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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 PDFTwo New Cytotoxic Maytansinoids Targeting Tubulin from Trewia nudiflora.
Planta Med
July 2022
School of Pharmacy, Fudan University, Shanghai, China.
Two new maytansinoids, -methyltreflorine (1: ) and methyltrewiasine (2: ), were isolated from the dried fruits of , together with three known congeners (3: - 5: ). Their structures were elucidated by spectroscopic methods, and the absolute configuration of 1: and 2: was determined by X-ray crystallographic analysis. Compounds 1: - 5: exhibited strong cytotoxicity against human tumor cell lines, including HeLa, MV-4 - 11, and MCF-7, with IC values ranging from 0.
View Article and Find Full Text PDFDetermination of maytansinoids in Trewia nudiflora using QuEChERS extraction combined with HPLC.
J Pharm Biomed Anal
May 2021
School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address:
Three maytansinoids with strong cytotoxicities, dehydrotrewiasine, maytanbutine, and trewiasine, were isolated and identified from Trewia nudiflora, and maytanbutine was obtained from this plant for the first time. A quick, easy, cheap, effective, rugged, and safe (QuEChERS) extraction combined with high-performance liquid chromatography (HPLC) was established to determine the three maytansinoids in T. nudiflora.
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 PDFCombination of traditional mutation and metabolic engineering to enhance ansamitocin P-3 production in Actinosynnema pretiosum.
Biotechnol Bioeng
December 2017
State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, and Laboratory of Molecular Biochemical Engineering and Advanced Fermentation Technology, Department of Bioengineering, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Ansamitocin P-3 (AP-3) is a maytansinoid with its most compelling antitumor activity, however, the low production titer of AP-3 greatly restricts its wide commercial application. In this work, a combinatorial approach including random mutation and metabolic engineering was conducted to enhance AP-3 biosynthesis in Actinosynnema pretiosum. First, a mutant strain M was isolated by N-methyl-N'-nitro-N-nitrosoguanidine mutation, which could produce AP-3 almost threefold that of wild type (WT) in 48 deep-well plates.
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