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A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis

文献类型：期刊论文

作者Li, Zhongyue1,4; Yang, Wanting1; Sun, Zhonglin1; Wang, Haoxin3; Lu, Chunhua1; Zhu, Deyu2; Shen, Yuemao1,3
刊名JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
出版日期2025-07-02
卷号147期号:28页码:24186-24192
ISSN号0002-7863
DOI10.1021/jacs.5c05398
通讯作者Shen, Yuemao(yshen@sdu.edu.cn)
英文摘要Primary amide-specific N-methyltransferases are extremely scarce in microbial secondary metabolism. Here, Asc-Orf2, an N-methyltransferase involved in the biosynthesis of ansacarbamitocins, was identified to catalyze the methylation of the 3-O-carbamoyl moiety. Structural analysis identified an unprecedented NPPH catalytic motif, offering a mechanistic basis to overcome the chemical inertness of primary amides. The 3-O-(N-methyl)-carbamoyl maytansinoid derivatives, modified via Asc-Orf2-catalyzed methylation, exhibited markedly enhanced antitumor activity, highlighting the magic methylation effect in bioactivity modulation. Furthermore, structure-targeted engineering expanded the catalytic scope of Asc-Orf2, enabling the directed synthesis of an N-allylated carbamoyl maytansinoid derivative optimized for antibody-drug conjugate payload.
WOS关键词GENE-CLUSTER ; ANSAMITOCIN ; IDENTIFICATION
资助项目National Natural Science Foundation of China[81673317] ; National Natural Science Foundation of China[81602979] ; National Natural Science Foundation of China[81530091] ; National Natural Science Foundation of China[30430020] ; National Natural Science Foundation of China[30325044] ; Program for Changjiang Scholars and Innovative Research Teams in University[IRT_17R68]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001521811400001
出版者AMER CHEMICAL SOC
源URL[http://ir.qdio.ac.cn/handle/337002/202635]  
专题海洋研究所_实验海洋生物学重点实验室
通讯作者Shen, Yuemao
作者单位1.Shandong Univ, Sch Pharmaceut Sci, Key Lab Chem Biol, Minist Educ, Jinan 250012, Peoples R China
2.Shandong Univ, Sch Basic Med Sci, Jinan 250012, Peoples R China
3.Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China
4.Chinese Acad Sci, CAS Key Lab Expt Marine Biol, Inst Oceanol, Qingdao 266071, Peoples R China
推荐引用方式
GB/T 7714		 Li, Zhongyue,Yang, Wanting,Sun, Zhonglin,et al. A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2025,147(28):24186-24192.
APA Li, Zhongyue.,Yang, Wanting.,Sun, Zhonglin.,Wang, Haoxin.,Lu, Chunhua.,...&Shen, Yuemao.(2025).A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,147(28),24186-24192.
MLA Li, Zhongyue,et al."A Carbamoyl N-Methyltransferase Catalyzes N-Methylation of the Primary Amide in Ansacarbamitocin Biosynthesis".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 147.28(2025):24186-24192.

入库方式： OAI收割

来源：海洋研究所

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