微生物合成白藜芦醇及其衍生物

doi:10.16085/j.issn.1000-6613.2024-1830

摘要/Abstract

摘要：

白藜芦醇具有抗氧化、抗炎、抗衰老、抗癌、预防心脑血管疾病等生物活性，经羟基化、糖基化、甲基化等结构修饰后的白藜芦醇衍生物展现出更好的溶解度、稳定性、生物相容性和生物活性。目前，白藜芦醇及其衍生物在医药、化妆品、食品等领域受到广泛应用。传统的白藜芦醇及其衍生物获取方式目前主要依赖植物提取，存在含量低、植物生长周期长、易受气候影响等局限。近年来，随着合成生物学的迅猛发展，构建微生物细胞工厂以廉价、易获得的碳源为原料生产白藜芦醇及其衍生物成为近年来研究的热点，并取得了显著进展。本文综述了白藜芦醇及其衍生物的微生物合成现状，着重探讨开发有效的代谢工程策略应用于构建高效的白藜芦醇及其衍生物微生物细胞工厂，包括强化前体供应、异源合成途径酶的挖掘、筛选与优化等。本文旨在为白藜芦醇及其衍生物的大规模生物制造提供借鉴与参考。

关键词: 合成生物学, 白藜芦醇, 细胞工厂, 代谢工程

Abstract:

Resveratrol exhibits a range of biological activities, including anti-oxidant, anti-inflammatory, anti-aging, anti-cancer properties, and the prevention of cardiovascular and cerebrovascular diseases. Structural modifications of resveratrol, such as hydroxylation, glycosylation, and methylation, have led to derivatives with improved solubility, stability, biocompatibility, and bioactivities. At present, resveratrol and its derivatives are widely applied in pharmaceuticals, cosmetics, and food industries. Traditionally, resveratrol and its derivatives have been produced by plant extraction. However, this approach is constrained by challenges such as low yield, longer cultivation periods, and susceptibility to climatic variations. In recent years, with the rapid development of synthetic biology, production of resveratrol and its derivatives by microbial cell factories using simple carbon sources has garnered significant attention and made great progress. This review summarizes the recent advances in microbial synthesis of resveratrol and its derivatives, putting emphasis on the application of advanced metabolic engineering strategies for constructing microbial cell factories, including enhancement of precursor supply, and mining, screening and optimization of enzymes for heterologous synthetic pathways. These efforts aim to provide valuable insights for large-scale bioproduction of resveratrol and its derivatives and demonstrate the potential of metabolic engineering in enabling efficient microbial production.

Key words: synthetic biology, resveratrol, cell factory, metabolic engineering

中图分类号:

Q812

盛华康, 张博, 申晓林, 孙新晓, 王佳, 袁其朋. 微生物合成白藜芦醇及其衍生物[J]. 化工进展, 2025, 44(5): 2463-2474.

SHENG Huakang, ZHANG Bo, SHEN Xiaolin, SUN Xinxiao, WANG Jia, YUAN Qipeng. Microbial synthesis of resveratrol and its derivatives[J]. Chemical Industry and Engineering Progress, 2025, 44(5): 2463-2474.

图/表 4

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产物	宿主	外源酶	宿主改造	前体	发酵方式	转化率 /mol·mol^-1	生产水平 /mg·L^-1	参考文献
白藜芦醇	E. coli	At4CL, VvSTS		对香豆酸	全细胞催化	0.683	2340	[16]
	E. coli	At4CL, VvSTS	△fumC, Pgk↑, GapA↑, AceF↑, AceF↑, LpdA↑	对香豆酸	全细胞催化	0.467	1600	[17]
	E. coli	TcTAL, Pc4CL, VvSTS, RtMatB, RtMatC	FabF↓, FabI↓, FabB↓, FabD↓, AroG^fbr↑, TyrA^fbr↑	葡萄糖	摇瓶发酵	0.048	304.5	[18]
	S. cerevisiae	HaTAL, At4CL, VvSTS	ARO4^K229L↑, ARO7^G141S↑, ACC1^S659A/S1157A ↑	葡萄糖/ 乙醇	1L发酵罐流加发酵	0.011/ 0.004	415.65/ 531.41	[19]
	S. cerevisiae	AtPAL2, AtC4H, AtATR2, At4CL2, VvVST1, EcAroL, SeACS^L641P	CYB5↑, ARO4^K229L↑, ARO7^G141S↑, △ARO10, ACC1^S659A/S1157A ↑	葡萄糖	1L发酵罐流加发酵	0.005	812	[20]
	S. cerevisiae	RtPAL/TAL, AtC4H, AtCPR1, VvSTS, Pc4CL, EcAroL,	△PHA2, ARO4^K229L↑, ARO7^G141S↑, ArRO2↑, ACC1^S659A/S1157A ↑	葡萄糖	3L发酵罐流加发酵	0.013	4100	[21]
	Y. lipolytica	FjTAL, At4CL1, VvVST, VvPAL, AtC4H		甘油	5L发酵罐分批发酵	0.002	430	[22]
	Y. lipolytica	FjTAL, At4CL, VvSTS	ARO4^K221L↑, ARO7^G139S↑	葡萄糖	1L发酵罐流加发酵	0.042	12400	[23]
	Y. lipolytica	FjTAL, Pc4CL1, VvSTS, AtPAL, AtC4H, AtATR2, CaFPK. BsPTA	ARO4^K221L↑, ARO7^G139S↑, ARO1↑, CYB5↑， ARO3^K225L↑, △DGA1	葡萄糖	5L发酵罐流加发酵	0.018	22500	[15]
白皮杉醇	E. coli	PaHpaBC		白藜芦醇	全细胞催化	0.767	5200	[24]
	E. coli	EcHpaBC		白藜芦醇	全细胞催化	0.748	1200	[25]
	E. coli	EcHpaBC^G209F		白藜芦醇	全细胞催化	0.806	2010	[26]
	E. coli	Pc4CL, VvSTS, EcHpaBC, StcMatB, StcMatC		对香豆酸	摇瓶发酵	0.508	124	[27]
虎杖苷	S. cerevisiae	PcR3GAT, AtPAL, AtC4H, At4CL, VvSTS, AtATR2	CYB5↑, ARO4^K229L↑, ARO7^G141S↑	葡萄糖	5L发酵罐分批发酵	0.010	545	[28]
	Y. lipolytica	RgTAL, At4CL, VvSTS, PcR3GAT, EcAroG^fbr, EcTyrA^fbr, BbPK, BsPTA	△MHY1, △ACE, △DGA1, △BGL2, △EXG1	葡萄糖	摇瓶发酵	0.003	6880	[29]
紫檀芪	C. glutamicum	Pc4CL, AhSTS, VvOMT		对香豆酸	摇瓶发酵	0.032	42	[30]
	E. coli	RgTAL^{S9N/A11T/E518V}, At4CL, VvSTS, VvROMT	△RppH, △YgdT, △MutH, △YgdQ, △YgdR, △TAS, △LplT, △Aas, △OmrB, △PtsP, △GalR	葡萄糖	摇瓶发酵	0.004	80.04	[31]
2-C-异戊二烯基白藜芦醇	E. coli	PfIacE, At4CL, VvSTS, SaHMGS, SaHMGR, SacMK, SacPMK, SacPMD, EcIDI	GltA↓, AcpS↓, AcpT↓	对香豆酸	摇瓶发酵	0.577	68.4	[32]

产物	宿主	外源酶	宿主改造	前体	发酵方式	转化率 /mol·mol^-1	生产水平 /mg·L^-1	参考文献
白藜芦醇	E. coli	At4CL, VvSTS		对香豆酸	全细胞催化	0.683	2340	[16]
	E. coli	At4CL, VvSTS	△fumC, Pgk↑, GapA↑, AceF↑, AceF↑, LpdA↑	对香豆酸	全细胞催化	0.467	1600	[17]
	E. coli	TcTAL, Pc4CL, VvSTS, RtMatB, RtMatC	FabF↓, FabI↓, FabB↓, FabD↓, AroG^fbr↑, TyrA^fbr↑	葡萄糖	摇瓶发酵	0.048	304.5	[18]
	S. cerevisiae	HaTAL, At4CL, VvSTS	ARO4^K229L↑, ARO7^G141S↑, ACC1^S659A/S1157A ↑	葡萄糖/ 乙醇	1L发酵罐流加发酵	0.011/ 0.004	415.65/ 531.41	[19]
	S. cerevisiae	AtPAL2, AtC4H, AtATR2, At4CL2, VvVST1, EcAroL, SeACS^L641P	CYB5↑, ARO4^K229L↑, ARO7^G141S↑, △ARO10, ACC1^S659A/S1157A ↑	葡萄糖	1L发酵罐流加发酵	0.005	812	[20]
	S. cerevisiae	RtPAL/TAL, AtC4H, AtCPR1, VvSTS, Pc4CL, EcAroL,	△PHA2, ARO4^K229L↑, ARO7^G141S↑, ArRO2↑, ACC1^S659A/S1157A ↑	葡萄糖	3L发酵罐流加发酵	0.013	4100	[21]
	Y. lipolytica	FjTAL, At4CL1, VvVST, VvPAL, AtC4H		甘油	5L发酵罐分批发酵	0.002	430	[22]
	Y. lipolytica	FjTAL, At4CL, VvSTS	ARO4^K221L↑, ARO7^G139S↑	葡萄糖	1L发酵罐流加发酵	0.042	12400	[23]
	Y. lipolytica	FjTAL, Pc4CL1, VvSTS, AtPAL, AtC4H, AtATR2, CaFPK. BsPTA	ARO4^K221L↑, ARO7^G139S↑, ARO1↑, CYB5↑， ARO3^K225L↑, △DGA1	葡萄糖	5L发酵罐流加发酵	0.018	22500	[15]
白皮杉醇	E. coli	PaHpaBC		白藜芦醇	全细胞催化	0.767	5200	[24]
	E. coli	EcHpaBC		白藜芦醇	全细胞催化	0.748	1200	[25]
	E. coli	EcHpaBC^G209F		白藜芦醇	全细胞催化	0.806	2010	[26]
	E. coli	Pc4CL, VvSTS, EcHpaBC, StcMatB, StcMatC		对香豆酸	摇瓶发酵	0.508	124	[27]
虎杖苷	S. cerevisiae	PcR3GAT, AtPAL, AtC4H, At4CL, VvSTS, AtATR2	CYB5↑, ARO4^K229L↑, ARO7^G141S↑	葡萄糖	5L发酵罐分批发酵	0.010	545	[28]
	Y. lipolytica	RgTAL, At4CL, VvSTS, PcR3GAT, EcAroG^fbr, EcTyrA^fbr, BbPK, BsPTA	△MHY1, △ACE, △DGA1, △BGL2, △EXG1	葡萄糖	摇瓶发酵	0.003	6880	[29]
紫檀芪	C. glutamicum	Pc4CL, AhSTS, VvOMT		对香豆酸	摇瓶发酵	0.032	42	[30]
	E. coli	RgTAL^{S9N/A11T/E518V}, At4CL, VvSTS, VvROMT	△RppH, △YgdT, △MutH, △YgdQ, △YgdR, △TAS, △LplT, △Aas, △OmrB, △PtsP, △GalR	葡萄糖	摇瓶发酵	0.004	80.04	[31]
2-C-异戊二烯基白藜芦醇	E. coli	PfIacE, At4CL, VvSTS, SaHMGS, SaHMGR, SacMK, SacPMK, SacPMD, EcIDI	GltA↓, AcpS↓, AcpT↓	对香豆酸	摇瓶发酵	0.577	68.4	[32]

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