合成生物学 ›› 2024, Vol. 5 ›› Issue (3): 527-547.DOI: 10.12211/2096-8280.2023-085
刘晓楠1,2(), 李静1,2,3, 祝晓熙1,2, 徐子硕1,2,4,5, 齐健1,2, 江会锋1,2
收稿日期:
2023-11-17
修回日期:
2024-04-12
出版日期:
2024-06-30
发布日期:
2024-07-12
通讯作者:
刘晓楠,江会锋
作者简介:
基金资助:
Xiaonan LIU1,2(), Jing LI1,2,3, Xiaoxi ZHU1,2, Zishuo XU1,2,4,5, Jian QI1,2, Huifeng JIANG1,2
Received:
2023-11-17
Revised:
2024-04-12
Online:
2024-06-30
Published:
2024-07-12
Contact:
Xiaonan LIU, Huifeng JIANG
摘要:
紫杉醇是目前已发现的最具抗癌活性的天然广谱抗癌药物之一,其生产方式主要依赖于从珍稀植物红豆杉中进行分离提取以及化学半合成,因其含量稀少,生产能力受到严重的限制。随着红豆杉基因组的全解析和合成生物学的迅速发展,通过合成生物技术,构建重组工程细胞合成紫杉醇及其关键前体成为解决当前供需不平衡和资源有限的有效方法。本文针对紫杉醇生物合成途径解析、红豆杉组学分析、底盘细胞构建、关键前体合成、紫杉醇合成途径关键酶的改造及催化机理解析等相关研究进展开展系统性的综述,尤其对近期发表的关于氧杂环丁烷环形成的相关突破性研究进行了详细介绍,并基于相关进展探讨当前紫杉醇合成生物学研究面临的关键酶催化效率低下、产物杂泛性严重、具体反应顺序未知等技术挑战及生物合成紫杉醇关键中间体的未来前景。助力加强对紫杉醇合成通路和催化过程的理解,进一步实现紫杉醇的绿色、高效生物合成。
中图分类号:
刘晓楠, 李静, 祝晓熙, 徐子硕, 齐健, 江会锋. 紫杉醇生物合成机制研究进展[J]. 合成生物学, 2024, 5(3): 527-547.
Xiaonan LIU, Jing LI, Xiaoxi ZHU, Zishuo XU, Jian QI, Huifeng JIANG. Research advances on paclitaxel biosynthesis[J]. Synthetic Biology Journal, 2024, 5(3): 527-547.
图2 紫杉醇生物合成途径解析[模块1代表巴卡亭Ⅲ生物合成途径推测1(蓝色)和巴卡亭Ⅲ生物合成途径推测2(黄色)。模块2(绿色)表示β-苯丙烯醇侧链生物合成途径。模块3(紫色)代表紫杉醇生物合成途径。TS—紫杉二烯合成酶;T5αOH—紫杉二烯-5α-羟化酶;TAT—紫杉二烯-5α-醇-O-乙酰基转移酶;T10βOH—紫杉烷-10β-羟化酶;T13αOH—紫杉烷-13α-羟化酶;T2αOH—紫杉烷-2α-羟化酶;T9αOH—紫杉烷-9α-羟化酶;T7βOH—紫杉烷-7β-羟化酶;T1βOH—紫杉烷-1β-羟化酶;TBT—紫杉烷-2α-O-苯甲酰转移酶;DBAT—10-去乙酰巴卡亭Ⅲ10-O-乙酰转移酶;TOT—紫杉烷环氧化酶;BAPT—巴卡亭Ⅲ-3-氨基,13-苯丙酰转移酶;T2′αOH—紫杉烷-2′α-羟化酶;DBTNBT—3′-N-去苯甲酰-2′-脱氧紫杉醇-N-苯酰转移酶;PAM—苯丙氨酸氨基变位酶;PCL—β-苯丙氨酸辅酶A连接酶]
Fig. 2 Recently discovered pathways for paclitaxel biosynthesis[Module 1 representing speculated baccatin Ⅲ biosynthetic pathway 1 (bule) and speculated baccatin Ⅲ biosynthetic pathway 2 (yellow). Module 2 (green) representing the β-phenylalanoyl side chain pathway. Module 3 (purple) representing paclitaxel biosynthetic pathway. TS—taxadiene synthase; T5αOH—taxane 5α-hydroxylase; TAT—taxadiene-5α-ol-O-acetyl transferase; T10βOH—taxane 10β-hydroxylase; T13αOH—taxane 13α- hydroxylase; T2αOH—taxane 2α-hydroxylase; T9αOH—taxane 9α-hydroxylase; T7βOH—taxane 7β-hydroxylase; T1βOH—taxane 1β-hydroxylase; TBT—taxane 2α-O-benzoyltransferase; DBAT—10-deacetyl baccatin Ⅲ-10-O-acetyltransferase; TOT—taxane oxetanase; BAPT—baccatin Ⅲ-3-amino, 13-phenylpropanoyltransferase; T2′αOH—taxane 2′α-hydroxylase; DBTNBT—3′-N-debenzoyl-2′-deoxytaxol-N-benzoyltransferase; PAM—phenylalanine aminomutase; PCL—β-phenylalanine coenzyme A ligase.]
酶名称 | 简写 | 登录号 | 参考文献 | |
---|---|---|---|---|
1 | Geranylgeranyl diphosphate synthase | GGPPS | AF081514 | [ |
2 | Taxadiene synthase | TS | AY364469 | [ |
3 | Taxadiene-5α-hydroxylase | T5αOH | AY289209 | [ |
4 | Taxadiene-13α-hydroxylase | T13αOH | AY056019 | [ |
5 | Taxadiene-5α-ol-O-acetyl transferase | TAT | AF190130 | [ |
6 | Taxadiene-10β-hydroxylase | T10βOH | AF318211/AY563635 | [ |
7 | Taxadiene-7β-hydroxylase | T7βOH | AY307951 | [ |
8 | Taxadiene-2α-hydroxylase | T2αOH | AY518383 | [ |
9 | Taxane-2α-O-benzoyl transferase | TBT | AF297618 | [ |
10 | 10-deacetylbaccatin Ⅲ-10-O-acetyl transferase | DBAT | AF193765 | [ |
11 | Phenylalanine aminomutase | PAM | AY582743 | [ |
12 | β-phenylalanoyl-CoA ligase | PCL | KM593667 | [ |
13 | Baccatin Ⅲ: 3-amino, 13-phenylpropanoyltransferase | BAPT | AY082804 | [ |
14 | Taxane-2′α-hydroxylase | T2′αOH | KP178208 | [ |
15 | N-benzoyl transferase | DBTNBT | AF466397 | [ |
16 | Taxadiene-14β-hydroxylase | T14βOH | AY188177 | [ |
17 | Cytochrome P450 reductase | TcCPR | AY571340 | [ |
18 | C4β-C20 epoxidase | [ | ||
19 | Taxane 1β-hydroxylase | T1βOH | [ | |
20 | Taxane 9α-hydroxylase | T9αOH | [ | |
21 | Taxane 9α-dioxygenase | [ | ||
22 | Phenylalanine-CoA ligase | PCL | [ | |
23 | Taxane oxetanase | TOT | [ | |
24 | Taxane 9α-hydroxylase | T9αH1 | [ | |
25 | Taxane 9α-hydroxylase | CYP725A37 | PP197199/PP197200 | [ |
26 | Taxane oxetanase | CYP725A55 | PP197201 | [ |
27 | Acyltransferase | AT5 | PP197202 | [ |
表1 已知的紫杉醇生物合成酶及参考文献
Table 1 Identified paclitaxel biosynthetic enzymes
酶名称 | 简写 | 登录号 | 参考文献 | |
---|---|---|---|---|
1 | Geranylgeranyl diphosphate synthase | GGPPS | AF081514 | [ |
2 | Taxadiene synthase | TS | AY364469 | [ |
3 | Taxadiene-5α-hydroxylase | T5αOH | AY289209 | [ |
4 | Taxadiene-13α-hydroxylase | T13αOH | AY056019 | [ |
5 | Taxadiene-5α-ol-O-acetyl transferase | TAT | AF190130 | [ |
6 | Taxadiene-10β-hydroxylase | T10βOH | AF318211/AY563635 | [ |
7 | Taxadiene-7β-hydroxylase | T7βOH | AY307951 | [ |
8 | Taxadiene-2α-hydroxylase | T2αOH | AY518383 | [ |
9 | Taxane-2α-O-benzoyl transferase | TBT | AF297618 | [ |
10 | 10-deacetylbaccatin Ⅲ-10-O-acetyl transferase | DBAT | AF193765 | [ |
11 | Phenylalanine aminomutase | PAM | AY582743 | [ |
12 | β-phenylalanoyl-CoA ligase | PCL | KM593667 | [ |
13 | Baccatin Ⅲ: 3-amino, 13-phenylpropanoyltransferase | BAPT | AY082804 | [ |
14 | Taxane-2′α-hydroxylase | T2′αOH | KP178208 | [ |
15 | N-benzoyl transferase | DBTNBT | AF466397 | [ |
16 | Taxadiene-14β-hydroxylase | T14βOH | AY188177 | [ |
17 | Cytochrome P450 reductase | TcCPR | AY571340 | [ |
18 | C4β-C20 epoxidase | [ | ||
19 | Taxane 1β-hydroxylase | T1βOH | [ | |
20 | Taxane 9α-hydroxylase | T9αOH | [ | |
21 | Taxane 9α-dioxygenase | [ | ||
22 | Phenylalanine-CoA ligase | PCL | [ | |
23 | Taxane oxetanase | TOT | [ | |
24 | Taxane 9α-hydroxylase | T9αH1 | [ | |
25 | Taxane 9α-hydroxylase | CYP725A37 | PP197199/PP197200 | [ |
26 | Taxane oxetanase | CYP725A55 | PP197201 | [ |
27 | Acyltransferase | AT5 | PP197202 | [ |
合成体系 | 产物 | 产量 | 研究方法 | 发表 时间 | 参考文献 |
---|---|---|---|---|---|
大肠杆菌 | 紫杉二烯 | 1.3 mg/L | 过表达IDI、GGPPS、TS、DXP | 2001 | [ |
大肠杆菌 | 紫杉二烯 | 1 g/L | 多变量模块化代谢工程,过表达TS和T5αOH | 2010 | [ |
大肠杆菌 | 紫杉二烯-5α-醇 | (58±3) mg/L | |||
大肠杆菌 | 紫杉二烯 | 4.5 mg/g DW | JM109(DE3)菌株,22 °C | 2012 | [ |
链格孢菌TPF6 | 紫杉二烯 | (61.9±6.3) μg/L | alcA启动子,过表达IDI、tHMGR | 2017 | [ |
大肠杆菌 | 氧化紫杉烷 | 27 mg/L | TbrTS,Taxus CPR,T5αOH-GSTGS-CPR,引入异源MVA途径 | 2022 | [ |
大肠杆菌 | 紫杉二烯-5α-醇 | 7 mg/L | |||
大肠杆菌 | 紫杉二烯 | 93.5 mg/L | 融合表达GGPP和TS | 2022 | [ |
大肠杆菌 | 氧化紫杉烷 | (570±45) mg/L | P450酶N端修饰 | 2016 | [ |
枯草芽孢杆菌 | 紫杉二烯 | 17.8 mg/L | 过表达MEP途径,GGPPS和TS | 2019 | [ |
酿酒酵母 | 紫杉二烯 | 8.7 mg/L | 共表达tHMGR、突变调节蛋白UPC2-1、GGPPS和TS | 2008 | [ |
酿酒酵母 | 紫杉二烯 | 72.8 mg/L | YSG50菌株,GGPPSbc | 2014 | [ |
酿酒酵母 | 氧化紫杉烷 | 33 mg/L | 大肠杆菌和酿酒酵母共培养 | 2015 | [ |
酿酒酵母 | 紫杉二烯 | 129 mg/L | 增加MBP标签的多拷贝TS,20 ℃ | 2020 | [ |
酿酒酵母 | 紫杉二烯-5α-醇 | 20 mg/L | 对发酵工艺的改进,pH优化 | 2021 | [ |
酿酒酵母 | 紫杉二烯-5α-yl-乙酸酯 | 3.7 mg/L | |||
酿酒酵母 | 氧化紫杉烷 | 78 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-醇 | 42 mg/L | 2×YP, 统计学确定性筛选设计 | 2022 | [ |
酿酒酵母 | 紫杉二烯-5α-yl-乙酸酯 | 22 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-醇 | (38.1±8.4) mg/L | 启动子pHXT7,融合表达T5OH和CPR,中性pH条件下静息细胞测定 | 2022 | [ |
酿酒酵母 | 氧化紫杉烷 | (361.4±52.4) mg/L | |||
解脂耶氏酵母 | 紫杉二烯 | 101.4 mg/L | 融合表达SUMO与TS,过表达tHMG1、GGS1和TS | 2023 | [ |
酿酒酵母 | 紫杉二烯 | 215 mg/L | 计算代谢工程 | 2023 | [ |
酿酒酵母 | 紫杉二烯-5α-醇 | 43.65 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-乙酸酯 | 26.2 mg/L | |||
酿酒酵母 | 1β-dehydroxybaccatin Ⅵ | 细胞共共表达已鉴定的12个基因并饲喂紫杉二烯-5α-醇 | 2024 | [ | |
拟南芥 | 紫杉二烯 | 600 ng/g DW | 糖皮质激素诱导表达TS | 2004 | [ |
本氏烟草 | 紫杉二烯 | 50 μg/g DW | 表达TS,MeJA诱导,沉默PSY和PDS | 2014 | [ |
本氏烟草 | 紫杉二烯 | (56.6±3.2) µg/g fresh weight | 区室化策略, DXS和GGPPS共表达 | 2019 | [ |
本氏烟草 | 紫杉二烯-5α-醇 | (1.3±0.5) µg/g fresh weight | |||
红花烟草 | 紫杉二烯 | 87.8 μg/g DW | TS的N端融合叶绿体转运肽 | 2021 | [ |
本氏烟草 | 巴卡亭Ⅲ | 154.87 ng/g fresh weight | 瞬时表达C4β-C20环氧化酶基因、T9αOH、T1βOH和T9OX与其他9个已知基因 | 2023 | [ |
紫杉醇 | 64.29 ng/g fresh weight | 瞬时表达PCL与BAPT、PAM、DBTNBT、T2′OH | |||
本氏烟草 | 紫杉二烯-5α-醇 | 弱组成型启动子NOS弱化T5αOH的表达 | |||
5α,10β-二乙酰氧基- 紫杉二烯-13α-醇 | 42 µg/g DW | (NOS)T10βOH、DBAT和(NOS)T13αOH | 2024 | [ | |
本氏烟草 | 巴卡亭Ⅲ | 瞬时表达TOT和T9αOH-1与其他7个已知合成基因 | 2024 | [ |
表2 紫杉醇生产的异源表达体系
Table 2 Heterologous expression systems for paclitaxel production
合成体系 | 产物 | 产量 | 研究方法 | 发表 时间 | 参考文献 |
---|---|---|---|---|---|
大肠杆菌 | 紫杉二烯 | 1.3 mg/L | 过表达IDI、GGPPS、TS、DXP | 2001 | [ |
大肠杆菌 | 紫杉二烯 | 1 g/L | 多变量模块化代谢工程,过表达TS和T5αOH | 2010 | [ |
大肠杆菌 | 紫杉二烯-5α-醇 | (58±3) mg/L | |||
大肠杆菌 | 紫杉二烯 | 4.5 mg/g DW | JM109(DE3)菌株,22 °C | 2012 | [ |
链格孢菌TPF6 | 紫杉二烯 | (61.9±6.3) μg/L | alcA启动子,过表达IDI、tHMGR | 2017 | [ |
大肠杆菌 | 氧化紫杉烷 | 27 mg/L | TbrTS,Taxus CPR,T5αOH-GSTGS-CPR,引入异源MVA途径 | 2022 | [ |
大肠杆菌 | 紫杉二烯-5α-醇 | 7 mg/L | |||
大肠杆菌 | 紫杉二烯 | 93.5 mg/L | 融合表达GGPP和TS | 2022 | [ |
大肠杆菌 | 氧化紫杉烷 | (570±45) mg/L | P450酶N端修饰 | 2016 | [ |
枯草芽孢杆菌 | 紫杉二烯 | 17.8 mg/L | 过表达MEP途径,GGPPS和TS | 2019 | [ |
酿酒酵母 | 紫杉二烯 | 8.7 mg/L | 共表达tHMGR、突变调节蛋白UPC2-1、GGPPS和TS | 2008 | [ |
酿酒酵母 | 紫杉二烯 | 72.8 mg/L | YSG50菌株,GGPPSbc | 2014 | [ |
酿酒酵母 | 氧化紫杉烷 | 33 mg/L | 大肠杆菌和酿酒酵母共培养 | 2015 | [ |
酿酒酵母 | 紫杉二烯 | 129 mg/L | 增加MBP标签的多拷贝TS,20 ℃ | 2020 | [ |
酿酒酵母 | 紫杉二烯-5α-醇 | 20 mg/L | 对发酵工艺的改进,pH优化 | 2021 | [ |
酿酒酵母 | 紫杉二烯-5α-yl-乙酸酯 | 3.7 mg/L | |||
酿酒酵母 | 氧化紫杉烷 | 78 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-醇 | 42 mg/L | 2×YP, 统计学确定性筛选设计 | 2022 | [ |
酿酒酵母 | 紫杉二烯-5α-yl-乙酸酯 | 22 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-醇 | (38.1±8.4) mg/L | 启动子pHXT7,融合表达T5OH和CPR,中性pH条件下静息细胞测定 | 2022 | [ |
酿酒酵母 | 氧化紫杉烷 | (361.4±52.4) mg/L | |||
解脂耶氏酵母 | 紫杉二烯 | 101.4 mg/L | 融合表达SUMO与TS,过表达tHMG1、GGS1和TS | 2023 | [ |
酿酒酵母 | 紫杉二烯 | 215 mg/L | 计算代谢工程 | 2023 | [ |
酿酒酵母 | 紫杉二烯-5α-醇 | 43.65 mg/L | |||
酿酒酵母 | 紫杉二烯-5α-乙酸酯 | 26.2 mg/L | |||
酿酒酵母 | 1β-dehydroxybaccatin Ⅵ | 细胞共共表达已鉴定的12个基因并饲喂紫杉二烯-5α-醇 | 2024 | [ | |
拟南芥 | 紫杉二烯 | 600 ng/g DW | 糖皮质激素诱导表达TS | 2004 | [ |
本氏烟草 | 紫杉二烯 | 50 μg/g DW | 表达TS,MeJA诱导,沉默PSY和PDS | 2014 | [ |
本氏烟草 | 紫杉二烯 | (56.6±3.2) µg/g fresh weight | 区室化策略, DXS和GGPPS共表达 | 2019 | [ |
本氏烟草 | 紫杉二烯-5α-醇 | (1.3±0.5) µg/g fresh weight | |||
红花烟草 | 紫杉二烯 | 87.8 μg/g DW | TS的N端融合叶绿体转运肽 | 2021 | [ |
本氏烟草 | 巴卡亭Ⅲ | 154.87 ng/g fresh weight | 瞬时表达C4β-C20环氧化酶基因、T9αOH、T1βOH和T9OX与其他9个已知基因 | 2023 | [ |
紫杉醇 | 64.29 ng/g fresh weight | 瞬时表达PCL与BAPT、PAM、DBTNBT、T2′OH | |||
本氏烟草 | 紫杉二烯-5α-醇 | 弱组成型启动子NOS弱化T5αOH的表达 | |||
5α,10β-二乙酰氧基- 紫杉二烯-13α-醇 | 42 µg/g DW | (NOS)T10βOH、DBAT和(NOS)T13αOH | 2024 | [ | |
本氏烟草 | 巴卡亭Ⅲ | 瞬时表达TOT和T9αOH-1与其他7个已知合成基因 | 2024 | [ |
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