• 特约评述 •
程峰1,2, 邹树平1,2, 徐建妙1,2, 汤恒1,2, 薛亚平1,2, 郑裕国1,2
出版日期:
2024-07-02
通讯作者:
薛亚平
作者简介:
Feng Cheng1,2, Shu-Ping Zou1,2, Jian-Miao Xu1,2, Heng Tang1,2, Ya-Ping Xue1,2, Yu-Guo Zheng1,2
Online:
2024-07-02
Contact:
Ya-Ping Xue
摘要:
草铵膦是全球三大除草剂之一,具有广谱、活性高、非选择性等特点,市场前景被广泛看好。然而,草铵膦具有两种对映异构体(D型和L型),其除草活性主要来自于其中的L型对映体(L-草铵膦)。因此,高光学纯L-草铵膦高效合成至关重要。笔者研究团队在中国“生物农药之父”沈寅初院士的指导下,开展生物合成L-草铵膦的科学研究和产业化实践长达20余年,涵盖合成路线重构、生物无机胺化技术建立、生物催化剂创制、产物分离纯化、反应装备、过程智能化控制等方面,开发了“生物高纯精草生产技术(BioHiPP TM)”,建成了万吨级L-草铵膦数字智能化生产线,利用智能传感器和执行器,实现超千个控制点的实时数据采集、传输、分析和反馈调节,全自动化参数采集与控制生产效率提高50%,劳动强度降低70%以上,实现了万吨级L-草铵膦的生物智能制造。本文在研究团队长期积累的基础上,总结和分析了D,L-草铵膦主流生产工艺路线,详述了创新生物制造技术、合成生物技术构筑L-草铵膦关键合成体系的原理和方法,从底物合成与选择、生物催化剂类型、氨基供体使用、分离纯化等方面比较了这些路线的各自特点及实现产业化的关键要点。可以预见,在合成生物技术的助力下,未来将有越来越多的高光学纯度手性农药通过生物制造实现大规模生产。
程峰, 邹树平, 徐建妙, 汤恒, 薛亚平, 郑裕国. 生物高纯精草:高光学纯L-草铵膦生物制造的创新与发展[J]. 合成生物学, DOI: 10.12211/2096-8280.2024-032.
Feng Cheng, Shu-Ping Zou, Jian-Miao Xu, Heng Tang, Ya-Ping Xue, Yu-Guo Zheng. BioHiPP TM: A Benchmark of Biomanufacturing for High Optically PureL-Phosphinothricin[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2024-032.
图1 三条草铵膦产业化生产路线。(A)热裂解-ACA工艺(简称“气相合成”);(B)格氏-Strecker工艺(简称“格氏合成”);(C)铝法-Strecker工艺(简称“铝法合成”)
Fig.1 Three industrial production routes of D,L-PPT. (A) Thermal cracking-ACA process (referred to as "Gas phase synthesis"); (B) Grignard-strecker process (referred to as "Grignard synthesis"); (C) Aluminum-strecker process (referred to as "Aluminum synthesis")
工艺 条目 | 热裂解-ACA工艺 (“气相合成”) | 铝法-Strecker工艺 (“铝法合成”) | 格氏-Strecker工艺 (“格氏合成”) |
---|---|---|---|
连续化程度 | 完全连续化 | 半连续化 | 间歇化 |
工艺特点 | 连续化程度高 对反应器装置要求高 | 工艺简单, 易燃易爆,使用剧毒氰化物,分离纯化困难 | 工艺简单, 易燃易爆,使用剧毒氰化物,分离纯化困难 |
三废排放 | 固废量少,可用来制备高附加值产品 | 固废量大 | 废水量大 |
生产成本 | 5-6万元/吨 | 6-7万元/吨 | 7-8万元/吨 |
表1 D,L-草铵膦三种生产工艺比较*
Table 1 Comparison of three production processes for D,L-PPT
工艺 条目 | 热裂解-ACA工艺 (“气相合成”) | 铝法-Strecker工艺 (“铝法合成”) | 格氏-Strecker工艺 (“格氏合成”) |
---|---|---|---|
连续化程度 | 完全连续化 | 半连续化 | 间歇化 |
工艺特点 | 连续化程度高 对反应器装置要求高 | 工艺简单, 易燃易爆,使用剧毒氰化物,分离纯化困难 | 工艺简单, 易燃易爆,使用剧毒氰化物,分离纯化困难 |
三废排放 | 固废量少,可用来制备高附加值产品 | 固废量大 | 废水量大 |
生产成本 | 5-6万元/吨 | 6-7万元/吨 | 7-8万元/吨 |
图2 混旋体衍生化-拆分路线示意图。(A)乙酰化外消旋草铵膦,再以乙酰-PPT为底物,动力学拆分合成得到L-草铵膦;(B)苯乙酰化外消旋草铵膦,再以苯乙酰-PPT为底物,动力学拆分合成得到L-草铵膦
Fig.2 Schematic diagram of racemate derivatization-resolution route. (A) Acetylation of racemic PPT, followed by dynamic splitting synthesis using acetyl-PPT as substrate to obtain L-PPT; (B) Benzoylation of racemic PPT, followed by dynamic splitting synthesis using benzoyl-PPT as substrate to obtain L-PPT
通用化合物氰基化再水解路线 | 外消旋D,L-草铵膦为底物的 混旋体合成-去消旋化路线 | 从常用化学品合成L-草铵膦路线 | 从头合成高丝氨酸再化学合成路线 | ||||
---|---|---|---|---|---|---|---|
生物拆分 | 生物有机胺胺化 | 生物无机氨胺化 | 生物无机胺胺化 | 生物有机胺胺化 | |||
生物 催化剂 | 腈水解酶等 | 酰化酶、酰胺酶等 | 氧化酶/多个转氨酶 | D-氧化酶/ L-脱氢酶等 | 脱氢酶等 | 转氨酶 | 生物发酵 |
供体 | 无 | 无 | 3-4倍当量有机胺 | 无机氨 | 无机氨 | 2-4倍当量有机胺 | 无机膦/有机膦 |
底物 | 氨基腈 | 草铵膦衍生物 | D,L-草铵膦 | D,L-草铵膦 | 潜手性酮 | D,L-草铵膦 | 葡糖糖 |
转化率/ 产物e.e.值 | 86%/ >99% | <50%/ >99% | 90-99%/ >99% | 100%/ >99% | <100%/ >99% | 90-99%/ >99% | e.e.>99% |
分离 纯化 | 容易 | 容易 | 困难 | 容易 | 容易 | 困难 | 容易 |
(原粉、水剂) | (原粉、水剂) | (水剂) | (原粉、水剂) | (原粉、水剂) | (水剂) | (原粉、水剂) |
表2 L-草铵膦四大技术路线比较
Table 2 Comparison of four technical routes for L-PPT
通用化合物氰基化再水解路线 | 外消旋D,L-草铵膦为底物的 混旋体合成-去消旋化路线 | 从常用化学品合成L-草铵膦路线 | 从头合成高丝氨酸再化学合成路线 | ||||
---|---|---|---|---|---|---|---|
生物拆分 | 生物有机胺胺化 | 生物无机氨胺化 | 生物无机胺胺化 | 生物有机胺胺化 | |||
生物 催化剂 | 腈水解酶等 | 酰化酶、酰胺酶等 | 氧化酶/多个转氨酶 | D-氧化酶/ L-脱氢酶等 | 脱氢酶等 | 转氨酶 | 生物发酵 |
供体 | 无 | 无 | 3-4倍当量有机胺 | 无机氨 | 无机氨 | 2-4倍当量有机胺 | 无机膦/有机膦 |
底物 | 氨基腈 | 草铵膦衍生物 | D,L-草铵膦 | D,L-草铵膦 | 潜手性酮 | D,L-草铵膦 | 葡糖糖 |
转化率/ 产物e.e.值 | 86%/ >99% | <50%/ >99% | 90-99%/ >99% | 100%/ >99% | <100%/ >99% | 90-99%/ >99% | e.e.>99% |
分离 纯化 | 容易 | 容易 | 困难 | 容易 | 容易 | 困难 | 容易 |
(原粉、水剂) | (原粉、水剂) | (水剂) | (原粉、水剂) | (原粉、水剂) | (水剂) | (原粉、水剂) |
酶类 | 国际酶学 编号 | 辅酶再生 底物 | 辅酶再 生产物 | 优点 | 缺点 |
---|---|---|---|---|---|
FDH | EC 1.2.1.2 | 甲酸(铵) | CO2和水 | 副产物CO2无毒具挥发性易于分离 | 催化效率低,底物亲和力差,具NAD+特异性 |
GDH | EC 1.1.1.47 | 葡萄糖 | 葡萄糖酸 | 催化活力高,辅底物价格低廉 | 副产物易溶于水难以分离,反应pH降低需要调控 |
ADH | EC 1.1.1.1-2 | 异丙醇 | 丙酮 | 催化活力较高,副产物沸点低易除去 | 反应可逆,副产物可能会影响酶活 |
表3 辅酶再生酶的分类及特点
Table 3 Classification and characteristics of coenzyme regeneration enzymes
酶类 | 国际酶学 编号 | 辅酶再生 底物 | 辅酶再 生产物 | 优点 | 缺点 |
---|---|---|---|---|---|
FDH | EC 1.2.1.2 | 甲酸(铵) | CO2和水 | 副产物CO2无毒具挥发性易于分离 | 催化效率低,底物亲和力差,具NAD+特异性 |
GDH | EC 1.1.1.47 | 葡萄糖 | 葡萄糖酸 | 催化活力高,辅底物价格低廉 | 副产物易溶于水难以分离,反应pH降低需要调控 |
ADH | EC 1.1.1.1-2 | 异丙醇 | 丙酮 | 催化活力较高,副产物沸点低易除去 | 反应可逆,副产物可能会影响酶活 |
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