化工学报 ›› 2022, Vol. 73 ›› Issue (10): 4311-4323.DOI: 10.11949/0438-1157.20220838
王欣慧1,2,3(), 王颖1,2, 姚明东1,2,3(), 肖文海1,2
收稿日期:
2022-06-15
修回日期:
2022-07-27
出版日期:
2022-10-05
发布日期:
2022-11-02
通讯作者:
姚明东
作者简介:
王欣慧(1998—),女,硕士研究生,1575799416@qq.com
基金资助:
Xinhui WANG1,2,3(), Ying WANG1,2, Mingdong YAO1,2,3(), Wenhai XIAO1,2
Received:
2022-06-15
Revised:
2022-07-27
Online:
2022-10-05
Published:
2022-11-02
Contact:
Mingdong YAO
摘要:
维生素A是维持人体代谢的必需维生素,在食品、药品及护肤品等多个领域占有重要地位,是三大维生素支柱产品之一,应用前景广阔。市场上的维生素A主要来源于化学合成和天然提取。近年来,随着绿色生物制造的发展,维生素A的生物合成研究取得了重大的进展。总结了维生素A生物合成的研究现状,并对维生素A生物合成的优化改造方案进行了分析归纳,概述了维生素A发酵生产以及产品组分调控和储存策略,最后对生物合成维生素A的现状进行总结与展望。
中图分类号:
王欣慧, 王颖, 姚明东, 肖文海. 维生素A生物合成的研究进展[J]. 化工学报, 2022, 73(10): 4311-4323.
Xinhui WANG, Ying WANG, Mingdong YAO, Wenhai XIAO. Research progress of vitamin A biosynthesis[J]. CIESC Journal, 2022, 73(10): 4311-4323.
公司 | 产地 | 上游中间体 | 生产工艺 | 产能/(t/a) |
---|---|---|---|---|
新和成 | 中国 | 自配 | Roche[ | 10000 |
帝斯曼 | 荷兰等 | 外购 | Roche | 7500 |
巴斯夫 | 德国等 | 自配 | BASF[ | 6000 |
浙江医药 | 中国 | 外购 | BASF | 5600 |
安迪苏 | 法国等 | 外购 | BASF | 5000 |
金达威 | 中国 | 外购 | Roche | 2900 |
表1 全球维生素A主要厂商
Table 1 Global major manufacturers of vitamin A
公司 | 产地 | 上游中间体 | 生产工艺 | 产能/(t/a) |
---|---|---|---|---|
新和成 | 中国 | 自配 | Roche[ | 10000 |
帝斯曼 | 荷兰等 | 外购 | Roche | 7500 |
巴斯夫 | 德国等 | 自配 | BASF[ | 6000 |
浙江医药 | 中国 | 外购 | BASF | 5600 |
安迪苏 | 法国等 | 外购 | BASF | 5000 |
金达威 | 中国 | 外购 | Roche | 2900 |
图2 维生素A生物合成路径Erg10—乙酰辅酶a C-乙酰转移酶;Erg13—羟甲基戊二酰辅酶a合酶;MVA—真核微生物和古细菌甲羟戊酸途径;MEP—原核微生物2-C-甲基-D-赤藓糖醇-4-磷酸途径;Bts1—法尼基转移酶;CrtE—GGPP合成酶;CrtB—八氢番茄红素合成酶;CrtI—八氢番茄红素脱氢酶;CrtY—番茄红素β-环化酶;实线箭头表示直接催化生成;虚线箭头表示部分路径信息省略;灰色标注表示维生素A合成基因
Fig.2 Vitamin A biosynthetic pathway
底盘细胞 | 工程化手段 | 产量 | 文献 |
---|---|---|---|
大肠杆菌 | 表达家鼠来源的β-胡萝卜素15,15′-氧化酶; 优化最佳反应条件:pH、温度、底物浓度和表面活性剂 | 视黄醛产量:72 mg/L | [ |
大肠杆菌 | 选择密码子优化后的β-胡萝卜素15,15′-氧化酶; 上调dxs,优化内源MEP途径; 引入外源性MVA途径,提供IPP和DMAPP; 筛选大肠菌株:MG1655、DH5a、X11-BLUE、S17-1和BL21; 发酵条件优化:氧浓度、碳源和温度 | 视黄醛产量:136 mg/L | [ |
大肠杆菌 | 引入两个异源基因blhSR和RALDH2; 删除内源编码醛还原酶的ybbO基因; 采用mRNA稳定区工程方法; 优化维生素A产生菌的培养条件:温度、pH和氧浓度 | 5 L生物反应器分批发酵;维甲酸产量: (8.20±0.05) mg/L | [ |
大肠杆菌 | 筛选了编码β-胡萝卜素裂解酶的基因:blh、brp和bcox; 采用mRNA稳定区工程提高blh催化效率; 共同表达合成视黄基棕榈酸酯路径基因LRAT和CRBP | 分批补料发酵培养;视黄基棕榈酸酯产量为(69.96±2.64) mg/L | [ |
大肠杆菌 | 优化发酵条件:温度、pH、搅拌速度; 筛选最佳表面活性剂 | 视黄醛产量:600 mg/L | [ |
大肠杆菌 | 过表达内源基因ybbO,增强醛→醇转化; 敲除编码O-乙酰转移酶的基因cat | 视黄醛、视黄醇、视黄醇醋酸酯产量的比例为6%、88%、6% | [ |
酿酒酵母 | 采用以木糖为碳源的酵母菌株; 采用十二烷和橄榄油两相原位萃取 | 3 L生物反应器分批补料;视黄醇、视黄醛产量为1256、2094 mg/L | [ |
酿酒酵母 | 引入人来源RDH12和乳球菌noxE; 优化发酵条件,以木糖为碳源,十二烷为萃取剂; 筛选最适培养和储存条件,包括温度、光照和抗氧化剂 | 250 ml摇瓶发酵;视黄醇产量:123.1 mg/L | [ |
酿酒酵母 | 过表达酵母内源ENV9和截短的Hmg1; 发酵添加1.44 mmol/L Fe2+以维持blh酶活性 | 视黄醇产量:443.43 mg/L | [ |
表2 维生素A相关的代谢工程改造进展
Table 2 Progress in metabolic engineering transformation related to vitamin A
底盘细胞 | 工程化手段 | 产量 | 文献 |
---|---|---|---|
大肠杆菌 | 表达家鼠来源的β-胡萝卜素15,15′-氧化酶; 优化最佳反应条件:pH、温度、底物浓度和表面活性剂 | 视黄醛产量:72 mg/L | [ |
大肠杆菌 | 选择密码子优化后的β-胡萝卜素15,15′-氧化酶; 上调dxs,优化内源MEP途径; 引入外源性MVA途径,提供IPP和DMAPP; 筛选大肠菌株:MG1655、DH5a、X11-BLUE、S17-1和BL21; 发酵条件优化:氧浓度、碳源和温度 | 视黄醛产量:136 mg/L | [ |
大肠杆菌 | 引入两个异源基因blhSR和RALDH2; 删除内源编码醛还原酶的ybbO基因; 采用mRNA稳定区工程方法; 优化维生素A产生菌的培养条件:温度、pH和氧浓度 | 5 L生物反应器分批发酵;维甲酸产量: (8.20±0.05) mg/L | [ |
大肠杆菌 | 筛选了编码β-胡萝卜素裂解酶的基因:blh、brp和bcox; 采用mRNA稳定区工程提高blh催化效率; 共同表达合成视黄基棕榈酸酯路径基因LRAT和CRBP | 分批补料发酵培养;视黄基棕榈酸酯产量为(69.96±2.64) mg/L | [ |
大肠杆菌 | 优化发酵条件:温度、pH、搅拌速度; 筛选最佳表面活性剂 | 视黄醛产量:600 mg/L | [ |
大肠杆菌 | 过表达内源基因ybbO,增强醛→醇转化; 敲除编码O-乙酰转移酶的基因cat | 视黄醛、视黄醇、视黄醇醋酸酯产量的比例为6%、88%、6% | [ |
酿酒酵母 | 采用以木糖为碳源的酵母菌株; 采用十二烷和橄榄油两相原位萃取 | 3 L生物反应器分批补料;视黄醇、视黄醛产量为1256、2094 mg/L | [ |
酿酒酵母 | 引入人来源RDH12和乳球菌noxE; 优化发酵条件,以木糖为碳源,十二烷为萃取剂; 筛选最适培养和储存条件,包括温度、光照和抗氧化剂 | 250 ml摇瓶发酵;视黄醇产量:123.1 mg/L | [ |
酿酒酵母 | 过表达酵母内源ENV9和截短的Hmg1; 发酵添加1.44 mmol/L Fe2+以维持blh酶活性 | 视黄醇产量:443.43 mg/L | [ |
图3 维生素A前体β-胡萝卜素生物合成策略Are1,Are2—甾醇酰基转移酶;pah1,lpp1,dpp1—磷脂酸磷酸酶;PA—磷脂酸;DAG—二酰基甘油;TAG—三酰基甘油;SE—甾醇酯;FPP—法呢基焦磷酸;GGPP—牻牛儿基牻牛儿基焦磷酸;R—酶结构域
Fig.3 Biosynthesis strategy of vitamin A precursor β-carotene
图4 维生素A辅因子改造优化策略ADH—乙醇脱氢酶;CHMO—环己酮氧化酶;ACS1—乙酰辅酶连接酶1;ZWF1—葡萄糖-6-磷酸脱氢酶;noxE—NADH氧化酶;NADH—烟酰胺腺嘌呤二核苷酸;NADPH—烟酰胺腺嘌呤二核苷酸磷酸
Fig.4 Optimization strategy of vitamin A cofactor transformation
图5 维生素A组分调控优化策略RDH—视黄醇脱氢酶;ADH—乙醇脱氢酶;BCMO—β-胡萝卜素15,15′-氧化酶;LRAT—卵磷脂视黄醇酰基转移酶;SR8A—维生素A酵母生产出发菌株1;RDH10—人来源视黄醇脱氢酶10;ybbO—NADP+依赖型醛还原酶;RDH12—人来源视黄醇脱氢酶12;Y03—维生素A酵母生产出发菌株2;sps19—2,4-二烯酰辅酶a还原酶;Ifa38—极长链3-氧代酰基辅酶a还原酶;Env9—短链乙醇脱氢酶
Fig.5 Optimization strategy of vitamin A component regulation
改造策略 | 具体改造信息 | 结果 | 文献 |
---|---|---|---|
碳源 | 葡萄糖、木糖 | 20.74 mg/L维生素A(44 g/L木糖) | [ |
温度、pH | 温度:24~33℃ pH:5.5~8.0 | 视黄醛产量最大(pH 7.0,30℃), 细胞量达到最大(27℃) | [ |
表面活性剂 | Span20、Span40、Span60、Span80、 Tween20、Tween40、Tween80、Brij58、Triton X-100 | 细胞量最大, 细胞积累量为15.2 g/L(10 g/L Span80) | [ |
搅拌速率 | 400、500、600、700、800 r/min | 视黄醛产量最大为600 mg/L(600 r/min) | [ |
萃取剂 | 十二烷、大豆油和橄榄油 | 十二烷效果最佳 | [ |
光 | 光照条件、黑暗条件 | 视黄醇浓度最高为124.6 mg/L(黑暗) | [ |
表3 维生素A生产下游改造策略
Table 3 The downstream transformation strategy of vitamin A production
改造策略 | 具体改造信息 | 结果 | 文献 |
---|---|---|---|
碳源 | 葡萄糖、木糖 | 20.74 mg/L维生素A(44 g/L木糖) | [ |
温度、pH | 温度:24~33℃ pH:5.5~8.0 | 视黄醛产量最大(pH 7.0,30℃), 细胞量达到最大(27℃) | [ |
表面活性剂 | Span20、Span40、Span60、Span80、 Tween20、Tween40、Tween80、Brij58、Triton X-100 | 细胞量最大, 细胞积累量为15.2 g/L(10 g/L Span80) | [ |
搅拌速率 | 400、500、600、700、800 r/min | 视黄醛产量最大为600 mg/L(600 r/min) | [ |
萃取剂 | 十二烷、大豆油和橄榄油 | 十二烷效果最佳 | [ |
光 | 光照条件、黑暗条件 | 视黄醇浓度最高为124.6 mg/L(黑暗) | [ |
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