|---|
动力学分析 | ODE&米氏方程 | 利用常微分方程(ODE)和米氏方程,能够描述胞内代谢物浓度随时间的变化趋势,从而建立代谢网络的动力学模型 | [ |
代谢控制分析(MCA) | MCA可用于估算动力学模型中各个通量的控制系数,从而确定代谢途径中需要过表达的目标基因,增加通过途径的通量 | [ | |
代谢网络分析 | 代谢通量分析(MFA) | MFA根据胞内代谢物的质量平衡确定线性方程组并求解,能够计算特定培养条件下细胞内的实际代谢通量分布。MFA需要依赖大量实验数据来增加可测量通量的数量,从而计算出不可测量通量向量 | [ |
通量平衡分析(FBA) | FBA可用于确定细胞代谢网络中每个反应的最佳通量,该方法基于凸分析,通过对系统施加最大化(最小化)的目标函数来确定代谢通量矢量 | [ | |
代谢途径分析(MPA) | MPA可用于识别代谢网络中存在的所有代谢通量向量,该方法仅以化学计量学和反应热力学为约束条件,不需要动力学参数进行计算(例如基元模式分析) | [ | |
整合了热力学的代谢网络分析 | 网络嵌入的热力学分析(NET) | 以热力学第二定律为依据,可用于检测代谢组学数据和假定的通量方向是否符合热力学一致性 | [ |
基于热力学的代谢通量分析(TMFA) | TMFA同时使用热力学方向性约束和质量守恒约束计算代谢通量分布 | [ | |
计算机应变优化算法 | 基于约束的重构与分析(COBRA) | COBRA采用基因组规模的计算机模拟,可用于代谢途径预测和优化,从而改善生产速率和产量 | [ |
最小化代谢调节(MOMA) | MOMA用于使野生型菌株和缺失突变体之间代谢通量分布的差别最小化,能够预测基因操作对代谢网络的影响 | [ | |
开/关最小化调节(ROOM) | 与MOMA的优化目标相同 | [ | |
OptKnock | 以产品产率为优化目标的基因敲除分析工具 | [ | |
生化网络集成计算浏览器(BNICE) | 使用广义酶反应规则发现新代谢途径的计算工具 | [ |
模型范围 | 模型名称 | 菌株 | 反应/代谢物 | 参考文献 |
---|---|---|---|---|
核心代谢模型 | 未报道 | 大肠杆菌 | 95/94 | [ |
未报道 | 谷氨酸棒杆菌 | 未报道 | [ | |
未报道 | 酿酒酵母 | 70/83 | [ | |
未报道 | 酿酒酵母 | 78/98 | [ | |
未报道 | 酿酒酵母 | 37/27 | [ | |
全基因组代谢模型(GSMM) | iFF708 | 酿酒酵母 | 1145/825 +708基因 | [ |
iND750 | 酿酒酵母 | 1149/646 +750基因 | [ | |
Yeast 4.0 | 酿酒酵母 | 1865/1319 +932基因 | [ | |
iJO1366 | 大肠杆菌 | 2583/1805 +1366基因 | [ | |
未报道 | 谷氨酸棒杆菌 | 495/408 +411基因 | [ | |
未报道 | 乳酸菌 | 621/509 +358基因 | [ | |
未报道 | 枯草芽孢杆菌 | 754/637 +614基因 | [ | |
全基因组代谢模型 +基因表达水平 | T. maritima | 海栖热袍菌 | 17535/18209 | [ |
iOL1650-ME | 大肠杆菌 | 76414/56902 | [ | |
全基因组代谢模型 +蛋白质结构特性 | T. maritima | 海栖热袍菌 | 645/503 +478酶结构 | [ |
E. coli GEM-PRO | 大肠杆菌 | 2583/1805 +1268酶结构 | [ | |
全基因组代谢模型 +转录调控 | iAF1260 PROM | 大肠杆菌 | 2583/1805 +1773转录调控作用 | [ |
iMH805/837 | 酿酒酵母 | 1489/972 +805基因+837转录调控作用 | [ | |
全细胞模型 | ‘Whole-cell’ M. genitalium | 生殖支原体 | 28个细胞过程子模块 +525基因 | [ |
Tab. 3 Summary of microbial metabolism models
模型范围 | 模型名称 | 菌株 | 反应/代谢物 | 参考文献 |
---|---|---|---|---|
核心代谢模型 | 未报道 | 大肠杆菌 | 95/94 | [ |
未报道 | 谷氨酸棒杆菌 | 未报道 | [ | |
未报道 | 酿酒酵母 | 70/83 | [ | |
未报道 | 酿酒酵母 | 78/98 | [ | |
未报道 | 酿酒酵母 | 37/27 | [ | |
全基因组代谢模型(GSMM) | iFF708 | 酿酒酵母 | 1145/825 +708基因 | [ |
iND750 | 酿酒酵母 | 1149/646 +750基因 | [ | |
Yeast 4.0 | 酿酒酵母 | 1865/1319 +932基因 | [ | |
iJO1366 | 大肠杆菌 | 2583/1805 +1366基因 | [ | |
未报道 | 谷氨酸棒杆菌 | 495/408 +411基因 | [ | |
未报道 | 乳酸菌 | 621/509 +358基因 | [ | |
未报道 | 枯草芽孢杆菌 | 754/637 +614基因 | [ | |
全基因组代谢模型 +基因表达水平 | T. maritima | 海栖热袍菌 | 17535/18209 | [ |
iOL1650-ME | 大肠杆菌 | 76414/56902 | [ | |
全基因组代谢模型 +蛋白质结构特性 | T. maritima | 海栖热袍菌 | 645/503 +478酶结构 | [ |
E. coli GEM-PRO | 大肠杆菌 | 2583/1805 +1268酶结构 | [ | |
全基因组代谢模型 +转录调控 | iAF1260 PROM | 大肠杆菌 | 2583/1805 +1773转录调控作用 | [ |
iMH805/837 | 酿酒酵母 | 1489/972 +805基因+837转录调控作用 | [ | |
全细胞模型 | ‘Whole-cell’ M. genitalium | 生殖支原体 | 28个细胞过程子模块 +525基因 | [ |
产物 | 宿主 | 原料 | 公司 | 参考文献 |
---|---|---|---|---|
琥珀酸 | 大肠杆菌 | 玉米糖 | BioAmber | [ |
大肠杆菌 克鲁斯假丝酵母 | 蔗糖 | Myriant(现名GC Innovation America) | ||
酿酒酵母 | 淀粉、糖类 | Reverdia | ||
巴斯夫产琥珀酸菌 | 甘油、糖类 | Succinity | ||
1,4-丁二醇 | 大肠杆菌 | 糖类 | Genomatica和DuPont Tate & Lyle | [ |
1,3-丙二醇 | 大肠杆菌 | 糖类 | DuPont Tate & Lyle | [ |
聚羟基链烷酸酯(PHA) | 大肠杆菌 | 糖类 | Metabolix(现名 Yeild10 science) | [ |
3-羟基丙酸 | 大肠杆菌 | 未报道 | OPXbio & Dow Chemical | [ |
未报道 | 未报道 | Perstorp | ||
乙醇 | 酿酒酵母 运动发酵单胞菌 马克斯克鲁维酵母 | 蔗糖、玉米糖、木质纤维素 | [ | |
异丁醇 | 酿酒酵母 | 糖类 | Gevo Butalco Butamax | [ |
法尼烯 | 酿酒酵母 | 未报道 | Amyris | [ |
青蒿素(半合成) | 酿酒酵母 | 未报道 | Amyris | [ |
Tab. 4 Commercial application of classic design strategies guided by metabolic engineering
产物 | 宿主 | 原料 | 公司 | 参考文献 |
---|---|---|---|---|
琥珀酸 | 大肠杆菌 | 玉米糖 | BioAmber | [ |
大肠杆菌 克鲁斯假丝酵母 | 蔗糖 | Myriant(现名GC Innovation America) | ||
酿酒酵母 | 淀粉、糖类 | Reverdia | ||
巴斯夫产琥珀酸菌 | 甘油、糖类 | Succinity | ||
1,4-丁二醇 | 大肠杆菌 | 糖类 | Genomatica和DuPont Tate & Lyle | [ |
1,3-丙二醇 | 大肠杆菌 | 糖类 | DuPont Tate & Lyle | [ |
聚羟基链烷酸酯(PHA) | 大肠杆菌 | 糖类 | Metabolix(现名 Yeild10 science) | [ |
3-羟基丙酸 | 大肠杆菌 | 未报道 | OPXbio & Dow Chemical | [ |
未报道 | 未报道 | Perstorp | ||
乙醇 | 酿酒酵母 运动发酵单胞菌 马克斯克鲁维酵母 | 蔗糖、玉米糖、木质纤维素 | [ | |
异丁醇 | 酿酒酵母 | 糖类 | Gevo Butalco Butamax | [ |
法尼烯 | 酿酒酵母 | 未报道 | Amyris | [ |
青蒿素(半合成) | 酿酒酵母 | 未报道 | Amyris | [ |
分类 | 名称 | 描述 | 参考 文献 |
---|---|---|---|
不可追踪技术 | MAGE | 基于重组的基因组编辑技术,可使用多个ssDNA同时对多个目标位点进行修饰。与其他基因编辑工具(如CRISPR/Cas9)联用可进一步提高基因编辑效率。主要用于原核基因组编辑 | [ |
YOGE | 原理与MAGE类似,主要用于真核基因组编辑 | [ | |
可追踪技术 | TRMR | 基于同源重组的基因组编辑技术,能够同时对基因组上千个基因位点进行修饰 | [ |
CREATE | 该技术基于同源重组和CRISPR/Cas9基因编辑技术,能够在全基因组范围内实现可追踪编辑 | [ | |
Prime Editor | 使用融合了工程逆转录酶的催化活性受损的Cas9和pegRNA,以更高的效率、更低的脱靶率在全基因组范围内实现所有12种单碱基的自由转换以及多碱基的精准插入和删除 | [ | |
Target AID | 激活诱导的胞嘧啶脱氨酶(AID)可实现C到T的突变,Target AID技术以核酸酶活性缺失的CRISPR/Cas9系统作为AID的DNA靶向模块,实现定点诱变 | [ | |
TAM | 该系统将AID-P182X与dCas9蛋白融合,可将G或C突变为另外三个碱基,从而在目标位点处产生大量突变 | [ | |
CRISPR-X | 使用dCas9募集更高活性的AIDΔ和MS2修饰的sgRNA变体,能以较低的脱靶率同时实现多个靶基因的特异性突变 | [ | |
EVOLVR | 该系统由一个CRISPR引导的切口酶和一个易错DNA聚合酶组成,可在靶位点处可调窗口长度内实现所有核苷酸的突变 | [ | |
CRISPRi | 使用dCas9蛋白及其sgRNA阻断靶基因转录,实现基因表达水平的下调 | [ | |
CRISPRa | 使用与转录激活因子融合的dCas9蛋白实现靶基因表达水平的上调 | [ |
Tab. 5 High-throughput genotype construction technologies
分类 | 名称 | 描述 | 参考 文献 |
---|---|---|---|
不可追踪技术 | MAGE | 基于重组的基因组编辑技术,可使用多个ssDNA同时对多个目标位点进行修饰。与其他基因编辑工具(如CRISPR/Cas9)联用可进一步提高基因编辑效率。主要用于原核基因组编辑 | [ |
YOGE | 原理与MAGE类似,主要用于真核基因组编辑 | [ | |
可追踪技术 | TRMR | 基于同源重组的基因组编辑技术,能够同时对基因组上千个基因位点进行修饰 | [ |
CREATE | 该技术基于同源重组和CRISPR/Cas9基因编辑技术,能够在全基因组范围内实现可追踪编辑 | [ | |
Prime Editor | 使用融合了工程逆转录酶的催化活性受损的Cas9和pegRNA,以更高的效率、更低的脱靶率在全基因组范围内实现所有12种单碱基的自由转换以及多碱基的精准插入和删除 | [ | |
Target AID | 激活诱导的胞嘧啶脱氨酶(AID)可实现C到T的突变,Target AID技术以核酸酶活性缺失的CRISPR/Cas9系统作为AID的DNA靶向模块,实现定点诱变 | [ | |
TAM | 该系统将AID-P182X与dCas9蛋白融合,可将G或C突变为另外三个碱基,从而在目标位点处产生大量突变 | [ | |
CRISPR-X | 使用dCas9募集更高活性的AIDΔ和MS2修饰的sgRNA变体,能以较低的脱靶率同时实现多个靶基因的特异性突变 | [ | |
EVOLVR | 该系统由一个CRISPR引导的切口酶和一个易错DNA聚合酶组成,可在靶位点处可调窗口长度内实现所有核苷酸的突变 | [ | |
CRISPRi | 使用dCas9蛋白及其sgRNA阻断靶基因转录,实现基因表达水平的下调 | [ | |
CRISPRa | 使用与转录激活因子融合的dCas9蛋白实现靶基因表达水平的上调 | [ |
技术 | 通量 | 功能 | 案例 | 参考文献 |
---|---|---|---|---|
FACS | 约105细胞/s | 分选 | 利用色氨酸传感器,实现紫色杆菌素高产大肠杆菌筛选 | [ |
利用甲羟戊酸细胞传感器,实现甲羟戊酸高产甲基杆菌筛选 | [ | |||
利用赖氨酸传感器,实现赖氨酸高产谷氨酸棒杆菌筛选 | [ | |||
FADS | 约104液滴/s | 培养+分选 | 将胞外重组酶活性与液滴荧光强度耦合,实现酶活测定及胞外重组酶高产菌株筛选 | [ |
将传感器菌与MCF菌株共培养,实现对香豆酸高产酵母的筛选 | [ | |||
将β-半乳糖苷酶产量与液滴荧光强度耦合,实现β-半乳糖苷酶高产大肠杆菌筛选 | [ | |||
Droplet-FACS | 培养+分选 | 通过检测核黄素的荧光,实现核黄素高产解脂耶氏酵母筛选 | [ | |
Gel FACS | 约3000液滴/s | 培养+分选 | 将胞外木聚糖酶的产量与凝胶液滴的荧光强度耦合,实现胞外木聚糖酶高产毕赤酵母筛选 | [ |
RADS | 260细胞/min | 培养+分选 | 利用虾青素的拉曼光谱,实现虾青素高产雨生红球藻的筛选 | [ |
Tab. 6 High-throughput selection/screening technologies in single-cell level
技术 | 通量 | 功能 | 案例 | 参考文献 |
---|---|---|---|---|
FACS | 约105细胞/s | 分选 | 利用色氨酸传感器,实现紫色杆菌素高产大肠杆菌筛选 | [ |
利用甲羟戊酸细胞传感器,实现甲羟戊酸高产甲基杆菌筛选 | [ | |||
利用赖氨酸传感器,实现赖氨酸高产谷氨酸棒杆菌筛选 | [ | |||
FADS | 约104液滴/s | 培养+分选 | 将胞外重组酶活性与液滴荧光强度耦合,实现酶活测定及胞外重组酶高产菌株筛选 | [ |
将传感器菌与MCF菌株共培养,实现对香豆酸高产酵母的筛选 | [ | |||
将β-半乳糖苷酶产量与液滴荧光强度耦合,实现β-半乳糖苷酶高产大肠杆菌筛选 | [ | |||
Droplet-FACS | 培养+分选 | 通过检测核黄素的荧光,实现核黄素高产解脂耶氏酵母筛选 | [ | |
Gel FACS | 约3000液滴/s | 培养+分选 | 将胞外木聚糖酶的产量与凝胶液滴的荧光强度耦合,实现胞外木聚糖酶高产毕赤酵母筛选 | [ |
RADS | 260细胞/min | 培养+分选 | 利用虾青素的拉曼光谱,实现虾青素高产雨生红球藻的筛选 | [ |
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