Advances in Production of Plant Isoquinoline Alkaloids in Heterologous Microbes

doi:10.13523/j.cb.20191114

China Biotechnology

2019, Vol. 39

Issue (11): 123-131 DOI: 10.13523/j.cb.20191114

Advances in Production of Plant Isoquinoline Alkaloids in Heterologous Microbes

MA Ya-ting¹,LIU Zhen-ning¹,LIU Xue¹,YU Hong-jian²,ZHAO Guang-rong^1,^**(

)

1 School of Chemical Engineering and Technology, Tianjin University, Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering, Ministry of Education, Tianjin 300350, China
2 Ubasio Biotech Co. , Ltd. , Tianjin 300450, China

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Abstract

Plant isoquinoline alkaloids (PIAs) include morphine, codeine, galantamine, berberine and other pharmaceutically active products. Currently, most high-value PIAs are extracted from plants, which is limited by low concentration in nature, seasonal production and extraction methods. Microbial biosynjournal provides an alternative way to gain PIAs at low cost, however, the long and complex biosynjournal pathways of PIAs bring it many challenges. With the development of synthetic biology and biotechnology, many progresses are made in the pathway elucidations and enzyme identifications, which make it possible to achieve the biosynjournal of PIAs in heterologous microbes. Recent advances in the PIAs pathway elucidations and metabolic engineering in heterologous microbes are reviewed, and current challenges as well as future perspectives are discussed.

Key words： Plant isoquinoline alkaloids Microbial synjournal Synthetic biology Metabolic engineering Natural drug

Received: 23 March 2019 Published: 17 December 2019

ZTFLH:

Q946.88

Corresponding Authors: Guang-rong ZHAO E-mail: grzhao@tju.edu.cn

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	Ya-ting MA
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	Guang-rong ZHAO

Cite this article:

MA Ya-ting,LIU Zhen-ning,LIU Xue,YU Hong-jian,ZHAO Guang-rong. Advances in Production of Plant Isoquinoline Alkaloids in Heterologous Microbes. China Biotechnology, 2019, 39(11): 123-131.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.20191114 OR https://manu60.magtech.com.cn/biotech/Y2019/V39/I11/123

Fig.1 Biogenesis of PIAs AADC: Amino acid decarboxylase; TYR: Tyrosinase; TH: Tyrosine hydroxylase; NCS: Norcoclaurine synthase; NBS: Norbelladine synthase; 6OMT: (S)-norcoclaurine-6-O-methyltransferase; CNMT: Coclaurine-N-methyltransferase; NMCH: N-methylcoclaurine-3'-hydroxylase; 4'OMT: 4'-O-methyltransferase

Fig.2 BIA gene cluster on chromosome 11 of Opium poppy

Fig.3 Biosynthetic pathway of noscapine BBE: Berberine bridge enzyme; TNMT: Tetrahydroprotoberberine-cis-N-methyltransferase; SOMT: (S)-scoulerine 9-O-methyltransferase; CAS: Canadine synthase; CYP82Y1: N-methylcanadine 1-hydroxylase; CYP82X2: 1-hydroxy-N-methylcanadine-13-hydroxylase; AT1: 1,13-dihydroxy-N-methylcandine 13-O-acetyltransferase; CYP82X1: 1-hydroxy-13-O-acetyl-N-methylcanadine 8-hydroxylase; MT2/MT3: narcotoline-4'-O-methyltransferase; CXE1: 3-O-acetylpapaveroxine carboxylesterase; SDR1: Short-chain dehydrogenase/reductase

Fig.4 Biosynthetic pathway of morphine STORR: (S)- to(R)-reticuline epimerase; SalSyn: Salutaridine synthase; SalR: Salutaridine reductase; SalAT: Salutaridinol 7-O-acetyltransferase; THS: Thebaine synthase; T6ODM: Thebaine 6-O-demethylase; COR: Codeinone reductase; CODM: Codeine 6-O-demethylase

产物	功能元件(来源物种)	前体	异源宿主菌	参考文献
(S)-网状番荔枝碱	PTPS、SepR、PCD、QDHPR、TyrH(褐家鼠),DODC(恶臭假单胞菌),NCS(日本黄连),6OMT、CNMT、 4'OMT、CPR(鸦片罂粟),CYP80B1(加州罂粟)	葡萄糖	酿酒酵母	[25]
四氢小蘖碱	CAS(日本黄连),MT1、BBE(鸦片罂粟),ATR1(拟南芥)	(S)-网状番荔枝碱	酿酒酵母	[26]
诺斯卡品	MT1、TNMT、CYP82Y1、CYP82X2、 AT1、CYP82X1、CXE1、SDR1、MT2、MT3(鸦片罂粟),CAS(日本黄连),ATR1(拟南芥)	(S)-四氢小蘖碱	酿酒酵母	[20]
诺斯卡品	6OMT、 CNMT、 4'OMT、 CPR、 BBE、MT1、TNMT、 CYP82Y1、CYP82X2、AT1、CYP82X1、CXE1、SDR1、MT2、MT3(鸦片罂粟),DODC(恶臭假单胞菌),NMCH(加州罂粟),CAS(日本黄连),SepR、PTPS、QDHPR、PCD、DHFR、TyrH(褐家鼠)	葡萄糖	酿酒酵母	[9]
(S)-网状番荔枝碱	MAO(藤黄微球菌),DODC(恶臭假单胞菌),TYR(青枯雷尔氏菌),NCS、6OMT、CNMT、4OMT(日本黄连)	甘油	大肠杆菌	[27]
(S)-网状番荔枝碱	DODC(恶臭假单胞菌),CYP76AD1(甜菜),NCS、6OMT、CNMT、4OMT、NMCH(鸦片罂粟)	葡萄糖	酿酒酵母	[28]
蒂巴因	SAS、CPR、SAR、SAT(鸦片罂粟)	(R)-网状番荔枝碱	酿酒酵母	[29]
吗啡	T6ODM、COR、CODM(鸦片罂粟)	蒂巴因	酿酒酵母	[30]
蒂巴因	PTPS、SepR、PCD、QDHPR、TyrH、DHFR(褐家鼠),DODC(恶臭假单胞菌),NCS(日本黄连),6OMT、CNMT、4'OMT、CPR、SalAT(鸦片罂粟),NMCH(加州罂粟),SalR、DRS-DRR(大红罂粟),CFS-SalSyn:CFS(加州罂粟)、SalSyn(大红罂粟)	葡萄糖	酿酒酵母	[8]
蒂巴因	TYR(青枯雷尔氏菌),DODC(恶臭假单胞菌),MAO(藤黄微球菌),CNMT、4'OMT(日本黄连),SalScut、SalR、 SalAT(鸦片罂粟),ATR2(拟南芥)	葡萄糖甘油	大肠杆菌	[31]
木兰花碱	MAO(藤黄微球菌),NCS、6OMT、CNMT、4'OMT、CYP80G2(日本黄连)	多巴胺	大肠杆菌酿酒酵母	[34]
血根碱	ATR1(拟南芥),CFS、STS、P6H(加州罂粟),6OMT、OMT、CNMT、BBE、TNMT、MSH(鸦片罂粟)	(R,S)-去甲劳丹碱	酿酒酵母	[35]
小蘖碱	CAS(日本黄连)、MT1、BBE(鸦片罂粟),ATR1(拟南芥),STOX(金花小蘖)	(S)-网状番荔枝碱	酿酒酵母	[26]

Table 1 Synjournal of benzylisoquinoline alkaloids in microbial hosts

Fig.5 Reconstruction of (S)-reticuline biosynthetic pathway in microbes


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