预酸化
丙炔基转移酶
角鲨烯
生物化学
生物合成
ATP合酶
化学
立体化学
部分
链霉菌
咔唑
生物
基因
酶
细菌
有机化学
遗传学
作者
Yaoyao Shen,Liu Zhang,Meifeng Yang,Ting Shi,Yongzhen Li,Lei Li,Yi Yu,Hai Deng,Hou-Wen Lin,Yongjun Zhou
标识
DOI:10.1021/acschembio.2c00756
摘要
Lavanduquinocin (LDQ) is a potent neuroprotective carbazole alkaloid from Streptomyces species that features a rare cyclic monoterpene/cyclolavandulyl moiety attached to the tricyclic carbazole nucleus. We elucidated the biosynthetic logic of LDQ by enzymatically reconstituting the total biosynthetic pathway and identified the genes required for generating the cyclolavandulyl moiety in LDQ based on mutagenetic analysis, including a cyclolavandulyl diphosphate synthase gene ldqA and a squalene synthase-like aromatic prenyltransferase gene ldqG. LdqG is homologous to carbazole prenyltransferases, NzsG and CqsB4, discovered from the biosynthetic pathways of two bacterial carbazoles, neocarazostatin and carquinostatin. Based on analysis of the sequences and modeled protein structures, further in vitro and in vivo site-directed mutagenetic analyses led to identification of two residue sites, F53 and C57 in NzsG vs I54 and A58 in LdqG, which play crucial roles in governing the prenyl donor specificities toward cyclolavandulyl, dimethylallyl, and geranyl diphosphates. By applying this knowledge in strain engineering, prenyl donor delivery was rationally switched to produce the desired prenylated carbazoles. The study provides an opportunity to rationally manipulate the prenylation modification to carbazole alkaloids, which could influence the biological activities by increasing the affinity for membranes as well as the interactions with cellular targets.
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