合成生物学 ›› 2022, Vol. 3 ›› Issue (6): 1150-1173.DOI: 10.12211/2096-8280.2022-039
刘启, 钱芷兰, 宋丽丽, 要超颖, 徐名强, 任燕娜, 蔡孟浩
收稿日期:
2022-07-04
修回日期:
2022-08-03
出版日期:
2022-12-31
发布日期:
2023-01-17
通讯作者:
蔡孟浩
作者简介:
基金资助:
Qi LIU, Zhilan QIAN, Lili SONG, Chaoying YAO, Mingqiang XU, Yanna REN, Menghao CAI
Received:
2022-07-04
Revised:
2022-08-03
Online:
2022-12-31
Published:
2023-01-17
Contact:
Menghao CAI
摘要:
优质的微生物底盘宿主是实现绿色、可持续生物制造的重要平台。巴斯德毕赤酵母底盘宿主因其在蛋白表达和发酵生产中的诸多优势受到了广泛的关注和应用。而作为一种工业甲基营养酵母,其可以有效地利用来源广泛的甲醇作为唯一碳源,使其成为碳一化合物潜在的生物转化平台。近年来,随着合成生物技术和生物制药技术的快速发展,围绕毕赤酵母底盘的工程化改造研究逐渐增多,并取得了卓有成效的进展,促进了毕赤酵母底盘的发展和升级。本文简述了毕赤酵母底盘细胞的发展和应用现状,从基因操纵技术、基因表达调控、代谢工程改造等方面介绍了毕赤酵母的工程化改造策略及应用效果,总结了毕赤酵母中合成生物技术、调控元器件、新型表达平台和生物转化体系的建立与开发情况。在此基础上,进一步强调了毕赤酵母中CRISPR介导的基因编辑及调控、转录系统的重构及人工设计,介绍了其在蛋白表达和化合物合成方面的应用,并分析了其在实际应用中的优势和问题。最后,对毕赤酵母在后续研究中的底盘升级方向和应用场景进行了展望。
中图分类号:
刘启, 钱芷兰, 宋丽丽, 要超颖, 徐名强, 任燕娜, 蔡孟浩. 巴斯德毕赤酵母底盘细胞的工程化改造及应用[J]. 合成生物学, 2022, 3(6): 1150-1173.
Qi LIU, Zhilan QIAN, Lili SONG, Chaoying YAO, Mingqiang XU, Yanna REN, Menghao CAI. Rewiring and application of Pichia pastoris chassis cell[J]. Synthetic Biology Journal, 2022, 3(6): 1150-1173.
图1 毕赤酵母CRISPR介导的基因编辑过程及工程化改造策略[29-30, 41, 57](标注蓝色字体代表该蛋白敲除后可以有效抑制NHEJ作用;标注红色字体代表该蛋白过表达可以提升HDR介导的修复效率)
Fig. 1 CRISPR mediated gene editing process and engineering strategy in Pichia pastoris[29-30, 41, 57](Blue font indicates that the knockout of target protein can inhibit NHEJ; red font indicates that the overexpression of target protein can enhance HDR efficiency)
菌株改造策略 | Cas9/gRNA表达方式 | 游离质粒ARS | HDR效率 | 参考 文献 | |
---|---|---|---|---|---|
敲除 | 敲入 | ||||
Wild type | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | 100%(单基因) | — | [ |
敲除ku70 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | 100%(单基因) | — | [ |
敲除ku70 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | — | 75%~97.9%(单位点) 57.7%~70.0%(双位点) 12.5%~32.1%(三位点) | [ |
Wild type | P GAP- Cas9 P SER -sgRNA | panARS | 80%(单基因) | — | [ |
敲除ku70 | P ENO1 -Cas9 P tRNA1 -tRNA1-sgRNA | PARS1 | — | 40%(三位点) | [ |
敲除MPH1和 过表达PpRAD52 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | panARS | 90%(单基因) | 43%~70%(单位点) 25%(三位点) | [ |
Wild type | P GAP -Cas9(整合) P SER -sgRNA | panARS | — | 98.6%(单位点) | [ |
PARS1 | 33.3%~93.1%(双位点) 10%~75%(三位点) | ||||
敲除ku70 | P GAP -Cas9(整合) P SER -sgRNA | PARS1 | — | 33.3%~57%(三位点) | [ |
过表达ScRAD52 ScRAD59 ScMRE11 | P GAP -Cas9(整合) P SER -sgRNA | PARS1 | — | 100%(单位点) 95.7%~97.9%(双位点) 64.5%~80.9%(三位点) | [ |
Wild type | P GAP -FnCpf1(整合) P SER -crRNA | panARS | 99%(单基因) 65%~80%(双基因) 30%(三基因) | — | [ |
表1 毕赤酵母中CRISPR介导的HDR效率及工程化改造策略
Tab. 1 CRISPR mediated HDR efficiency and engineering strategy in Pichia pastoris
菌株改造策略 | Cas9/gRNA表达方式 | 游离质粒ARS | HDR效率 | 参考 文献 | |
---|---|---|---|---|---|
敲除 | 敲入 | ||||
Wild type | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | 100%(单基因) | — | [ |
敲除ku70 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | 100%(单基因) | — | [ |
敲除ku70 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | PARS1 | — | 75%~97.9%(单位点) 57.7%~70.0%(双位点) 12.5%~32.1%(三位点) | [ |
Wild type | P GAP- Cas9 P SER -sgRNA | panARS | 80%(单基因) | — | [ |
敲除ku70 | P ENO1 -Cas9 P tRNA1 -tRNA1-sgRNA | PARS1 | — | 40%(三位点) | [ |
敲除MPH1和 过表达PpRAD52 | P HTX1 -Cas9 P HTX1 -HH-sgRNA-HDV | panARS | 90%(单基因) | 43%~70%(单位点) 25%(三位点) | [ |
Wild type | P GAP -Cas9(整合) P SER -sgRNA | panARS | — | 98.6%(单位点) | [ |
PARS1 | 33.3%~93.1%(双位点) 10%~75%(三位点) | ||||
敲除ku70 | P GAP -Cas9(整合) P SER -sgRNA | PARS1 | — | 33.3%~57%(三位点) | [ |
过表达ScRAD52 ScRAD59 ScMRE11 | P GAP -Cas9(整合) P SER -sgRNA | PARS1 | — | 100%(单位点) 95.7%~97.9%(双位点) 64.5%~80.9%(三位点) | [ |
Wild type | P GAP -FnCpf1(整合) P SER -crRNA | panARS | 99%(单基因) 65%~80%(双基因) 30%(三基因) | — | [ |
图2 毕赤酵母中转录调控系统的改造及工程化设计[24-28, 40, 59, 78, 82, 88, 94-103, 108-115]URS—上游调控序列;CP—核心启动子;AD—激活结构域;RD—阻遏结构域;DBP—DNA结合蛋白;BS—结合位点;ER—雌二醇受体;βE—β-雌二醇
Fig. 2 Rewiring and engineering design of transcription regulation system in Pichia pastoris[24-28, 40, 59, 78, 82, 88, 94-103, 108-115]URS—upstream regulatory sequence; CP—core promoter; AD—activation domain; RD—repression domain; DBP—DNA binding protein; BS—binding site; ER—estradiol receptor; βE—β-estradiol
外源蛋白 | 分子 伴侣 | 效价提升倍数 | 参考 文献 |
---|---|---|---|
狂犬病病毒糖蛋白 | PDI1 ERO1 GPX1 | 9.6倍 3倍 8.2倍 | [ |
白介素-2-人血清白蛋白融合蛋白 | PDI1 KAR2 ERO1 | 2.2倍 1.9倍 2.3倍 | [ |
猪肽聚糖识别蛋白 | PDI1 | 5倍(高拷贝) | [ |
疏水蛋白HFBI | KAR2 | 14倍(单拷贝) 9.8倍(双拷贝) 22倍(三拷贝) | [ |
PDI ERO1 | 7.8倍(三拷贝) 30倍(三拷贝) | ||
人溶菌酶 | HAC1 | 1.2倍 | [ |
铜绿假单胞菌弹性蛋白酶 | HAC1 | 1.8~3.9倍 | [ |
大肠杆菌植酸酶 | HAC1 PDI1 | 1.36倍 1.40倍 | [ |
家蚕乙酰胆碱酯酶 | PDI1 | 5倍 | [ |
几丁质酶 | HAC1 | 1.3倍 | [ |
表2 分子伴侣共表达提高毕赤酵母蛋白表达量
Tab. 2 Co-expression of chaperone to enhance protein expression in Pichia pastoris
外源蛋白 | 分子 伴侣 | 效价提升倍数 | 参考 文献 |
---|---|---|---|
狂犬病病毒糖蛋白 | PDI1 ERO1 GPX1 | 9.6倍 3倍 8.2倍 | [ |
白介素-2-人血清白蛋白融合蛋白 | PDI1 KAR2 ERO1 | 2.2倍 1.9倍 2.3倍 | [ |
猪肽聚糖识别蛋白 | PDI1 | 5倍(高拷贝) | [ |
疏水蛋白HFBI | KAR2 | 14倍(单拷贝) 9.8倍(双拷贝) 22倍(三拷贝) | [ |
PDI ERO1 | 7.8倍(三拷贝) 30倍(三拷贝) | ||
人溶菌酶 | HAC1 | 1.2倍 | [ |
铜绿假单胞菌弹性蛋白酶 | HAC1 | 1.8~3.9倍 | [ |
大肠杆菌植酸酶 | HAC1 PDI1 | 1.36倍 1.40倍 | [ |
家蚕乙酰胆碱酯酶 | PDI1 | 5倍 | [ |
几丁质酶 | HAC1 | 1.3倍 | [ |
图4 毕赤酵母中不同碳源底物的代谢途径及各类天然产物的合成[33-34, 60, 82, 171-184, 199-203]DHA—二羟丙酮;GAP—3-磷酸甘油醛;Xu5P—5-磷酸木酮糖;DHAP—磷酸二羟丙酮;XuMP cycle—单磷酸木酮糖循环;Aox—醇氧化酶;Cat—过氧化氢酶;Das—二羟丙酮合成酶;Dak—二羟丙酮激酶;Tpi—磷酸丙糖异构酶;Fld—甲醛脱氢酶;Fgh—S-甲酰基谷胱甘肽水解酶;Fdh—甲酸脱氢酶;Pdh—丙酮酸脱氢酶;Pdc—丙酮酸脱羧酶;Adh—乙醇脱氢酶;Ald—乙醛脱氢酶;Acs—乙酰辅酶A合成酶;Acc—乙酰辅酶A羧化酶;Fas—脂肪酸合成酶;表示酶催化反应;表示代谢物在细胞内外或不同细胞器间的穿梭;表示多步代谢途径
Fig. 4 Metabolic pathways of different carbon sources and synthesis of various natural products based on in Pichia pastoris[33-34, 60, 82, 171-184, 199- 203]DHA—dihydroxyacetone; GAP—glyceraldehyde-3-phosphate; Xu5P—xylulose 5-phosphate; DHAP—dihydroxyacetone phosphate; XuMP cycle—xylulose monophosphate cycle; Aox—alcohol oxidase; Cat—catalase; Das—dihydroxyacetone synthase; Dak—dihydroxyacetone kinase; Tpi—triosephosphate isomerase; Fld—formaldehyde dehydrogenase; Fgh—S-formylglutathione hydrolase; Fdh—formate dehydrogenase; Pdh—Pyruvate dehydrogenase; Pdc—pyruvate decarboxylase; Adh—alcohol dehydrogenase; Ald—acetaldehyde dehydrogenase; Acs—acetyl-CoA synthetase; Acc—acetyl-CoA carboxylase; Fas—fatty acid synthetase; indicate enzyme catalyzed reaction; indicate the shuttle of metabolites between extracellular and intracellular or between different organelles; indicate a multistep metabolic pathway.
种类 | 化合物 | 底物及培养方式 | 产量 | 参考文献 |
---|---|---|---|---|
四碳有机酸 | 苹果酸 | 甲醇(摇瓶) | 2.79 g/L | [ |
葡萄糖(摇瓶) | 8.55 g/L | |||
甲醇(反应器) | 42.28 g/L | [ | ||
富马酸 | 甲醇(反应器) | 0.76 g/L | ||
琥珀酸 | 甲醇(反应器) | 9.42 g/L | ||
脂肪酸衍生物 | 蓖麻油酸 | 甲醇(摇瓶) | 171.44 mg/L | [ |
长链α-烯烃 | 甲醇(摇瓶) | 1.6 mg/L | [ | |
脂肪酸 | 甲醇(反应器) | 23.4 g/L | [ | |
脂肪醇 | 甲醇(反应器) | 2.0 g/L | ||
萜类化合物 | 番茄红素 | 葡萄糖(摇瓶) | 1.141 μg/g DCW | [ |
甲醇(反应器) | 714 mg/L | [ | ||
β-胡萝卜素 | 葡萄糖(摇瓶) | 339 μg/g DCW | [ | |
虾青素 | 葡萄糖(摇瓶) | 3.7 μg/g DCW | [ | |
诺卡酮 | 甲醇(反应器) | 208 mg/L | [ | |
达玛烯二醇 | 甲醇(摇瓶) | 1.073 mg/g DCW | [ | |
聚酮类化合物 | 6-甲基水杨酸 | 甲醇(反应器) | 2.2 g/L | [ |
橘霉素 | 甲醇(摇瓶) | 0.6 mg/L | [ | |
洛伐他汀 | 甲醇(反应器) | 250.8 mg/L | [ | |
甲醇(反应器) | 419.0 mg/L | [ | ||
莫纳可林J | 甲醇(反应器) | 593.9 mg/L | [ | |
乙醇(反应器) | 3.2 g/L | [ | ||
黄酮类化合物 | 黄芩素 | 乙醇(摇瓶) | 401.9 mg/L | [ |
千层纸素 | 乙醇(摇瓶) | 339.5 mg/L |
表3 基于毕赤酵母底盘细胞的天然产物合成
Tab. 3 Production of natural products in Pichia pastoris chassis cell
种类 | 化合物 | 底物及培养方式 | 产量 | 参考文献 |
---|---|---|---|---|
四碳有机酸 | 苹果酸 | 甲醇(摇瓶) | 2.79 g/L | [ |
葡萄糖(摇瓶) | 8.55 g/L | |||
甲醇(反应器) | 42.28 g/L | [ | ||
富马酸 | 甲醇(反应器) | 0.76 g/L | ||
琥珀酸 | 甲醇(反应器) | 9.42 g/L | ||
脂肪酸衍生物 | 蓖麻油酸 | 甲醇(摇瓶) | 171.44 mg/L | [ |
长链α-烯烃 | 甲醇(摇瓶) | 1.6 mg/L | [ | |
脂肪酸 | 甲醇(反应器) | 23.4 g/L | [ | |
脂肪醇 | 甲醇(反应器) | 2.0 g/L | ||
萜类化合物 | 番茄红素 | 葡萄糖(摇瓶) | 1.141 μg/g DCW | [ |
甲醇(反应器) | 714 mg/L | [ | ||
β-胡萝卜素 | 葡萄糖(摇瓶) | 339 μg/g DCW | [ | |
虾青素 | 葡萄糖(摇瓶) | 3.7 μg/g DCW | [ | |
诺卡酮 | 甲醇(反应器) | 208 mg/L | [ | |
达玛烯二醇 | 甲醇(摇瓶) | 1.073 mg/g DCW | [ | |
聚酮类化合物 | 6-甲基水杨酸 | 甲醇(反应器) | 2.2 g/L | [ |
橘霉素 | 甲醇(摇瓶) | 0.6 mg/L | [ | |
洛伐他汀 | 甲醇(反应器) | 250.8 mg/L | [ | |
甲醇(反应器) | 419.0 mg/L | [ | ||
莫纳可林J | 甲醇(反应器) | 593.9 mg/L | [ | |
乙醇(反应器) | 3.2 g/L | [ | ||
黄酮类化合物 | 黄芩素 | 乙醇(摇瓶) | 401.9 mg/L | [ |
千层纸素 | 乙醇(摇瓶) | 339.5 mg/L |
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