A new biosynthetic gene cluster for the bacterial maytansinoids, ansacarbamitocins (ASCs), was identified in DSM 44262. The post-PKS modifications of ASCs were elucidated on the basis of bioinformatics analysis. Specific gene disruption and heterologous expression led to the isolation of seven new bacterial maytansinoids. The 3'--methyltransferase and 3--carbamyltransferase involved in bacterial maytansinoid biosynthesis were identified for the first time. The new bacterial maytansinoids and showed strong antitumor activities against four human cancer cell lines.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.orglett.9b01891 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Combinatorial Biosynthesis of 3--Carbamoylmaytansinol by Rational Engineering of the Tailoring Steps of Ansamitocins.
ACS Synth Biol
March 2024
State Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao 266237, China.
Currently, most maytansine-containing antibody-drug conjugates (ADCs) in clinical trials are prepared with DM1 or DM4, which in turn is synthesized mainly from ansamitocin P-3 (AP-3), a bacterial maytansinoid, isolated from . However, due to the high self-toxicity of AP-3 to , the yield of AP-3 has been difficult to improve. Herein, a new maytansinoid with much lower self-toxicity to , 3--carbamoylmaytansinol (CAM, ), was designed and generated by introducing the 3--carbamoyltransferase gene together with the -methyltransferase genes from exogenous maytansinoid gene clusters into the 3--acyltransferase gene () deleted mutant HGF052.
View Article and Find Full Text PDFIdentification of the Bacterial Maytansinoid Gene Cluster Provides Insights into the Post-PKS Modifications of Ansacarbamitocin Biosynthesis.
Org Lett
August 2019
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University, No. 44 West Wenhua Road , Jinan , Shandong 250012 , P. R. China.
A new biosynthetic gene cluster for the bacterial maytansinoids, ansacarbamitocins (ASCs), was identified in DSM 44262. The post-PKS modifications of ASCs were elucidated on the basis of bioinformatics analysis. Specific gene disruption and heterologous expression led to the isolation of seven new bacterial maytansinoids.
View Article and Find Full Text PDFConstitutive overexpression of asm18 increases the production and diversity of maytansinoids in Actinosynnema pretiosum.
Appl Microbiol Biotechnol
March 2016
Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, 250012, People's Republic of China.
Ansamitocins isolated from Actinosynnema pretiosum, potent antitumor compounds, belong to the family of maytansinoids, and the antibody-maytansinoid conjugates are currently under different phases of clinical trials. The clinical applications of ansamitocins have stimulated extensive studies to improve their production yields. In this study, we investigated the function of a pathway-specific S treptomyces antibiotic regulatory protein (SARP) family regulator, Asm18, and observed that ectopic overexpression of the asm18 gene increased the production of N-demethyl-4,5-desepoxy-maytansinol (2) to 50 mg/L in the HGF052 + pJTU824-asm18 strain, an increase by 4.
View Article and Find Full Text PDFA study of the bacterial community in the root system of the maytansine containing plant Putterlickia verrucosa.
Phytochemistry
July 2013
Institut fuer Pharmazeutische Biologie, Rheinische Friedrich Wilhelms-Universität, Bonn, Germany.
Maytansinoid compounds are ansa antibiotics occurring in the bacterium Actinosynnema pretiosum, in mosses and in higher plants such as Putterlickia verrucosa (E. Meyer ex Sonder) Szyszyl. The disjunct occurrence of maytansinoids has led to the consideration that plant-associated bacteria may be responsible for the presence of maytansinoids in P.
View Article and Find Full Text PDFAmide N-glycosylation by Asm25, an N-glycosyltransferase of ansamitocins.
Chem Biol
August 2008
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China.
Ansamitocins are potent antitumor maytansinoids produced by Actinosynnema pretiosum. Their biosynthesis involves the initial assembly of a macrolactam polyketide, followed by a series of postpolyketide synthase (PKS) modifications. Three ansamitocin glycosides were isolated from A.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!