Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the1970 s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in ...Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the1970 s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in vivo efficacy in mouse infection models as well as preliminary clinical trials.But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery. Herein, we report the identification of a stretch of DNA from the genome of A. tsinanensis CPCC 200056 that encodes genes for biosynthesis of chuangxinmycin by bioinformatics analysis. The designated cxn cluster was then confirmed to be responsible for chuangxinmycin biosynthesis by direct cloning and heterologous expressing in Streptomyces coelicolor M1146. The cytochrome P450 CxnD was verified to be involved in the dihydrothiopyran ring closure reaction by the identification of seco-chuangxinmycin in S. coelicolor M1146 harboring the cxn gene cluster with an inactivated cxn D. Based on these results, a plausible biosynthetic pathway for chuangxinmycin biosynthesis was proposed, by hijacking the primary sulfur transfer system for sulfur incorporation. The identification of the biosynthetic gene cluster of chuangxinmycin paves the way for elucidating the detail biochemical machinery for chuangxinmycin biosynthesis, and provides the basis for the generation of novel chuangxinmycin derivatives by means of combinatorial biosynthesis and synthetic biology.展开更多
Swainsonine （1） belongs to the family of indolizine alkaloid with strong neurologically toxic effects on herbivorous livestock. Recently, a great amount of evidence confirmed that this alkaloid displayed a wide rang...Swainsonine （1） belongs to the family of indolizine alkaloid with strong neurologically toxic effects on herbivorous livestock. Recently, a great amount of evidence confirmed that this alkaloid displayed a wide range of bioactivities especially anti-cancer biological effects. The potential targets of swainsonine （1） were now revealed to be the mannosidase and Golgi mannosidase 1I. Its low yield in plants or fungi, and no economically total synthesis route in practice as the key bottleneck restricted its further structure- activities relationships （SAR） investigation in drug discovery. This mini-review highlighted the biosynthetic advance of swainsonine （1） from 1973 to 2017 based on the results of isotope-labelled experiments and the recent research of its biosynthetic gene cluster, which could provide some thoughts for further biosynthetic investigation and efficiently biomimetic synthesis of swainsonine （1） in order to increase its output in practice.展开更多
基金supported by the National Natural Science Foundation of China (81621064, 81603006, 81402836 and 31170042)the National Mega-Project for Innovative Drugs (2015ZX09102007016 and 2017ZX09101003-006-011)the CAMS Initiative for Innovative Medicine (2016-I2M-3–012)
文摘Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the1970 s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in vivo efficacy in mouse infection models as well as preliminary clinical trials.But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery. Herein, we report the identification of a stretch of DNA from the genome of A. tsinanensis CPCC 200056 that encodes genes for biosynthesis of chuangxinmycin by bioinformatics analysis. The designated cxn cluster was then confirmed to be responsible for chuangxinmycin biosynthesis by direct cloning and heterologous expressing in Streptomyces coelicolor M1146. The cytochrome P450 CxnD was verified to be involved in the dihydrothiopyran ring closure reaction by the identification of seco-chuangxinmycin in S. coelicolor M1146 harboring the cxn gene cluster with an inactivated cxn D. Based on these results, a plausible biosynthetic pathway for chuangxinmycin biosynthesis was proposed, by hijacking the primary sulfur transfer system for sulfur incorporation. The identification of the biosynthetic gene cluster of chuangxinmycin paves the way for elucidating the detail biochemical machinery for chuangxinmycin biosynthesis, and provides the basis for the generation of novel chuangxinmycin derivatives by means of combinatorial biosynthesis and synthetic biology.
基金financial support from the National Natural Science Foundation of China(No. 31570340, for G. Ding)The National Key Research and Development Program of China (No. 2017ZX09101003-006-006)the Central Public-interest Scientific Institution Basal Research Fund for Chinese Academy of Agricultural Sciences(No.502-17)
文摘Swainsonine （1） belongs to the family of indolizine alkaloid with strong neurologically toxic effects on herbivorous livestock. Recently, a great amount of evidence confirmed that this alkaloid displayed a wide range of bioactivities especially anti-cancer biological effects. The potential targets of swainsonine （1） were now revealed to be the mannosidase and Golgi mannosidase 1I. Its low yield in plants or fungi, and no economically total synthesis route in practice as the key bottleneck restricted its further structure- activities relationships （SAR） investigation in drug discovery. This mini-review highlighted the biosynthetic advance of swainsonine （1） from 1973 to 2017 based on the results of isotope-labelled experiments and the recent research of its biosynthetic gene cluster, which could provide some thoughts for further biosynthetic investigation and efficiently biomimetic synthesis of swainsonine （1） in order to increase its output in practice.
