酵母细胞催化合成18α-甘草酸

doi:10.11949/0438-1157.20240310

化工学报 ›› 2024, Vol. 75 ›› Issue (9): 3266-3276.DOI: 10.11949/0438-1157.20240310

酵母细胞催化合成18α-甘草酸

邢登雪¹(), 张良², 李文强³, 梁建华², 秦磊³, 张根林¹(), 李春¹^,²^,³()

^1.石河子大学化学化工学院，新疆兵团绿色化工过程重点实验室，新疆石河子 832003
^2.北京理工大学化学与化工学院，生物化工研究所医药分子科学与制剂工信部重点实验室，北京 100081
^3.清华大学化学工程系，工业生物催化教育部重点实验室，北京 100084

收稿日期:2024-03-18 修回日期:2024-06-20 出版日期:2024-09-25 发布日期:2024-10-10
通讯作者: 张根林,李春
作者简介:邢登雪（1996—），女，硕士研究生，xueunchallenge@163.com
基金资助:
国家自然科学基金项目(22138006)

Synthesis of 18α-glycyrrhizic acid by yeast cells

Dengxue XING¹(), Liang ZHANG², Wenqiang LI³, Jianhua LIANG², Lei QIN³, Genlin ZHANG¹(), Chun LI¹^,²^,³()

^1.Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, School of Chemistry and Chemical Engineering, Shihezi University, Shihezi 832003, Xinjiang, China
^2.Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, Institute of Biochemical Engineering, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 100081, China
^3.Key Laboratory for Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China

Received:2024-03-18 Revised:2024-06-20 Online:2024-09-25 Published:2024-10-10
Contact: Genlin ZHANG, Chun LI

摘要/Abstract

摘要：

18α-甘草酸（18α-GL）是一种齐墩果烷型皂苷，比其差向异构体18β-GL极性小、亲脂性好，更强的抗毒抗炎作用和更高的肝脏靶向性使18α-GL成为保肝护肝领域的主要药物成分。但目前18α-GL的制备方法污染大、效率低，亟需开发一种绿色简单地合成18α-GL的方法。利用酵母细胞异源表达糖基转移酶，通过全细胞催化方式鉴定出可催化18α-甘草次酸（18α-GA）特异性合成18α-单葡萄糖醛酸甘草次酸（18α-GAMG）的糖基转移酶cGuCSyGT和催化18α-GAMG特异性合成18α-GL的糖基转移酶GgUGT1。进一步运用蛋白质结构预测和分子动力学模拟探究cGuCSyGT对18α-GA的催化活性比18β-GA低的原因。最后采用优化底物添加浓度、底盘细胞、底物添加时间、反应时间、培养基成分补加和底物溶剂的策略构建了酵母催化合成18α-GAMG和18α-GL的最优工艺，使18α-GAMG和18α-GL的产量分别达到（36.38±1.87）mg/L和（39.32±0.75）mg/L。本研究实现了18α-GAMG和18α-GL的微生物催化合成，可为18α-GL的微生物全合成提供理论基础和技术支撑。

关键词: 甘草, 18α-甘草酸, 18α-单葡萄糖醛酸甘草次酸, 糖基转移酶, 酵母细胞催化

Abstract:

18α-Glycyrrhizin (18α-GL) is an oleanane-type saponin. 18α-GL is less polar and more lipophilic than its diastereomer 18β-GL. Its stronger anti-toxic and anti-inflammatory effects and higher liver targeting make 18α-GL a major drug ingredient in the field of liver protection. However, the current preparation method of 18α-GL is highly polluting and has low efficiency. Therefore, there is an urgent need to develop a green and simple method to synthesize 18α-GL. Glycosyltransferases were heterologously expressed in yeast cells. Through whole-cell catalysis, glycosyltransferases cGuCSyGT was identified as being able to catalyze the specific synthesis of 18α-glycyrrhetinic acid 3-O-monoglucuronide (18α-GAMG) from 18α-glycyrrhetinic acid (18α-GA) and GgUGT1 was identified as being able to catalyze the specific synthesis of 18α-glycyrrhizin (18α-GL) from 18α-GAMG. We further employed protein structure prediction and molecular dynamics simulation to explore the reason why cGuCSyGT has lower catalytic activity for 18α-GA than 18β-GA. Finally, an optimal process for yeast catalytic synthesis of 18α-GAMG and 18α-GL was constructed by optimizing various parameters, including substrate addition concentration, chassis host cells, substrate addition time, catalytic time, medium component addition and substrate solvent. Thus, the production of 18α-GAMG and 18α-GL reached (36.38±1.87) mg/L and (39.32±0.75) mg/L, respectively. This research achieved the microbial catalytic synthesis of 18α-GAMG and 18α-GL, which will provide a theoretical basis and technical support for the total microbial synthesis of 18α-GL.

Key words: licorice, 18α-glycyrrhizic acid, 18α-glycyrrhetinic acid 3-O-monoglucuronide, glycosyltransferase, yeast cell catalysis

中图分类号:

Q 814

邢登雪, 张良, 李文强, 梁建华, 秦磊, 张根林, 李春. 酵母细胞催化合成18α-甘草酸[J]. 化工学报, 2024, 75(9): 3266-3276.

Dengxue XING, Liang ZHANG, Wenqiang LI, Jianhua LIANG, Lei QIN, Genlin ZHANG, Chun LI. Synthesis of 18α-glycyrrhizic acid by yeast cells[J]. CIESC Journal, 2024, 75(9): 3266-3276.

图/表 10

参考文献 29

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菌株名称	基因型	来源
BY4742	S. cerevisiae MATαhis3Δ1 leu2Δ0 lys2Δ0 ura3Δ0	实验室保藏
BY4741	S. cerevisiae MATαhis3Δ1 leu2Δ0 met15Δ0 ura3Δ0	实验室保藏
CEN.PK2-1C	S. cerevisiae Matαura3-52 trp1-289 leu2-3 112 his3Δ1; MAL2-8c; SUC2	实验室保藏
CEN.PK2-1D	S. cerevisiae Matαura3-52 trp1-289 leu2-3 112 his3Δ1; MAL2-8c; SUC2	实验室保藏
SynV	BY4741.MATa his3Δ1 leu2 met15Δ ura3-52 with synthetic chromosome V	赠予
pPHR3	GS115-His4::P _GAP-hCas9; His4::P _TEF₁-ScRAD52; Int11::P _GAP -ScRAD59; Int20::P _TEF₁-ScMRE11	赠予
GAMG_X00	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X01	BY4742::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X02	BY4741::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁;Δgal80	本研究构建
GAMG_X03	CEN.PK2-1C::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X04	CEN.PK2-1D::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X05	pPHR3::Int1::P _GAP -UGDH-T _AOX₁; Int33::P _GAP -cGuCSyGT- T _AOX₁	本研究构建
GL_X00	GAMG_X00::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X01	GAMG_X01::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X02	GAMG_X02::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X03	GAMG_X03::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X04	GAMG_X04::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X05	pPHR3:: Int1::P _GAP -UGDH- T _AOX₁; Int33::P _GAP -cGuCSyGT- T _AOX₁-P _TEF -GgUGT1-T₀₅₄₇	本研究构建
GAMG_S01	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TP_I1-P _GAL₂-UGT73F15-T _ADH1; Δgal80	本研究构建
GAMG_S02	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73F17-T _ADH1; Δgal80	本研究构建
GAMG_S04	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73F24-T _ADH₁; Δgal80	本研究构建
GAMG_S05	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73C11-T _ADH₁; Δgal80	本研究构建
GAMG_S06	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73C33-T _ADH₁; Δgal80	本研究构建
GAMG_S07	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT109A1-T _ADH₁; Δgal80	本研究构建
GAMG_S08	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TP_I1-P _GAL₂-Yojk-T _ADH₁; Δgal80	本研究构建
GAMG_S09	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-BsYjic-T _ADH₁; Δgal80	本研究构建
GL_S01	SynV:: YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁;HO::P _GAL₇-UGT73P12-T _PGK₁; Δgal80	本研究构建
GL_S02	SynV:: YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁;HO::P _GAL₇-GgUGT1-T _PGK₁; Δgal80	本研究构建

菌株名称	基因型	来源
BY4742	S. cerevisiae MATαhis3Δ1 leu2Δ0 lys2Δ0 ura3Δ0	实验室保藏
BY4741	S. cerevisiae MATαhis3Δ1 leu2Δ0 met15Δ0 ura3Δ0	实验室保藏
CEN.PK2-1C	S. cerevisiae Matαura3-52 trp1-289 leu2-3 112 his3Δ1; MAL2-8c; SUC2	实验室保藏
CEN.PK2-1D	S. cerevisiae Matαura3-52 trp1-289 leu2-3 112 his3Δ1; MAL2-8c; SUC2	实验室保藏
SynV	BY4741.MATa his3Δ1 leu2 met15Δ ura3-52 with synthetic chromosome V	赠予
pPHR3	GS115-His4::P _GAP-hCas9; His4::P _TEF₁-ScRAD52; Int11::P _GAP -ScRAD59; Int20::P _TEF₁-ScMRE11	赠予
GAMG_X00	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X01	BY4742::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X02	BY4741::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁;Δgal80	本研究构建
GAMG_X03	CEN.PK2-1C::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X04	CEN.PK2-1D::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-cGuCSyGT-T _ADH₁; Δgal80	本研究构建
GAMG_X05	pPHR3::Int1::P _GAP -UGDH-T _AOX₁; Int33::P _GAP -cGuCSyGT- T _AOX₁	本研究构建
GL_X00	GAMG_X00::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X01	GAMG_X01::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X02	GAMG_X02::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X03	GAMG_X03::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X04	GAMG_X04::HO::P _GAL₇-GgUGT1-T _PGK₁	本研究构建
GL_X05	pPHR3:: Int1::P _GAP -UGDH- T _AOX₁; Int33::P _GAP -cGuCSyGT- T _AOX₁-P _TEF -GgUGT1-T₀₅₄₇	本研究构建
GAMG_S01	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TP_I1-P _GAL₂-UGT73F15-T _ADH1; Δgal80	本研究构建
GAMG_S02	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73F17-T _ADH1; Δgal80	本研究构建
GAMG_S04	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73F24-T _ADH₁; Δgal80	本研究构建
GAMG_S05	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73C11-T _ADH₁; Δgal80	本研究构建
GAMG_S06	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT73C33-T _ADH₁; Δgal80	本研究构建
GAMG_S07	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-UGT109A1-T _ADH₁; Δgal80	本研究构建
GAMG_S08	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TP_I1-P _GAL₂-Yojk-T _ADH₁; Δgal80	本研究构建
GAMG_S09	SynV::YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁-P _GAL₂-BsYjic-T _ADH₁; Δgal80	本研究构建
GL_S01	SynV:: YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁;HO::P _GAL₇-UGT73P12-T _PGK₁; Δgal80	本研究构建
GL_S02	SynV:: YPRC3::P _GAL₁₀-HsUGDH-T _TPI₁;HO::P _GAL₇-GgUGT1-T _PGK₁; Δgal80	本研究构建

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酵母细胞催化合成18α-甘草酸

Synthesis of 18α-glycyrrhizic acid by yeast cells

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