合成生物学 ›› 2021, Vol. 2 ›› Issue (6): 964-981.DOI: 10.12211/2096-8280.2021-042
郭亮1,2, 高聪1,2, 柳亚迪1,2, 陈修来1,2, 刘立明1,2
收稿日期:
2021-04-09
修回日期:
2021-05-21
出版日期:
2021-12-31
发布日期:
2022-01-21
通讯作者:
刘立明
作者简介:
基金资助:
Liang GUO1,2, Cong GAO1,2, Yadi LIU1,2, Xiulai CHEN1,2, Liming LIU1,2
Received:
2021-04-09
Revised:
2021-05-21
Online:
2021-12-31
Published:
2022-01-21
Contact:
Liming LIU
摘要:
随着畜牧业的快速发展,人们对畜牧饲料蛋白的需求日益剧增。由于人们对食品安全意识的增强,迫切需要开发安全、高效、可持续动物饲料蛋白的供应途径。由于氨基酸是组成蛋白质的基本单元,所以在饲料中添加氨基酸可以替代饲料中的蛋白质,为动物细胞生长发育提供足够的营养。因此,饲用氨基酸作为动物饲料食品添加剂被广泛应用,具有广阔的市场应用前景。利用合成生物学技术,工程化改造大肠杆菌,构建的细胞工厂,以生物质为原料可绿色高效合成饲用氨基酸,而且其具有原料可再生、成本低廉、反应条件温和、环境污染小等优点,为解决动植物提取和化学炼制引起的环境污染问题提供了一种有效解决方案。本文针对饲用氨基酸(赖氨酸、甲硫氨酸、色氨酸、苏氨酸、缬氨酸和精氨酸)的生物合成途径,介绍了大肠杆菌合成饲用氨基酸的生产瓶颈,并从饲用氨基酸大肠杆菌细胞工厂的构建与优化,综述了利用合成生物学技术改造大肠杆菌细胞工厂合成饲用氨基酸的研究现状。提升饲用氨基酸的生产技术水平、提高大肠杆菌细胞的鲁棒性和增强大肠杆菌细胞对不利环境的耐受能力,可以提升饲用氨基酸发酵性能,简化发酵过程控制,降低饲用氨基酸的生产成本,是未来饲用氨基酸生产菌株工程化改造的方向。
中图分类号:
郭亮, 高聪, 柳亚迪, 陈修来, 刘立明. 大肠杆菌生产饲用氨基酸的研究进展[J]. 合成生物学, 2021, 2(6): 964-981.
Liang GUO, Cong GAO, Yadi LIU, Xiulai CHEN, Liming LIU. Advances in bioproduction of feed amino acid by Escherichia coli[J]. Synthetic Biology Journal, 2021, 2(6): 964-981.
图1 大肠杆菌天冬氨酸族氨基酸的合成路径及其反馈调节示意图(红色虚线箭头表示反馈抑制、蓝色虚线箭头表示反馈阻遏、实线箭头表示一步代谢路径)途径涉及的关键酶:AAT—天冬氨酸氨基转移酶;AK Ⅰ,AK Ⅱ,AK Ⅲ—天冬氨酸激酶;ASD—天冬氨酸半醛脱氢酶;HD Ⅰ,HD Ⅱ—高丝氨酸脱氢酶;HK—高丝氨酸激酶;TS—苏氨酸合酶; DS—二氢吡啶二羧酸合酶;DR—二氢吡啶二羧酸还原酶;THS—四氢二吡啶琥珀酰酶;SDAT Ⅰ,SDAT Ⅱ—N-琥珀酰二氨基庚二酸氨基转移酶;SDD—N-琥珀酰二氨基庚二酸脱琥珀酰酶;DE—二氨基庚二酸差向异构酶;DDC—二氨基庚二酸脱羧酶;HST—O-琥珀酰高丝氨酸转琥珀酰酶;SHL—琥珀酰高丝氨酸裂解酶;CL—胱硫醚β-合成酶;HMT Ⅰ,HMT Ⅱ—半胱氨酸甲基转移酶.途径涉及的关键基因:aspC—天冬氨酸转氨酶编码基因;thrA—天冬氨酸激酶Ⅰ编码基因;metL—天冬氨酸激酶Ⅱ编码基因;lysC—天冬氨酸激酶Ⅲ编码基因;asd—天冬氨酸半醛脱氢酶编码基因;thrA—高丝氨酸脱氢酶Ⅰ编码基因;thrB—高丝氨酸激酶编码基因;thrC—苏氨酸合酶编码基因;dapA—二氢吡啶二羧酸合酶编码基因;dapB—二氢吡啶二羧酸还原酶编码基因;dapD—四氢二吡啶琥珀酰酶编码基因;argD—N-琥珀酰二氨基庚二酸氨基转移酶Ⅰ编码基因;argM—N-琥珀酰二氨基庚二酸氨基转移酶II编码基因;dapE—N-琥珀酰二氨基庚二酸脱琥珀酰酶编码基因;dapF—二氨基庚二酸差向异构酶编码基因;lysA—二氨基庚二酸脱羧酶编码基因;metA—O-琥珀酰高丝氨酸转琥珀酰酶编码基因;metB—琥珀酰高丝氨酸裂解酶编码基因;metC—胱硫醚β-合成酶编码基因;metE—半胱氨酸甲基转移酶编码基因;metH—半胱氨酸甲基转移酶编码基因;metK—蛋氨酸腺苷转移酶编码基因;gdh—谷氨酸脱氢酶编码基因;glyA—丝氨酸羟甲基转移酶编码基因;metF—亚甲基四氢叶酸还原酶编码基因
Fig. 1 Metabolic pathways of aspartate family amino acids and feedback regulations involved in E. coli(Blue dotted lines indicate feedback repression, red dotted lines indicate feedback inhibition, and solid arrows indicate one-step metabolic pathways)Key enzymes in metabolic pathway: AAT—aspartate aminotransferase; AK Ⅰ, AK Ⅱ, AK Ⅲ—aspartate kinase; ASD—aspartate semialdehyde dehydrogenase; HD Ⅰ, HD Ⅱ—homoserine dehydrogenase; HK—homoserine kinase; TS—threonine synthase; DS—dihydrodipicolinate synthase; DR—dihydrodipicolinate reductase; THS—tetrahydrodipicolinate succinyltransferase; SDAT Ⅰ, SDAT Ⅱ—succinyl diaminopimelate (DAP) aminotransferase; SDD—succinyl DAP desuccinylase; DE—L,L-DAP epimerase; DDC—meso-DAP decarboxylase; HST—homoserine succinyltransferase; SHL—succinyl homoserine lyase; CL—cystathionine lyase; HMT Ⅰ, HMT Ⅱ—homocysteine methyltransferase.Key genes in metabolic pathway: aspC—aspartate aminotransferase-encoding gene; thrA—aspartate kinase Ⅰ-encoding gene; metL—aspartate kinase Ⅱ-encoding gene; lysC—aspartate kinase Ⅲ-encoding gene; asd—aspartate semialdehyde dehydrogenase-encoding gene; thrA—homoserine dehydrogenase Ⅰ-encoding gene; thrB—homoserine kinase-encoding gene; thrC—threonine synthase-encoding gene; dapA—dihydrodipicolinate synthase-encoding gene; dapB—dihydrodipicolinate reductase-encoding gene; dapD—tetrahydrodipicolinate succinyltransferase-encoding gene; argD—succinyl diaminopimelate (DAP) aminotransferase Ⅰ-encoding gene; argM—succinyl diaminopimelate (DAP) aminotransferase Ⅱ-encoding gene; dapE—succinyl DAP desuccinylase-encoding gene; dapF—L,L-DAP epimerase; lysA—meso-DAP decarboxylase-encoding gene; metA—homoserine succinyltransferase-encoding gene; metB—succinyl homoserine lyase-encoding gene; metC—cystathionine lyase-encoding gene; metE—homocysteine methyltransferase Ⅰ-encoding gene; metH—homocysteine methyltransferase Ⅱ-encoding gene; metK—methionine adenosyltransferase-encoding gene; gdh—glutamate dehydrogenase-encoding gene; glyA—serine hydroxymethyltransferase-encoding gene; metF—methylenetetrahydrofolate reductase-encoding gene)
产品 | 菌株 | 性状 | 发酵 方式 | 产量 /(g/L) | 生产强度 /[g/(L·h)] | 文献 |
---|---|---|---|---|---|---|
赖氨酸 | E. coli NT1003 | E. coli Δmet Δthr ↑ppc ↑pntB ↑aspA | 发酵罐 | 134.9 | 1.87 | [ |
E. coli LATR11/pWG-DCSMASMBHc.gLP | E. coli LATR11 ↑lysCT344M ↑asd ↑dapAH56K↑dapB ↑lysA ↑ppc ↑ddh | 发酵罐 | 125.6 | 3.14 | [ | |
E. coli DL2 | E. coli MG1655 ↑lysCT253R ↑dapAE84T | 摇瓶 | 9.5 | — | [ | |
E. coli RS3 | E. coli DL2 ↑lysCD340P ↑dapAE84TspeBA302VatpBS165NsecYM145V | 发酵罐 | 155 | 3.69 | [ | |
E. coli Lc(H)‐Fe(M) | E. coli CCTCC M2019435 ↑lysC ↑fre | 发酵罐 | 193.6 | 4.03 | [ | |
苏氨酸 | E. coli TWF006/pFW01-thrA*BC-asd | E. coli TWF006 ↑thrBC ↑asd ↑thrAS345A | 摇瓶 | 15.85 | 0.44 | [ |
E. coli W3110 pWYE134 | E. coli W3110 ↑thrL ↑thrBC ↑thrAS345A | 发酵罐 | 9.22 | 0.19 | [ | |
E. coli THPZ | E. coli THRD ↑zwf | 发酵罐 | 126.1 | 5.25 | [ | |
E. coli TWF106/pFT24rp | E. coli TWF001 ΔpoxB ΔpflB ΔldhA ΔadhE ΔtdcC ↑rhtC ↑pycmt | 发酵罐 | 80 | 2.22 | [ | |
E. coli THPE5 | E. coli THRD ↑pycA ↑pckA ↑fdh ↑aspC↑gdhA ↑udhA ↑citA | 发酵罐 | 70.8 | 1.77 | [ | |
甲硫 氨酸 | E. coli W3110 ΔmetJ/pTrcA*H | E. coli W3110 ΔmetJ ΔmetA ΔlysA ↑yjeH | 发酵罐 | 9.75 | 0.20 | [ |
E. coli M3/PAmZ | E. coli W3110 IJAHFEBC ↑metAfbr ↑yjeH↑serAfbr ↑metZ | 摇瓶 | 3.96 | 0.083 | [ | |
E. coli Me05 (pETMAFbr-B-Y/pKKmetH) | E. coli W3110 ΔmetJ ΔthrC Δ lysA ↓metKpG↑metAFbr ↑metB ↑metH | 发酵罐 | 5.62 | 0.12 | [ | |
E. coli W3110 IJAHFEBC/pAm | E. coli W3110 IJAHFEBC ↑metAFbr ↑yjeH↑serAfbr | 发酵罐 | 16.86 | 0.35 | [ | |
色氨酸 | E. coli w3110 trpAE1 trpR tnaA | E. coli W3110 ΔtrpR ΔtnaA ↑trpEDCBA | 发酵罐 | 54.5 | 0.70 | [ |
E. coli FB-04/pSV03E. coli W3110 ΔtrpRΔtnaA ΔpheA ΔtyrA ↑aroFfbr ↑trpES40FD | 发酵罐 | 13.3 | 0.029 | [ | ||
E. coli Tna (pSC101 trp·I15) | — | 发酵罐 | 6.2 | 0.23 | [ | |
E. coli KW023 | E. coli KW ΔtrpR ΔpykF ΔptsH ↑trpEDCBA↑aroGfbr ↓pta ↑galP ↑glk | 发酵罐 | 39.7 | 1.6 | [ | |
E. coli T16 | E. coli TRTH Δppc ↑acs ↑aceB ↑mdh ↑pck | 发酵罐 | 54.6 | 1.52 | [ | |
缬氨酸 | E. coli Val (pKBRilvBNCED, pTrc184ygaZHlrp | E. coli Val ↑ilvBNCED ↑ygaZH ↑lrp | 摇瓶 | 7.55 | 0.16 | [ |
E. coli VAMF (pKBRilvBNmutCED, pTrc184ygaZHlrp) | E. coli VAMF ↑ygaZH ↑lrp ↑ilv ↑ilvBNmutCED | 发酵罐 | 32.3 | 0.58 | [ | |
E. coli V1 cat-PL-ilvE5.7 | E. coli K12 ΔilvIH ΔilvBN ΔlvGME ↑ilvE ↑ilvBNN17KDA | 摇瓶 | 9.8 | 0.20 | [ | |
E. coli VHY18 | W3110 ΔlacI ΔycdN ΔycgH ΔydeU ΔyjiT Δyee ΔyjiV ΔpflB ΔldhA ΔadhE↑alsS ↑bcd ↑ilvD↑ilvCM ↑brnFE ↑spoT[R290E, K292D] | 发酵罐 | 84 | 2.33 | [ | |
精氨酸 | E. coli JM109-9039 | E. coli JM109 ΔargR ↑argCJBDFRGH | 摇瓶 | 0.040 | — | [ |
E. coli SJB009 | E. coli C600+ ΔspeC ΔspeF ΔadiA ΔargR ΔargA ↑argA215 ↑argO | 发酵罐 | 11.64 | 0.24 | [ | |
E. coli KO | E. coli MG1655 ↑argO ↑argAH15A ΔargR | 摇瓶 | 1.03 | — | [ |
表1 大肠杆菌细胞工厂生产饲用氨基酸进展比较
Tab. 1 Comparison of feed amino acid production by E. coli cell factories
产品 | 菌株 | 性状 | 发酵 方式 | 产量 /(g/L) | 生产强度 /[g/(L·h)] | 文献 |
---|---|---|---|---|---|---|
赖氨酸 | E. coli NT1003 | E. coli Δmet Δthr ↑ppc ↑pntB ↑aspA | 发酵罐 | 134.9 | 1.87 | [ |
E. coli LATR11/pWG-DCSMASMBHc.gLP | E. coli LATR11 ↑lysCT344M ↑asd ↑dapAH56K↑dapB ↑lysA ↑ppc ↑ddh | 发酵罐 | 125.6 | 3.14 | [ | |
E. coli DL2 | E. coli MG1655 ↑lysCT253R ↑dapAE84T | 摇瓶 | 9.5 | — | [ | |
E. coli RS3 | E. coli DL2 ↑lysCD340P ↑dapAE84TspeBA302VatpBS165NsecYM145V | 发酵罐 | 155 | 3.69 | [ | |
E. coli Lc(H)‐Fe(M) | E. coli CCTCC M2019435 ↑lysC ↑fre | 发酵罐 | 193.6 | 4.03 | [ | |
苏氨酸 | E. coli TWF006/pFW01-thrA*BC-asd | E. coli TWF006 ↑thrBC ↑asd ↑thrAS345A | 摇瓶 | 15.85 | 0.44 | [ |
E. coli W3110 pWYE134 | E. coli W3110 ↑thrL ↑thrBC ↑thrAS345A | 发酵罐 | 9.22 | 0.19 | [ | |
E. coli THPZ | E. coli THRD ↑zwf | 发酵罐 | 126.1 | 5.25 | [ | |
E. coli TWF106/pFT24rp | E. coli TWF001 ΔpoxB ΔpflB ΔldhA ΔadhE ΔtdcC ↑rhtC ↑pycmt | 发酵罐 | 80 | 2.22 | [ | |
E. coli THPE5 | E. coli THRD ↑pycA ↑pckA ↑fdh ↑aspC↑gdhA ↑udhA ↑citA | 发酵罐 | 70.8 | 1.77 | [ | |
甲硫 氨酸 | E. coli W3110 ΔmetJ/pTrcA*H | E. coli W3110 ΔmetJ ΔmetA ΔlysA ↑yjeH | 发酵罐 | 9.75 | 0.20 | [ |
E. coli M3/PAmZ | E. coli W3110 IJAHFEBC ↑metAfbr ↑yjeH↑serAfbr ↑metZ | 摇瓶 | 3.96 | 0.083 | [ | |
E. coli Me05 (pETMAFbr-B-Y/pKKmetH) | E. coli W3110 ΔmetJ ΔthrC Δ lysA ↓metKpG↑metAFbr ↑metB ↑metH | 发酵罐 | 5.62 | 0.12 | [ | |
E. coli W3110 IJAHFEBC/pAm | E. coli W3110 IJAHFEBC ↑metAFbr ↑yjeH↑serAfbr | 发酵罐 | 16.86 | 0.35 | [ | |
色氨酸 | E. coli w3110 trpAE1 trpR tnaA | E. coli W3110 ΔtrpR ΔtnaA ↑trpEDCBA | 发酵罐 | 54.5 | 0.70 | [ |
E. coli FB-04/pSV03E. coli W3110 ΔtrpRΔtnaA ΔpheA ΔtyrA ↑aroFfbr ↑trpES40FD | 发酵罐 | 13.3 | 0.029 | [ | ||
E. coli Tna (pSC101 trp·I15) | — | 发酵罐 | 6.2 | 0.23 | [ | |
E. coli KW023 | E. coli KW ΔtrpR ΔpykF ΔptsH ↑trpEDCBA↑aroGfbr ↓pta ↑galP ↑glk | 发酵罐 | 39.7 | 1.6 | [ | |
E. coli T16 | E. coli TRTH Δppc ↑acs ↑aceB ↑mdh ↑pck | 发酵罐 | 54.6 | 1.52 | [ | |
缬氨酸 | E. coli Val (pKBRilvBNCED, pTrc184ygaZHlrp | E. coli Val ↑ilvBNCED ↑ygaZH ↑lrp | 摇瓶 | 7.55 | 0.16 | [ |
E. coli VAMF (pKBRilvBNmutCED, pTrc184ygaZHlrp) | E. coli VAMF ↑ygaZH ↑lrp ↑ilv ↑ilvBNmutCED | 发酵罐 | 32.3 | 0.58 | [ | |
E. coli V1 cat-PL-ilvE5.7 | E. coli K12 ΔilvIH ΔilvBN ΔlvGME ↑ilvE ↑ilvBNN17KDA | 摇瓶 | 9.8 | 0.20 | [ | |
E. coli VHY18 | W3110 ΔlacI ΔycdN ΔycgH ΔydeU ΔyjiT Δyee ΔyjiV ΔpflB ΔldhA ΔadhE↑alsS ↑bcd ↑ilvD↑ilvCM ↑brnFE ↑spoT[R290E, K292D] | 发酵罐 | 84 | 2.33 | [ | |
精氨酸 | E. coli JM109-9039 | E. coli JM109 ΔargR ↑argCJBDFRGH | 摇瓶 | 0.040 | — | [ |
E. coli SJB009 | E. coli C600+ ΔspeC ΔspeF ΔadiA ΔargR ΔargA ↑argA215 ↑argO | 发酵罐 | 11.64 | 0.24 | [ | |
E. coli KO | E. coli MG1655 ↑argO ↑argAH15A ΔargR | 摇瓶 | 1.03 | — | [ |
图2 大肠杆菌色氨酸合成代谢路径途径涉及的关键酶:PykF,PykA—丙酮酸激酶;PpsA—磷酸烯醇式丙酮酸合酶;AroG—3-脱氧-D-阿拉伯庚酮糖-7-磷酸合酶;AroB—3-脱氢奎宁酸合酶; AroD—3-脱氢奎宁酸脱水酶; AroE—莽草酸脱氢还原酶; AroK—莽草酸激酶;AroA—5-烯醇式丙酮酰胺莽草酸合酶; AroC—分支酸合酶; TrpE—邻氨基苯甲酸合酶; TrpD—邻氨基苯甲酸焦磷酸转移酶;TrpC—邻氨基苯甲酸异构酶;TrpB—色氨酸合酶;TrpA—吲哚甘油3-磷酸酶; TyrA—预苯酸脱氢酶; PheA—预苯酸脱水酶
Fig. 2 Schematic of the tryptophan biosynthetic pathway in E. coliKey enzymes in metabolic pathway: PykF, PykA—pyruvate kinase; PpsA—phosphoenolpyruvate synthase; AroG—3-deoxy-D-arabinoheptulosonate-7-phosphate (DHAP) synthase; AroB—3-dehydroquinate synthase; AroD—3-dehydroshikimate dehydratase; AroE—shikimate 5-dehydrogenase; AroK—shikimate kinase; AroA—EPSP synthase; AroC—chorismate synthase; TrpE—anthranilate synthase I; TrpD—anthranilate synthase II; TrpC—(1S,2R)-1-C-(indol-3-yl)glycerol 3-phosphate isomerase; TrpB—tryptophan synthase B; TrpA—tryptophan synthase A; TyrA—chorismate dehydrogenase; PheA—chorismate dehydratase
图3 大肠杆菌缬氨酸合成代谢路径(绿色虚线箭头表示缬氨酸的反馈抑制,蓝色箭头表示Lrp反馈阻遏,红色箭头表示Lrp反馈激活)途径涉及的关键酶:IlvC—乙酰羟酸还原异构酶;IlvD—二羟酸脱水酶;Bcd—亮氨酸脱氢酶;LeuA—异丙基苹果酸合酶;LeuCD—异丙基苹果酸异构酶;LeuB—3-异丙基苹果酸脱氢酶;ThrB,IlvE—芳香族氨基酸转移酶;PanB—3-甲基-2-氧代丁酸羟甲基转移酶;PanE—2-脱氢抗坏血酸还原酶;PanC—泛酸-β-丙氨酸连接酶途径涉及的关键基因:livJ—缬氨酸转运蛋白编码基因;ygaZH—缬氨酸外排蛋白编码基因;ilvBN—乙酰羟酸合酶I编码基因;ilvGM—乙酰羟酸合酶II编码基因;ilvIH—乙酰羟酸合酶Ⅲ编码基因
Fig. 3 Schematic of valine biosynthetic pathway in E. coli (Green dotted arrows indicate feedback inhibition by valine, blue dotted arrows indicate feedback repression, red arrows indicate activation of gene expression, and black arrows indicate one-step metabolic pathways)Key enzymes in metabolic pathway: IlvC—acetohydroxy acid isomeroreductase; IlvD—dihydroxy acid dehydratease; Bcd—leucine dehydrogenase; LeuA—isopropylmalate synthase; LeuCD—isopropylmalate isomerase; LeuB—3-isopropylmalate dehydrogenase; ThrB, IlvE—aromatic amino acid transaminase; PanB—3-methyl-2-oxobutanoate hydroxymethyltransferase; PanE—2-dehydropantoate reductase; PanC—pantoate-β-alanine ligase Key genes in metabolic pathway: livJ—valine transporter-encoding gene; ygaZH—valine exporter-encoding gene; ilvBN—acetohydroxy acid synthase I-encoding gene; ilvGM—acetohydroxy acid synthase II-encoding gene; ilvIH—acetohydroxy acid synthase Ⅲ-encoding gene
图4 微生物体内精氨酸合成代谢路径途径涉及的关键酶:ArgA—N-乙酰谷氨酸合酶;ArgJ—乙酰鸟氨酸转移酶;ArgB—乙酰谷氨酸激酶;ArgC—N-乙酰谷氨酸半醛脱氢酶;ArgD—乙酰鸟氨酸转氨酶;ArgE—乙酰鸟氨酸酶;ArgF—鸟氨酸转氨甲酰酶;ArgF′—乙酰鸟氨酸氨甲酰转移酶;ArgG—精胺琥珀酸合酶;ArgH—精氨琥珀酸酶
Fig. 4 Schematic of arginine biosynthetic pathway inmicroorganismsKey enzymes in metabolic pathway:ArgA—acetylglutamate synthase; ArgJ—ornithine acetyltransferase; ArgB—acetylglutamate kinase;ArgC—acetylglutamate semialdehyde dehydrogenase; ArgD—acetylornithine transaminase; ArgE—acetylornithine deacetylase; ArgF—ornithine transcarbamylase; ArgF′—acetylornithine carbamoyltransferase; ArgG—argininosuccinate synthase; ArgH—arginosuccinase
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