Oxidative modification of plant natural products and microbial manufacturing

doi:10.11949/0438-1157.20220325

Abstract

Abstract:

Oxidation reaction is the key reaction in the synthesis and modification of many plant natural products, oxidase is an indispensable biocatalyst for catalytic oxidation, and it is also an indispensable key enzyme in the synthesis of plant natural products by microorganisms. In this article, the oxidative modification of terpenoids, alkaloids, flavonoids and other plant natural products was reviewed, the oxidases in the synthesis of plant natural products were classified and introduced according to the differences of auxiliary groups, and the mechanism of the different auxiliary groups involved in the oxidation reaction was explained. In addition, this paper also introduces the difficulties of plant natural product oxidation in microbial synthesis and methods to improve the catalytic efficiency of oxidase. Finally, the future prospects of oxidase in the field of microbial synthesis of plant natural products in synthetic biology are prospected.

Key words: plant natural products, oxidative modification, oxidase, enzyme engineering

摘要：

在植物天然产物合成过程中，氧化反应是其中的关键反应，氧化酶是催化氧化反应不可或缺的生物催化剂，也是利用微生物合成植物天然产物过程中不可或缺的关键酶。介绍了萜类、生物碱、黄酮等植物天然产物骨架的氧化修饰，按照辅基的差异对合成植物天然产物过程中的氧化酶进行分类介绍，阐释了不同辅基参与氧化反应的机理。此外，还介绍了植物天然产物氧化过程在微生物合成过程中的难点，以及提高氧化酶催化效率的方法。最后，对未来合成生物学中氧化酶在微生物合成植物天然产物领域的前景进行了展望。

关键词: 植物天然产物, 氧化修饰, 氧化酶, 酶工程

CLC Number:

Q 814.9

Xinzhe ZHANG, Wentao SUN, Bo LYU, Chun LI. Oxidative modification of plant natural products and microbial manufacturing[J]. CIESC Journal, 2022, 73(7): 2790-2805.

张昕哲, 孙文涛, 吕波, 李春. 植物天然产物氧化与微生物制造[J]. 化工学报, 2022, 73(7): 2790-2805.

Figures/Tables 11

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种类	辅因子	电子供体	反应类型	举例	文献
A	FAD	NAD(P)H	羟基化反应	对羟基苯酸3-羟化酶	[39]
			磺化氧化反应	MICAL	[40]
B	FAD	NAD(P)H	拜尔-维立格氧化反应	环己酮单加氧酶	[41]
			杂原子氧化反应	二甲基苯胺单加氧酶	[42]
			N-羟基化反应	L-鸟氨酸单加氧酶	[43]
			氧化脱羧反应	吲哚-3-丙酮酸单加氧酶	[44]
C	FMN	FMNH₂	光化学反应	烷醛单加氧酶	[45]
			拜尔-维立格氧化反应	二酮环烷单加氧酶	[46]
			环氧化反应	二酮环烷单加氧酶	[46]
			脱硫反应, 磺化氧化反应	烷烃磺酸盐单加氧酶	[47]
			羟基化反应	长链烷烃单氧酶	[48]
D	FAD/FMN	FADH₂/FMNH₂	羟基化反应	对羟基苯乙酸3-羟化酶	[49]
			N-羟基化反应	KijD3 糖 N-氧化酶	[50]
E	FAD	FADH₂	环氧化反应	苯乙烯单加氧酶	[51]
F	FAD	FADH₂	卤代反应	色氨酸7-卤化酶	[52]
G	FAD	底物	氧化脱羧反应	色氨酸2-单加氧酶	[53]
H	FMN	底物	氧化脱羧反应	乳酸2-单加氧酶	[54]
			氧化脱硝反应	硝酸单加氧酶	[55]

种类	辅因子	电子供体	反应类型	举例	文献
A	FAD	NAD(P)H	羟基化反应	对羟基苯酸3-羟化酶	[39]
			磺化氧化反应	MICAL	[40]
B	FAD	NAD(P)H	拜尔-维立格氧化反应	环己酮单加氧酶	[41]
			杂原子氧化反应	二甲基苯胺单加氧酶	[42]
			N-羟基化反应	L-鸟氨酸单加氧酶	[43]
			氧化脱羧反应	吲哚-3-丙酮酸单加氧酶	[44]
C	FMN	FMNH₂	光化学反应	烷醛单加氧酶	[45]
			拜尔-维立格氧化反应	二酮环烷单加氧酶	[46]
			环氧化反应	二酮环烷单加氧酶	[46]
			脱硫反应, 磺化氧化反应	烷烃磺酸盐单加氧酶	[47]
			羟基化反应	长链烷烃单氧酶	[48]
D	FAD/FMN	FADH₂/FMNH₂	羟基化反应	对羟基苯乙酸3-羟化酶	[49]
			N-羟基化反应	KijD3 糖 N-氧化酶	[50]
E	FAD	FADH₂	环氧化反应	苯乙烯单加氧酶	[51]
F	FAD	FADH₂	卤代反应	色氨酸7-卤化酶	[52]
G	FAD	底物	氧化脱羧反应	色氨酸2-单加氧酶	[53]
H	FMN	底物	氧化脱羧反应	乳酸2-单加氧酶	[54]
			氧化脱硝反应	硝酸单加氧酶	[55]

氧化酶	来源	种类	反应底物	反应产物	文献
CYP71AV9	Cynara cardunculus	P450	吉玛烯A	吉玛烯酸	[79]
CYP71BL5	Cynara cardunculus	P450	吉玛烯酸	6-羟基吉玛烯酸	[79]
CYP76AJ1	Persicaria hydropiper	P450	补身醇	水蓼二醛	[80]
CYP701A26	Zea mays	P450	ent-贝壳杉烯	ent-贝壳杉烯酸	[81]
CYP716A179	Glycyrrhiza uralensis	P450	羽扇豆醇	桦木酸	[83]
			β-香树脂醇	齐墩果酸	[84]
			α-香树脂醇	熊果酸	[85]
CYP716A175	Malus pumila	P450	日耳曼醇	模绕酸	[87]
CYP716A141	Platycodon grandiflorus	P450	β-香树脂醇	马尼拉二醇	[88]
CYP716E26	Solanum lycopersicum	P450	β-香树脂醇	曼陀罗萜二醇	[86]
CYP716C49	Crataegus pinnatifida	P450	齐墩果酸	山楂酸	[90]
			熊果酸	科罗索酸	[90]
			桦木酸	麦珠子酸	[90]
CYP714E19	Centella asiatica	P450	齐墩果酸	丝石竹酸	[91]
CYP72A68	Medicago truncatula	P450	齐墩果酸	常春藤素	[94]
CYP72A67	Medicago truncatula	P450	常春藤素	贝萼皂苷元	[94]
DBOX	Papaver somniferum	黄素依赖型氧化酶	二氢血根碱	血根碱	[95]
TPOX	Papaver somniferum	黄素依赖型氧化酶	四氢罂粟碱	罂粟碱	[95]
MAO-N		黄素依赖型氧化酶	(±)-毒芹碱	(R)-毒芹碱	[96]
			(±)-胡秃子碱	(R)-胡秃子碱	[96]
			(±)-细茜花碱	(R)-细茜花碱	[96]
FsDAAO	Aspergillus niger	黄素依赖型氧化酶	四氢异喹啉	(S)-四氢异喹啉	[100]
HypC	Aspergillus nidulans	蒽酮氧化酶	降散盘衣酸蒽酮	降散盘衣酸	[107]
TpcL	Aspergillus fumigatus	蒽酮氧化酶	大黄素蒽酮	大黄素	[108]
Trametes pubescens漆酶	Trametes pubescens	漆酶	葡萄糖	葡萄糖醛酸	[109]
			桃柘酚	二聚桃柘酚	[111]
CYP106A1	Bacillus megaterium	P450	强的松醇	15β-羟基强的松	[113]
			地塞米松	11-羰基地塞米松	[113]

氧化酶	来源	种类	反应底物	反应产物	文献
CYP71AV9	Cynara cardunculus	P450	吉玛烯A	吉玛烯酸	[79]
CYP71BL5	Cynara cardunculus	P450	吉玛烯酸	6-羟基吉玛烯酸	[79]
CYP76AJ1	Persicaria hydropiper	P450	补身醇	水蓼二醛	[80]
CYP701A26	Zea mays	P450	ent-贝壳杉烯	ent-贝壳杉烯酸	[81]
CYP716A179	Glycyrrhiza uralensis	P450	羽扇豆醇	桦木酸	[83]
			β-香树脂醇	齐墩果酸	[84]
			α-香树脂醇	熊果酸	[85]
CYP716A175	Malus pumila	P450	日耳曼醇	模绕酸	[87]
CYP716A141	Platycodon grandiflorus	P450	β-香树脂醇	马尼拉二醇	[88]
CYP716E26	Solanum lycopersicum	P450	β-香树脂醇	曼陀罗萜二醇	[86]
CYP716C49	Crataegus pinnatifida	P450	齐墩果酸	山楂酸	[90]
			熊果酸	科罗索酸	[90]
			桦木酸	麦珠子酸	[90]
CYP714E19	Centella asiatica	P450	齐墩果酸	丝石竹酸	[91]
CYP72A68	Medicago truncatula	P450	齐墩果酸	常春藤素	[94]
CYP72A67	Medicago truncatula	P450	常春藤素	贝萼皂苷元	[94]
DBOX	Papaver somniferum	黄素依赖型氧化酶	二氢血根碱	血根碱	[95]
TPOX	Papaver somniferum	黄素依赖型氧化酶	四氢罂粟碱	罂粟碱	[95]
MAO-N		黄素依赖型氧化酶	(±)-毒芹碱	(R)-毒芹碱	[96]
			(±)-胡秃子碱	(R)-胡秃子碱	[96]
			(±)-细茜花碱	(R)-细茜花碱	[96]
FsDAAO	Aspergillus niger	黄素依赖型氧化酶	四氢异喹啉	(S)-四氢异喹啉	[100]
HypC	Aspergillus nidulans	蒽酮氧化酶	降散盘衣酸蒽酮	降散盘衣酸	[107]
TpcL	Aspergillus fumigatus	蒽酮氧化酶	大黄素蒽酮	大黄素	[108]
Trametes pubescens漆酶	Trametes pubescens	漆酶	葡萄糖	葡萄糖醛酸	[109]
			桃柘酚	二聚桃柘酚	[111]
CYP106A1	Bacillus megaterium	P450	强的松醇	15β-羟基强的松	[113]
			地塞米松	11-羰基地塞米松	[113]

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