合成生物学 ›› 2021, Vol. 2 ›› Issue (6): 1000-1016.DOI: 10.12211/2096-8280.2021-010
陈久洲, 王钰, 蒲伟, 郑平, 孙际宾
收稿日期:
2021-01-24
修回日期:
2021-03-30
出版日期:
2021-12-31
发布日期:
2022-01-21
通讯作者:
郑平
作者简介:
基金资助:
Jiuzhou CHEN, Yu WANG, Wei PU, Ping ZHENG, Jibin SUN
Received:
2021-01-24
Revised:
2021-03-30
Online:
2021-12-31
Published:
2022-01-21
Contact:
Ping ZHENG
摘要:
5-氨基乙酰丙酸(5-ALA)是生物体内天然存在的一种功能性非蛋白质氨基酸,在医药保健和农牧领域具有重要的应用价值。尽管化学合成技术率先打通了5-ALA的制备路线,但工艺的复杂性和高成本问题,限制了其生产规模和应用推广。随着生物技术的兴起,生物合成作为一种绿色替代技术成为解决上述问题的突破口。本文回顾了近50年来5-ALA生物合成技术的发展历程,综述了5-ALA生物合成的3种主要策略,即天然菌株诱变筛选、利用重组外源C4途径的工程菌株催化合成以及基于代谢工程的高效细胞工厂构建,总结了每种策略的技术特点和主要问题,重点介绍了代谢工程改造策略和合成生物技术在5-ALA微生物细胞工厂开发中的应用和研究进展。在此基础上,本文进一步分析了限制5-ALA生物合成的瓶颈,阐述了血红素合成代谢的复杂调控作用和多底物的协同供给在5-ALA生物合成中的重要作用,并从新靶点、新底盘和新技术策略的角度,对合成生物学时代5-ALA生物合成技术未来的发展进行了展望。
中图分类号:
陈久洲, 王钰, 蒲伟, 郑平, 孙际宾. 5-氨基乙酰丙酸生物合成技术的发展及展望[J]. 合成生物学, 2021, 2(6): 1000-1016.
Jiuzhou CHEN, Yu WANG, Wei PU, Ping ZHENG, Jibin SUN. Advances and perspective on bioproduction of 5-aminolevulinic acid[J]. Synthetic Biology Journal, 2021, 2(6): 1000-1016.
图1 5-ALA及四吡咯化合物生物合成途径3-PG—3-phosphoglycerate; PEP—phosphoenolpyruvate; GSA—glutamate-1-semialdehyde; 5-ALA—5-aminolevulinic acid; PBG— porphobilinogen; HMB—hydroxymethylbilane; PPC—phosphoenolpyruvate carboxylase; SerA—3-phosphoglycerate dehydrogenase; SerC—phosphoserine aminotransferase; SerB—phosphoserine phosphatase; GlyA—serine hydroxymethyltransferase; GDH—glutamate dehydrogenase; GluTS—glutamyl-tRNA synthetase; GluTR—glutamyl-tRNA reductase; GSAM—glutamate-1-semialdehyde aminotransferase; ALAS—5-aminolevulinate synthase; ALAD—5-aminolevulinic acid dehydratase; HemC—porphobilinogen deaminase; HemD—uroporphyrinogen Ⅲ synthase; HemE—uroporphyrinogen decarboxylase; HemF— coproporphyrinogen Ⅲ oxidase; HemG—protoporphyrin oxidase; HemH—ferrochelatase
Fig. 1 Biosynthesis of 5-ALA and tetrapyrrole compounds
Strategies | Strains | Main substrates | Titer /(g/L) | References |
---|---|---|---|---|
C4 pathway | ||||
Overexpression of ALAS from R. sphaeroides and maeB, anaerobic conditions | E. coli | Glucose | 0.05 | [ |
Overexpression of ALAS from R. sphaeroides in the succinate production strain QZ1111 | E. coli | Glucose | 0.44 | [ |
Overexpression of ALAS from R. palustris ATCC 17001, deletion of sdhAB | E. coli | Glucose, glycine | 6.38 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc, deletion of pck | E. coli | Glucose, glycine | 4.84 | [ |
Overexpression of ALAS from R. palustris ATCC 17001 and native ppc, coaA, addition calcium pantothenate | E. coli | Glucose, glycine | 4.12 | [ |
Overexpression of ALAS from R. palustris ATCC 17001 and native ppc, deletion of sdhAB, weakening ALAD by site mutation | E. coli | Glucose, glycine | 7.17 | [ |
Overexpression of ALAS from Saccharomyces cerevisiae controlled via the auto-induced expression approach and the antibiotic-free stabilized plasmid, expressing synthesis pathways of PHB | E. coli | Glucose, succinic acid, glycine | 3.60 | [ |
Overexpression of ALAS from R. capsulatus, pathway optimization for CoA and precursor biosynthesis, downregulation of hemB by substituting the start codon ATG to GTG | E. coli | Glucose | 2.81 | [ |
Overexpression of ALAS from R. sphaeroides, agxT from Homo sapiens and aceA | E. coli | Glucose | 0.52 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc and eamA, deletion of aceA | E. coli | Glucose, glycine | 4.47 | [ |
Overexpression of ALAS from R. sphaeroides, aceA and agxT from Homo sapiens, downregulation of hemB by synthetic glycine-OFF riboswitches | E. coli | Glucose | 0.24 | [ |
Overexpression of ALAS from R. palustris ATCC 17001, reinforcing the antioxidant defense system by expression KatE and SodB | E. coli | Glucose, glycine | 11.5 | [ |
Dynamic upregulation of ALAS from R. sphaeroides and dynamic downregulation of hemB by quorum sensing-based dual-function switch | E. coli | Glucose, succinic acid, glycine | 2.50 | [ |
Overexpression of ALAS from R. sphaeroides DSM158, deletion of ldhA, sdhA and iclR, downregulation of hemB by CRISPRi, aerobic condition | E. coli | glycerol | 6.93 | [ |
Overexpression of ALAS from R. sphaeroides DSM158, deletion of ldhA and sdhA, downregulation of hemB by CRISPRi, microaerobic condition | E. coli | glycerol | 5.95 | |
Overexpression of ALAS from R. sphaeroides, native ppc and rhtA from E. coli, deletion of ldhA, pqo, cat, pta, ackA and pbp1b | C. glutamicum | Glucose, glycine | 7.53 | [ |
Overexpression of ALAS from R. capsulatus SB1003, deletion of sucCD | C. glutamicum | Glucose, glycine | 7.60 | [ |
Overexpression of ALAS from R. capsulatus SB1003 and rhtA from E. coli, deletion of sucCD, two-stage fermentation | C. glutamicum | Glucose, glycine | 14.70 | |
Overexpression of ALAS from R. sphaeroides, serA∆197, serB, serC and glyA | C. glutamicum | Glucose, glycine | 3.40 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc to balance 5-ALA biosynthetic and anaplerotic pathways | C. glutamicum | Glucose, glycine | 16.30 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc to balance 5-ALA biosynthetic and anaplerotic pathways | C. glutamicum | Cassava bagasse hydrolysate, glycine | 18.50 | |
C5 pathway | ||||
Overexpression of mutated GluTR from Salmonella arizona, GSAM and RhtA | E. coli | Glucose | 4.13 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, RhtA and RyhB | E. coli | Glucose | 1.78 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, HemD and HemF | E. coli | Glucose | 3.25 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, HemD and HemF, optimization of the in vitro iron concentration | E. coli | Glucose | 4.05 | [ |
Overexpression of mutated GluTR from Salmonella typhimurium, GSAM and AceA with different promoters, deletion of sucA | E. coli | Glucose | 3.40 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM and RhtA in multiplexed PHB operon chromosomally integrated strain | E. coli | Glucose | 3.60 | [ |
High gene copy expression of mutated GluTR from S. arizona and GSAM in the chromosome, deletion of recA | E. coli | Glucose | 4.55 | [ |
Overexpression of mutated GluTR and GBP from Arabidopsis thaliana in E. coli Transetta (DE3) | E. coli | Glucose, glutamate | 7.64 | [ |
Optimization of the C5 pathway with RBS engineering, downregulation of hemB by fliC promoter in the stationary phase, enhancement of the PLP biosynthesis, deletion of recA and endA improved the plasmid stability | E. coli | Glucose | 5.25 | [ |
Overexpression of mutated GluTR from S. arizona and GSAM from E. coli | C. glutamicum | Glucose | 1.79 | [ |
Overexpression of mutated GluTR from S. typhimurium and GSAM from E. coli | C. glutamicum | Glucose | 2.20 | [ |
Overexpression of mutated GluTR from S. typhimurium, GSAM and RhtA from E. coli, deletion ncgl1221, putP and lysE, downregulation of hemB by a relatively weak RBS replacement | C. glutamicum | Glucose | 0.90 | [ |
Overexpression of mutated GluTR from S. typhimurium, GSAM and RhtA from E. coli, OdhI (T14A/T15A), addition ethambutol | C. glutamicum | Glucose | 2.90 | [ |
Overexpression of mutated GluTR from S. arizona and GSAM from E. coli, PPC, GltA, PckA, GapA, Cgl0788 and Cgl0789, downregulation of odhA by growth-regulated promoter PCP_2836, dynamic upregulation of rhtA by the two-component system HrrSA | C. glutamicum | Glucose | 3.16 | [ |
表1 利用代谢工程改造的大肠杆菌和谷氨酸棒杆菌合成5-ALA
Tab. 1 Bioproduction of 5-ALA by metabolically engineered E. coli and C. glutamicum
Strategies | Strains | Main substrates | Titer /(g/L) | References |
---|---|---|---|---|
C4 pathway | ||||
Overexpression of ALAS from R. sphaeroides and maeB, anaerobic conditions | E. coli | Glucose | 0.05 | [ |
Overexpression of ALAS from R. sphaeroides in the succinate production strain QZ1111 | E. coli | Glucose | 0.44 | [ |
Overexpression of ALAS from R. palustris ATCC 17001, deletion of sdhAB | E. coli | Glucose, glycine | 6.38 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc, deletion of pck | E. coli | Glucose, glycine | 4.84 | [ |
Overexpression of ALAS from R. palustris ATCC 17001 and native ppc, coaA, addition calcium pantothenate | E. coli | Glucose, glycine | 4.12 | [ |
Overexpression of ALAS from R. palustris ATCC 17001 and native ppc, deletion of sdhAB, weakening ALAD by site mutation | E. coli | Glucose, glycine | 7.17 | [ |
Overexpression of ALAS from Saccharomyces cerevisiae controlled via the auto-induced expression approach and the antibiotic-free stabilized plasmid, expressing synthesis pathways of PHB | E. coli | Glucose, succinic acid, glycine | 3.60 | [ |
Overexpression of ALAS from R. capsulatus, pathway optimization for CoA and precursor biosynthesis, downregulation of hemB by substituting the start codon ATG to GTG | E. coli | Glucose | 2.81 | [ |
Overexpression of ALAS from R. sphaeroides, agxT from Homo sapiens and aceA | E. coli | Glucose | 0.52 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc and eamA, deletion of aceA | E. coli | Glucose, glycine | 4.47 | [ |
Overexpression of ALAS from R. sphaeroides, aceA and agxT from Homo sapiens, downregulation of hemB by synthetic glycine-OFF riboswitches | E. coli | Glucose | 0.24 | [ |
Overexpression of ALAS from R. palustris ATCC 17001, reinforcing the antioxidant defense system by expression KatE and SodB | E. coli | Glucose, glycine | 11.5 | [ |
Dynamic upregulation of ALAS from R. sphaeroides and dynamic downregulation of hemB by quorum sensing-based dual-function switch | E. coli | Glucose, succinic acid, glycine | 2.50 | [ |
Overexpression of ALAS from R. sphaeroides DSM158, deletion of ldhA, sdhA and iclR, downregulation of hemB by CRISPRi, aerobic condition | E. coli | glycerol | 6.93 | [ |
Overexpression of ALAS from R. sphaeroides DSM158, deletion of ldhA and sdhA, downregulation of hemB by CRISPRi, microaerobic condition | E. coli | glycerol | 5.95 | |
Overexpression of ALAS from R. sphaeroides, native ppc and rhtA from E. coli, deletion of ldhA, pqo, cat, pta, ackA and pbp1b | C. glutamicum | Glucose, glycine | 7.53 | [ |
Overexpression of ALAS from R. capsulatus SB1003, deletion of sucCD | C. glutamicum | Glucose, glycine | 7.60 | [ |
Overexpression of ALAS from R. capsulatus SB1003 and rhtA from E. coli, deletion of sucCD, two-stage fermentation | C. glutamicum | Glucose, glycine | 14.70 | |
Overexpression of ALAS from R. sphaeroides, serA∆197, serB, serC and glyA | C. glutamicum | Glucose, glycine | 3.40 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc to balance 5-ALA biosynthetic and anaplerotic pathways | C. glutamicum | Glucose, glycine | 16.30 | [ |
Moderate overexpression of ALAS from R. palustris ATCC 17001 and native ppc to balance 5-ALA biosynthetic and anaplerotic pathways | C. glutamicum | Cassava bagasse hydrolysate, glycine | 18.50 | |
C5 pathway | ||||
Overexpression of mutated GluTR from Salmonella arizona, GSAM and RhtA | E. coli | Glucose | 4.13 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, RhtA and RyhB | E. coli | Glucose | 1.78 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, HemD and HemF | E. coli | Glucose | 3.25 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM, HemD and HemF, optimization of the in vitro iron concentration | E. coli | Glucose | 4.05 | [ |
Overexpression of mutated GluTR from Salmonella typhimurium, GSAM and AceA with different promoters, deletion of sucA | E. coli | Glucose | 3.40 | [ |
Overexpression of mutated GluTR from S. arizona, GSAM and RhtA in multiplexed PHB operon chromosomally integrated strain | E. coli | Glucose | 3.60 | [ |
High gene copy expression of mutated GluTR from S. arizona and GSAM in the chromosome, deletion of recA | E. coli | Glucose | 4.55 | [ |
Overexpression of mutated GluTR and GBP from Arabidopsis thaliana in E. coli Transetta (DE3) | E. coli | Glucose, glutamate | 7.64 | [ |
Optimization of the C5 pathway with RBS engineering, downregulation of hemB by fliC promoter in the stationary phase, enhancement of the PLP biosynthesis, deletion of recA and endA improved the plasmid stability | E. coli | Glucose | 5.25 | [ |
Overexpression of mutated GluTR from S. arizona and GSAM from E. coli | C. glutamicum | Glucose | 1.79 | [ |
Overexpression of mutated GluTR from S. typhimurium and GSAM from E. coli | C. glutamicum | Glucose | 2.20 | [ |
Overexpression of mutated GluTR from S. typhimurium, GSAM and RhtA from E. coli, deletion ncgl1221, putP and lysE, downregulation of hemB by a relatively weak RBS replacement | C. glutamicum | Glucose | 0.90 | [ |
Overexpression of mutated GluTR from S. typhimurium, GSAM and RhtA from E. coli, OdhI (T14A/T15A), addition ethambutol | C. glutamicum | Glucose | 2.90 | [ |
Overexpression of mutated GluTR from S. arizona and GSAM from E. coli, PPC, GltA, PckA, GapA, Cgl0788 and Cgl0789, downregulation of odhA by growth-regulated promoter PCP_2836, dynamic upregulation of rhtA by the two-component system HrrSA | C. glutamicum | Glucose | 3.16 | [ |
图2 动态调控在5-ALA生物合成中的应用
Fig. 2 Application of dynamic regulation in 5-ALA biosynthesis5-ALA—5-aminolevulinic acid; PBG—porphobilinogen; ODH—oxoglutarate dehydrogenase; GDH—glutamate dehydrogenase; ALAS—5-aminolevulinate synthase; ALAD—5-aminolevulinic acid dehydratase; Tm—temperature; QS—quorum sensing; upregulation; downregulation
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