芳香族氨基酸及其衍生物的细胞工厂构建策略

doi:10.12211/2096-8280.2021-002

合成生物学 ›› 2021, Vol. 2 ›› Issue (6): 982-999.DOI: 10.12211/2096-8280.2021-002

芳香族氨基酸及其衍生物的细胞工厂构建策略

孙薇¹^,², 丁冬芹², 柏丹阳², 朱亚如², 解晓彤²^,³, 张大伟²

^1.天津科技大学生物工程学院，天津 300457
^2.中国科学院天津工业生物技术研究所，天津 300308
^3.大连工业大学生物工程学院，辽宁大连 116000

收稿日期:2021-01-05 修回日期:2021-04-16 出版日期:2021-12-31 发布日期:2021-04-21
通讯作者: 张大伟
作者简介:孙薇（1998—），女，硕士研究生。研究方向为氨基酸代谢。E-mail：sunw@tib.cas.cn
张大伟（1978—），男，博士，研究员。主要研究方向为采用分子遗传、合成生物技术、生物传感技术等，合成维生素、氨基酸及高附加值化合物；建立蛋白表达平台，实现蛋白质胞内表达或分泌表达，并开发新型表达系统。E-mail：zhang_dw@tib.cas.cn
基金资助:
国家重点研发计划(2018YFA0903700);天津市杰出青年科学基金(17JCJQJC45300);天津市合成生物技术创新能力提升行动项目(TSBICIP-CXRC-029)

Strategies of cell factory construction for the production of aromatic amino acids and their derivatives

Wei SUN¹^,², Dongqin DING², Danyang BAI², Yaru ZHU², Xiaotong XIE²^,³, Dawei ZHANG²

^1.Tianjin Institute of Industrial Biotechnology，Chinese Academy of Sciences，Tianjin 300308，China
^2.College of Bioengineering，Tianjin University of Science and Technology，Tianjin 300308，China
^3.College of Bioengineering，Dalian University of Technology，Dalian 116000，Liaoning，China

Received:2021-01-05 Revised:2021-04-16 Online:2021-12-31 Published:2021-04-21
Contact: Dawei ZHANG

摘要/Abstract

摘要：

芳香族氨基酸及其衍生物由于其特定的生理活性，已广泛应用于医药、食品、饲料和化工等行业。利用重组微生物发酵生产芳香族氨基酸及其衍生物是满足全球日益增长需求的有效途径。通过将代谢工程策略与合成生物学、系统生物学和生物工程的发展相结合，在菌株的改造及优化方面取得了显著的进展。然而，合成芳香族氨基酸及其衍生物的代谢途径长且调控机制复杂，通过简单的代谢途径改造难以大幅提高产量，因此，近年来出现了很多相关的改造方法，为克服代谢途径中的限速问题提供了很好的借鉴意义。本文回顾和比较了最近在芳香族氨基酸及其衍生物合成方面应用的成熟技术和策略，包括常用的代谢途径改造策略（如增加前体供给、解除关键酶和阻遏蛋白的反馈抑制和阻遏抑制、改造转运系统、全局调节系统）以及菌株生长与生产产品耦联和菌株构建方法（如基于生物传感器的高通量筛选以及对培养基和培养条件的优化等），未来相关前沿技术如计算机辅助途径酶改造技术和筛选高产菌株的定向进化技术将助力芳香族氨基酸及其衍生物高产菌株的构建。

关键词: 芳香族氨基酸, 前体, 反馈抑制, 菌株构建, 芳香族氨基酸衍生物

Abstract:

Aromatic amino acids (including L-tryptophan, L-phenylalanine and L-tyrosine) and their derivatives have been widely used in medicine, food, feed and chemical industry due to their specific physiological properties. The production of aromatic amino acids and their derivatives by recombinant microbial fermentation is an effective way to meet the increasing global demand. By combining metabolic engineering strategy with the developments of synthetic biology, systems biology and bioengineering, remarkable progress has been made in the strains modifications and improvements. However, the metabolic pathways for the synthesis of aromatic amino acids and their derivatives are long and their regulatory mechanisms are complicated, so it is very difficult to significantly improve the yield through simple metabolic pathway-modification. Therefore, many relevant modification methods have emerged in recent years, providing a good reference for overcoming the rate limit problem in the metabolic pathways. In this paper, we review and compare the recent mature technologies and strategies applied in the synthesis of aromatic amino acids and their derivatives, including the commonly used metabolic pathway modification strategies, such as increasing the supply of precursors, removing the feedback inhibition for key enzymes, eliminating the repression of repressor proteins, regulating the transport system and global metabolic network, the coupling of strain's growth and product's production and introducing exogenous related enzymes and so on. Various methods of strain construction are also included, such as the high-throughput screening based on biosensors and optimization of culture medium and culture conditions and so on. Finally, we also discuss the prospect of relevant cutting-edge technologies such as computer design of protein, computer de novo design of enzyme, computer design of metabolic pathway, alphafold algorithm for accurate prediction of protein structure and bifunctional enzyme, and the directed evolution technology for screening high yield strains such as the batch and continuation of the directed evolution.

Key words: aromatic amino acids, precursors, feedback inhibition, strain construction, aromatic amino acid derivatives

中图分类号:

孙薇, 丁冬芹, 柏丹阳, 朱亚如, 解晓彤, 张大伟. 芳香族氨基酸及其衍生物的细胞工厂构建策略[J]. 合成生物学, 2021, 2(6): 982-999.

Wei SUN, Dongqin DING, Danyang BAI, Yaru ZHU, Xiaotong XIE, Dawei ZHANG. Strategies of cell factory construction for the production of aromatic amino acids and their derivatives[J]. Synthetic Biology Journal, 2021, 2(6): 982-999.

图/表 9

图1 芳香族氨基酸的合成途径PTS—磷酸转移酶系统；G6P—葡萄糖-6-磷酸；3PG—3-磷酸甘油酸；PYR—丙酮酸；ACoA—乙酰辅酶A；Cit—柠檬酸；Oxa—草酰琥珀酸；AKG—α-酮戊二酸；OAA—草酰乙酸；6PGNL—6-磷酸葡萄糖内脂；ANT—邻氨基苯甲酸；Indole—吲哚；PRE—预苯酸；PPN—苯丙酮酸；HPP—4-羟基苯丙酮酸；ptsGHIccr—编码磷酸转移酶基因；ppc—编码PEP羧化酶基因；pckA—编码PEP羧激酶基因；tktA—编码转酮酶基因；aroG/F/H—编码DAHP合酶基因；trpE/D—编码ANT合酶基因，tyrA/pheA—编码CHA变位酶基因

Fig. 1 Synthesis of aromatic amino acidsPTS—phosphotransferase system; G6P—glucose-6-phosphate; 3PG—3-phosphoglyceric acid; PYR—pyruvic acid; ACoA—acetyl coenzyme A; Cit—citrate; Oxa—oxalylsuccinic acid; AKG—α-ketoglutarate; OAA—oxaloacetic acid; 6PGNL—glucose 6-phosphate endolipid; ANT—o-aminobenzoic acid; PRE—prephenic acid; PPN—phenylpyruvic acid; HPP—4-hydroxyphenylpyruvic acidGene: ptsGHccr—ecoding phosphotransferase; ppc—encoding PEP carboxylase; pckA—encoding PEP carboxykinase; tktA—encoding transketolase; aroG/F/H—encoding DAHP synthase; trpE/D—encoding ANTA synthase; tyrA/pheA—encoding CHA mutase

表1 芳香族氨基酸生产方法的比较

Tab. 1 Comparison of production methods of aromatic amino acids

生产方法	原理	优点	缺点	参考文献
天然蛋白质水解法	利用盐酸使蛋白质发生水解	最初的提取方法	方法原始、产率极低、产物易被破坏	[7]
化学合成法	添加化学试剂，改变碳链结构	快速、高效	工艺复杂、成本高、副产物多	[8]
酶法	利用微生物中的芳香族氨基酸合成酶系	产物转化率高、副产物少、操作简便	筛选强活力酶困难、反应平衡难操控	[9]
微生物转化法	以糖类为碳源，同时添加芳香族氨基酸的前体	耗能少、纯化简便	前体价格昂贵、改造周期较长	[10]
微生物发酵法	以葡萄糖为碳源，利用微生物发酵生产芳香族氨基酸	成本低、环保、工艺流程易控制	获得工业化高产菌株较难	[11]

表2 芳香族氨基酸合成的影响因素

Tab. 2 Factors affecting synthesis of aromatic amino acids

影响因素	详情
前体的供给	PEP，涉及其生成和消耗的系统和酶有：PEP合酶、PEP羧激酶^[14]、磷酸转移酶系统（PTS）^[15]、PEP羧化酶^[16]、丙酮酸羧激酶^[17] E4P，涉及其生成的酶有转酮酶、转醛酶^[18-19]
关键酶的反馈抑制	DAHP合酶、ANT合酶^[20]、分支酸变位酶/预苯酸脱水酶（CM-PDT)^[21]
调控因子TyrR和TrpR对合成途径的转录调节	TyrR调控蛋白调节8个非连续操纵子的表达^[22] TrpR调控蛋白调节基因aroH、mtr和色氨酸操纵子^[23]
转运系统	分泌系统：转运基因tnaB、mtr、aroP负责芳香族氨基酸的运输^[24-25] 膜蛋白YddG^[26]：参与芳香族氨基酸由胞内向胞外的转运
其他因素	L-Trp分支途径：色氨酸酶（tnaA）^[27]、磷酸甘油酸脱氢酶（serA）^[28] L-Tyr分支途径：SHIK脱氢酶（aroB)、SHIK激酶（aroK）^[29] L-Phe分支途径：全局调节系统——Csr^[30]

图2 PEP和E4P合成途径的改造（“绿色箭头”表示过表达，“红色叉号”表示敲除）F6P—果糖-6-磷酸；FBP—果糖1，6-二磷酸；G3P—甘油醛-3-磷酸；1，3-2PG—1，3-二磷酸甘油酸；3PG—3-磷酸甘油酸；2PG—2-磷酸甘油酸；Isocit—异柠檬酸；AKG—α-酮戊二酸；6PG—6-磷酸葡萄糖酸；RU5P—核酮糖-5-磷酸；X5P—木酮糖-5-磷酸；R5P—核酮糖-5-磷酸；S7P—景天庚酮糖-7-磷酸；G3P—甘油醛-3-磷酸；acnBA—编码乌头酸酶基因；icd—编码异柠檬酸脱氢酶基因；zwf—编码葡萄糖-6-磷酸脱氢酶基因

Fig. 2 Modification of synthesis route of PEP and E4P(''Green arrow'' indicates overexpression, ''red cross'' indicates knockout) F6P—fructose-6-phosphate; FBP—fructose 1,6-diphosphate; G3P—glyceraldehyde-3-phosphate; 1,3-2PG—1,3-diphosphoglyceride; 3PG—3-phosphoglyceric acid; 2PG—2-phosphoglyceric acid; Isocit—Isocitric acid; AKG—α-ketoglutarate; 6PG—6-phosphogluconic acid; RU5P—ketose-5-phosphate; X5P—xylulose-5-phosphate; R5P—ketose-5-phosphate; S7P—sedum heptanulose-7-phosphate; G3P—glyceraldehyde-3-phosphateGene: acnBA—encoding aconitase; icd—encoding isocitrate dehydrogenase; zwf—encoding glucose-6-phosphate dehydrogenase

表3 芳香族氨基酸合成途径中抗反馈抑制的关键酶

Tab. 3 Key enzymes in aromatic amino acid synthesis against feedback inhibition

菌种	关键酶	编码基因	终端产物反馈抑制	定点突变	参考文献
大肠杆菌	DAHP合酶	aroF（占比19%)	L-Tyr	Pro148Leu	[14, 16]
				Gln152Ile	[16, 46]
				Asn8Lys（N末端)	[14, 16]
		aroG（占比80%)	L-Phe	Leu76Val	[16]
				Pro150Leu	[16, 47]
				Asp146Asn	[16, 47]
		aroH（占比1%)	L-Trp		[16]
	ANT合酶	trpE	L-Trp	Ser40Phe	[48-49]
	ANT合酶	trpE	L-Trp	Met1293Thr	[49-50]
	CM-PDT	pheA	L-Phe	Glu39Lys	[51]
		pheA	L-Phe	Gly309Cys	[52]
		tyrA	L-Tyr	缺失305～386位基因	[51, 53]
				Ala354Val, Met53Ile	[51, 53]
				Gla534Val, Phe357Leu, Tyr263His	[54]

图3 关键酶的反馈抑制和调控蛋白的阻遏作用（“虚线”表示反馈抑制，“红色实线箭头”表示阻遏作用）

Fig. 3 Feedback inhibition of key enzymes and repression of regulatory proteins("Dotted line" indicates feedback inhibition, "red solid line arrow" indicates inhibition)

表4 芳香族氨基酸及其衍生物生产概况

Tab. 4 General profile of production of aromatic amino acids and their derivatives

芳香族氨基酸及其衍生物	宿主细胞/ 生产菌株	改造策略	发酵方式	产量 /(g/L)	参考文献
L-Phe	E.coli W3110 突变菌株	pheA^Thr326Pro、aroF、galp、glk、aroD、tyrR^T495I、ΔptsH	分批补料	72.9	[61]
S/R-扁桃酸	E.coli	引入A. orientalis的HamS、ΔtyrA和共表达S. coelicolor的hmo、Rhodotorula graminis的dmd	摇瓶发酵	0.74/0.68	[62]
苯乳酸	E.coli (L-Phe 高产菌株)	ldhA、来自Wickerhamia fluorescens的pprA	分批发酵	29	[63]
肉桂酸/醛	E.coli	pal/pal、ccl、ccr	摇瓶发酵	0.287/0.075	[64]
肉桂醇	S.cerevisiae	pal2、acar、entD、Adh6	摇瓶发酵	0.0278	[65]
苯乙烯	E.coli	pal2、fdc1	摇瓶发酵	0.26	[66]
L-Trp	E.coli W3110	多次随机诱变	分批补料	54.5	[55]
生长素	E.coli	aspC、ipdC、iad1	催化转化	3	[67]
紫色杆菌素	C.glutamicum	vioA、vioB、vioC、vioD、vioE	分批补料	5.436	[68]
脱氧紫色杆菌素	E.coli	vioA、vioB、vioC、vioE	摇瓶发酵	0.3241	[69]
血清素	E.coli	T-5H、共表达来自Catharanthus roseus的TDC	催化转化	24	[70]
靛红、靛蓝	E.coli	tnaA、引入来自Methylophaga aminisulfidivorans的fmo	催化转化	5/0.92	[71]
L-Tyr	E.coli MG1655衍生菌株	tyrA、ΔpheA、ΔpheL	分批补料	55	[50]
丹参素	E.coli	d-ldh^Y52A、hpaBC	分批补料	7.1	[72]
对羟基肉桂酸	Yeast	TAL、用SET3p、CDC24p和ALD5p替换PFK1、PFK2和PYK1天然启动子	分批补料	12.5	[18]
4-羟基苯乙烯	E.coli	pal、pdc	分批补料	0.4	[73]
L-多巴	E.coli	引入来自Zymomonas mobilis的tyrC、hpaBC	分批补料	1.51	[59]

表5 培养基中各组分的优化

Tab. 5 The components optimization in the medium

影响组分	作用	不同种类	参考文献
碳源	提供能量和碳链骨架	葡萄糖、果糖、蔗糖、乳糖、麦芽糖、淀粉	[89]
氮源	合成氨基酸、蛋白质和含氮代谢物	酵母粉、牛肉膏、蛋白胨、酵母膏、NH₄Cl、NH₄NO₃、(NH₄)₂SO₄、NH₄H₂PO₄	[90-91]
无机盐	调节pH，维持渗透压	MgSO₄、MgCl、CaCO₃、KCl、KH₂PO₄	[92]

图4 几种芳香族氨基酸衍生物的具体合成途径Pdh—苯丙氨酸脱氢酶；HamS—4-羟基扁桃酸合酶；LdhA—乳酸脱氢酶；TPH—色氨酸5-羟化酶；TDC—色氨酸脱羧酶；DDC—芳香族L-氨基酸脱羧酶；ASMT—乙酰羟色胺O-甲基转移酶；SNAT—芳烷基胺N-乙酰基转移酶；TnaA—色氨酸酶；Fmo—黄素单加氧酶；TAL—苯丙氨酸解氨酶；TYR—酪氨酸酶

Fig. 4 Full synthetic routes of several aromatic amino acid derivativesPdh—phenylalanine dehydrogenase; HamS—4-hydroxymandelate synthase; LdhA—lactate dehydrogenase; TPH—tryptophan 5-hydroxylase; TDC—tryptophan decarboxylase; DDC—aromatic L-amino acid decarboxylase; ASMT—acetyl hydroxytryptamine O-methyltransferase; SNAT—arylalkylamine N-acetyltransferase; TnaA—tryptophan enzyme; Fmo—flavin monooxygenase; TAL—phenylalanine ammonia lyase; TYR—tyrosinase

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芳香族氨基酸及其衍生物的细胞工厂构建策略

Strategies of cell factory construction for the production of aromatic amino acids and their derivatives

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