The Antitumor Agent Ansamitocin P-3 Binds to Cell Division Protein FtsZ in Actinosynnema pretiosum
Open Access
- 30 April 2020
- journal article
- research article
- Published by MDPI AG in Biomolecules
- Vol. 10 (5), 699
- https://doi.org/10.3390/biom10050699
Abstract
Ansamitocin P-3 (AP-3) is an important antitumor agent. The antitumor activity of AP-3 is a result of its affinity towards β-tubulin in eukaryotic cells. In this study, in order to improve AP-3 production, the reason for severe growth inhibition of the AP-3 producing strain Actinosynnema pretiosum WXR-24 under high concentrations of exogenous AP-3 was investigated. The cell division protein FtsZ, which is the analogue of β-tubulin in bacteria, was discovered to be the AP-3 target through structural comparison followed by a SPR biosensor assay. AP-3 was trapped into a less hydrophilic groove near the GTPase pocket on FtsZ by hydrogen bounding and hydrophobic interactions, as revealed by docking analysis. After overexpression of the APASM_5716 gene coding for FtsZ in WXR-30, the resistance to AP-3 was significantly improved. Moreover, AP-3 yield was increased from 250.66 mg/L to 327.37 mg/L. After increasing the concentration of supplemented yeast extract, the final yield of AP-3 reached 371.16 mg/L. In summary, we demonstrate that the cell division protein FtsZ is newly identified as the bacterial target of AP-3, and improving resistance is an effective strategy to enhance AP-3 production.Funding Information
- National Natural Science Foundation of China (31800023, 31830104, 21661140002)
This publication has 41 references indexed in Scilit:
- Ansamitocin P3 Depolymerizes Microtubules and Induces Apoptosis by Binding to Tubulin at the Vinblastine SitePLOS ONE, 2013
- Self‐Resistance to an Antitumor Antibiotic: A DNA Glycosylase Triggers the Base‐Excision Repair System in Yatakemycin BiosynthesisAngewandte Chemie, 2012
- Biosynthesis of 3,5-AHBA-derived natural productsNatural Product Reports, 2012
- Validation Studies of the Site-Directed Docking Program LibDockJournal of Chemical Information and Modeling, 2007
- Growth Rate-Dependent Regulation of Medial FtsZ Ring FormationJournal of Bacteriology, 2003
- The Intracellular Target for the Antiresorptive Aminobisphosphonate Drugs in Dictyostelium discoideum Is the Enzyme Farnesyl Diphosphate SynthaseJournal of Bone and Mineral Research, 2000
- Tubulin and FtsZ form a distinct family of GTPasesNature Structural & Molecular Biology, 1998
- FtsZ, a prokaryotic homolog of tubulin?Cell, 1995
- Overproduction of FtsZ induces minicell formation in E. coliCell, 1985
- Ansamycine, eine neuartige Klasse von mikrobiellen StoffwechselproduktenHelvetica Chimica Acta, 1973