Discovery and Engineering of the Cocaine Biosynthetic Pathway

doi:10.1021/jacs.2c09091

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	Discovery and Engineering of the Cocaine Biosynthetic Pathway
	Wang, Yong-Jiang; Huang, Jian-Ping; Tian, Tian; Yan, Yijun; Chen, Yin; Yang, Jing; Chen, Jianghua; Gu, Yu-Cheng; Huang, Sheng-Xiong
	2022
发表期刊	JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
摘要	Cocaine, the archetypal tropane alkaloid from the plant genus Erythroxylum, has recently been used clinically as a topical anesthesia of the mucous membranes. Despite this, the key biosynthetic step of the requisite tropane skeleton (methylecgonone) from the identified inter -mediate 4-(1-methyl-2-pyrrolidinyl)-3-oxobutanoic acid (MPOA) has remained, until this point, unknown. Herein, we identify two missing enzymes (EnCYP81AN15 and EnMT4) necessary for the biosynthesis of the tropane skeleton in cocaine by transient expression of the candidate genes in Nicotiana benthamiana. Cytochrome P450 EnCYP81AN15 was observed to selectively mediate the oxidative cyclization of S-MPOA to yield the unstable intermediate ecgonone, which was then methylated to form optically active methylecgonone by methyltransferase EnMT4 in Erythrox-ylum novogranatense. The establishment of this pathway corrects the long-standing (but incorrect) biosynthetic hypothesis of MPOA methylation first and oxidative cyclization second. Notably, the de novo reconstruction of cocaine was realized in N. benthamiana with the two newly identified genes, as well as four already known ones. This study not only reports a near-complete biosynthetic pathway of cocaine and provides new insights into the metabolic networks of tropane alkaloids (cocaine and hyoscyamine) in plants but also enables the heterologous synthesis of tropane alkaloids in other (micro)organisms, entailing significant implications for pharmaceutical production.
关键词	TROPANE ALKALOID BIOSYNTHESIS ERYTHROXYLUM COCA METHYLATION STEP
DOI	10.1021/jacs.2c09091
收录类别	SCI
WOS记录号	WOS:000885931600001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75663
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Wang, Yong-Jiang,Huang, Jian-Ping,Tian, Tian,et al. Discovery and Engineering of the Cocaine Biosynthetic Pathway[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2022.
APA	Wang, Yong-Jiang.,Huang, Jian-Ping.,Tian, Tian.,Yan, Yijun.,Chen, Yin.,...&Huang, Sheng-Xiong.(2022).Discovery and Engineering of the Cocaine Biosynthetic Pathway.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY.
MLA	Wang, Yong-Jiang,et al."Discovery and Engineering of the Cocaine Biosynthetic Pathway".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (2022).

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