首页|Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa
Identification and characterization of camptothecin tailoring enzymes in Nothapodytes tomentosa
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Camptothecin is a complex monoterpenoid indole alkaloid with remarkable antitumor activity.Given that two C-10 modified camptothecin derivatives,topotecan and irinotecan,have been approved as potent anticancer agents,there is a critical need for methods to access other aromatic ring-functionalized congeners(e.g.,C-9,C-10,etc.).However,contemporary methods for chemical oxi-dation are generally harsh and low-yielding when applied to the camptothecin scaffold,thereby lim-iting the development of modified derivatives.Re-ported herein,we have identified four tailoring enzymes responsible for C-9 modifications of camptothecin from Nothapodytes tomentosa,via metabolomic and transcriptomic analysis.These consist of a cytochrome P450(NtCPT9H)which catalyzes the regioselective oxidation of campto-thecin to 9-hydroxycamptothecin,as well as two methyltransferases(NtOMT1/2,converting 9-hydroxycamptothecin to 9-methoxycamptothecin),and a uridine diphosphate-glycosyltransferase(NtUGT5,decorating 9-hydroxycamptothecin to 9-β-D-glucosyloxycamptothecin).Importantly,the critical residues that contribute to the specific cat-alytic activity of NtCPT9H have been elucidated through molecular docking and mutagenesis ex-periments.This work provides a genetic basis for producing camptothecin derivatives through meta-bolic engineering.This will hasten the discovery of novel C-9 modified camptothecin derivatives,with profound implications for pharmaceutical manufacture.
State Key Laboratory of Phytochemistry and Plant Resources in West China and Yunnan Key Laboratory of Natural Medicinal Chemistry,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,China
University of Chinese Academy of Sciences,Beijing 100049,China
Key Laboratory for Economic Plants and Biotechnology,Kunming Institute of Botany,Chinese Academy of Sciences,Kunming 650201,China
National Natural Science Foundation of ChinaBiological Resources ProgramYunnan Revitalization Talent Support Program"Yunling Scholar"Project(S.-X.H.)Yunnan Revitalization Talent Support Program"Young Talent"Project(J.-P.H.)
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