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Functional Plasticity of Methyltransferases in Anthracycline Biosynthesis: A Single Residue Reversal between Decarboxylation and Hydroxylation

文献类型：期刊论文

作者Sang, Moli1,5; Yang, Qingyu1,5; Guo, Jiawei5; Feng, Peiyuan1; Gao, Yu1; Ma, Wencheng1,5; Li, Shengying5; Metsa-Ketela, Mikko2; Zhang, Wei1,3,4,5
刊名ACS CATALYSIS
出版日期2026-01-27
页码12
关键词anthracyclines biosynthesis methyltransferase hydroxylation enzymaticmechanism
ISSN号2155-5435
DOI10.1021/acscatal.5c07819
通讯作者Zhang, Wei(weizhang@qdio.ac.cn)
英文摘要The structurally homologous methyltransferases DnrK and RdmB catalyze mechanistically distinct and chemically atypical reactions during anthracycline biosynthesis. Through comprehensive functional analysis, we identified glutamic acid 299 as the critical molecular determinant responsible for their divergent catalytic behaviors. The substitution of E299 with a hydrophobic residue in DnrK was sufficient to confer RdmB-like hydroxylation activity, while the reverse mutation in RdmB introduced the decarboxylation capability. By systematically substituting E299 with residues of different properties, we successfully engineered a hybrid variant that integrates the functions of both parental enzymes capable of simultaneously producing four distinct types of anthracycline derivatives. These findings provide mechanistic insights into how subtle active-site modifications can drive the functional diversification of enzymes during evolution. Compounds 2 and 4 exhibited cytotoxicity against K-562 cells at the nanomolar level, demonstrating approximately 15-fold and 20-fold greater potency, respectively, compared to doxorubicin. This enhancement in antiproliferative activity underscores how strategic structural diversification of the anthracycline scaffold can improve pharmacological properties. Collectively, by elucidating the evolutionary strategy of DnrK and RdmB, our work provides potential next-generation anthracycline derivatives with optimized therapeutic profiles.
WOS关键词ADENOSYL-L-METHIONINE ; COFACTOR-INDEPENDENT DIOXYGENATION ; CRYSTAL-STRUCTURE ; S-ADENOSYLMETHIONINE ; STRUCTURAL BASIS ; IN-VITRO ; DAUNORUBICIN ; DOXORUBICIN ; EVOLUTION ; ENZYME
资助项目Shenzhen Municipal Fundamental Research Program[JCYJ20220530141208018] ; National Natural Science Foundation of China[82022066] ; China Postdoctoral Science Foundation[2025M772727] ; Institute of Oceanology, Chinese Academy of Sciences[IOCASZZCG009]
WOS研究方向Chemistry
语种英语
WOS记录号WOS:001672315000001
出版者AMER CHEMICAL SOC
源URL[http://ir.qdio.ac.cn/handle/337002/204649]  
专题海洋研究所_实验海洋生物学重点实验室
通讯作者Zhang, Wei
作者单位1.Chinese Acad Sci, Inst Oceanol, Lab Expt Marine Biol, Qingdao 266000, Peoples R China
2.Univ Turku, Dept Life Technol, FIN-20014 Turku, Finland
3.Shandong Univ, Shenzhen Res Inst, Shenzhen 518057, Peoples R China
4.Qingdao Marine Sci & Technol Ctr, Lab Marine Biol & Biotechnol, Qingdao 266237, Shandong, Peoples R China
5.Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Sang, Moli,Yang, Qingyu,Guo, Jiawei,et al. Functional Plasticity of Methyltransferases in Anthracycline Biosynthesis: A Single Residue Reversal between Decarboxylation and Hydroxylation[J]. ACS CATALYSIS,2026:12.
APA Sang, Moli.,Yang, Qingyu.,Guo, Jiawei.,Feng, Peiyuan.,Gao, Yu.,...&Zhang, Wei.(2026).Functional Plasticity of Methyltransferases in Anthracycline Biosynthesis: A Single Residue Reversal between Decarboxylation and Hydroxylation.ACS CATALYSIS,12.
MLA Sang, Moli,et al."Functional Plasticity of Methyltransferases in Anthracycline Biosynthesis: A Single Residue Reversal between Decarboxylation and Hydroxylation".ACS CATALYSIS (2026):12.

入库方式： OAI收割

来源：海洋研究所

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