O-methyltransferase CbzMT catalyzes iterative 3,4-dimethylations for carbazomycin biosynthesis  

作　　者：Baixin Lin Dashan Zhang Junbo Wang Yongjian Qiao Jinjin Wang Zixin Deng Lingxin Kong Delin You 

机构地区：[1]State Key Laboratory of Microbial Metabolism,Joint International Research Laboratory of Metabolic and Developmental Sciences,School of Life Sciences&Biotechnology,Shanghai Jiao Tong University,Shanghai 200030,China

出　　处：《Engineering Microbiology》2024年第2期51-61,共11页工程微生物学（英文）

基　　金：supported by a grant from the National Key research and development Program of China (2021YFA0909500,2021YFC2100100);National Natural Science Foundation of China (32170077,32170075).

摘　　要：Carbazomycins(1-8)are a subgroup of carbazole derivatives that contain oxygen at the C3 and C4 positions and an unusual asymmetric substitution pattern.Several of these compounds exhibit antifungal and antioxidant activities.To date,no systematic biosynthetic studies have been conducted on carbazomycins.In this study,carbazomycins A and B(1 and 2)were isolated from Streptomyces luteosporeus NRRL 2401 using a one-strain-many-compound(OSMAC)-guided natural product mining screen.A biosynthetic gene cluster(BGC)was iden-tified,and possible biosynthetic pathways for 1 and 2 were proposed.The in vivo genetic manipulation of the O-methyltransferase-encoding gene cbzMT proved indispensable for 1 and 2 biosynthesis.Size exclusion chro-matography indicated that CbzMT was active as a dimer.In vitro biochemical assays confirmed that CbzMT could repeatedly act on the hydroxyl groups at C3 and C4,producing monomethylated 2 and dimethylated 1.Monomethylated carbazomycin B(2)is not easily methylated;however,CbzMT seemingly prefers the dimethy-lation of the dihydroxyl substrate(12)to 1,even with a low conversion efficiency.These findings not only improve the understanding of carbazomycin biosynthesis but also expand the inventory of OMT-catalyzing it-erative methylations on different acceptor sites,paving the way for engineering biocatalysts to synthesize new active carbazomycin derivatives.

关 键 词：One-strain-many-compounds(OSMAC) CARBAZOLE Carbazomycins O-METHYLTRANSFERASE Iterative methylation 

分 类 号：O62[理学—有机化学]