Progress in camptothecin biosynthesis

Camptothecin is a monoterpene indole alkaloid isolated and identified from Camptotheca acuminata, which has a unique anti-tumor mechanism Its derivatives topotecan and irinotecan are used to treat dozens of common tumors such as small cell lung cancer and ovarian cancer Luo Yinggang, the Key Laboratory of natural products and clinical transformation, Chengdu Institute of biology, Chinese Academy of Sciences, recently discovered the cytochrome P450 enzymes cyp72a565 and cacyp72a610 with dual catalytic function by analyzing and mining the transcriptome data of Camptotheca acuminata They catalyze the C-C bond breaking reaction between C-7 and C-8 of loganin and generate corresponding secologanin Different from the previously reported crsls of Catharanthus roseus, which can only accept loganin as substrate, cyp72a565 and cacyp72a610 can also catalyze the C-C bond breaking of loganic acid to generate seclogical acid The phylogenetic tree analysis showed that the two P450s were closely related to the reported crdl7h, and the sequence similarity was also high The authors speculated that cyp72a565 and cacyp72a610 might have the same catalytic activity of crdl7h The results show that cyp72a565 and cacy72a610 can indeed catalyze the regionally and stereoselectively C-7 hydroxylation of 7-deoxygenic acid to generate loganic acid, which is consistent with the reported catalytic function of crdl7h Therefore, cyp72a565 and cacy72a610 are novel dual functional P450 enzymes that catalyze C-7 hydroxylation of 7-deoxygenic acid and C-C bond breaking reaction between C7-C8 of loganic acid / loganin, and participate in two-step continuous reaction in camptothecin biosynthesis The results of metabonomics analysis showed that loganic acid, secorganic acid and strict organic acid existed in all tissues of Camptotheca acuminata, but loganin, secorganic and strict organic acid were not detected under this condition This work not only found a novel P450 enzyme with dual functions, but also provided an important reference for the study of camptothecin biosynthesis This work was published in ACS Chemical Biology (2019, 14, 61091-1096 Doi: 10.1021 / accchembio 8b01124) under the title of bifunctional cyclochrome P450 enzymes involved in camptothecin biosynthesis This work was supported by NSFC (21172216), Chinese Academy of Sciences (zsth-003) and Sichuan applied basic research project (2015jy0058).