Coptisine-induced inhibition ofHelicobacter pylori: elucidation of specific mechanisms by probing urease active site and its maturation process
| Autor: | Jian-Hui Xie, Chaodan Luo, Lixiang Zhu, Chunlai Tam, Hanbin Chen, Kam-Bo Wong, Zi-Ren Su, Qiang Lu, Ping Huang, Lihua Tan, Yifei Xu, Cailan Li |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Coptisine Berberine Urease Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine sulfhydryl group Catalytic Domain Drug Discovery heterocyclic compounds Maturation process Enzyme Inhibitors Pharmacology Dose-Response Relationship Drug Helicobacter pylori Molecular Structure biology Chemistry Rhizoma Coptidis lcsh:RM1-950 Helicobacter pylori urease Active site General Medicine Hydrogen-Ion Concentration coptisine biology.organism_classification Anti-Bacterial Agents Molecular Docking Simulation lcsh:Therapeutics. Pharmacology UreG 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis biology.protein Nickel ions nickel ion Research Paper |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 33, Iss 1, Pp 1362-1375 (2018) |
| ISSN: | 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2018.1501044 |
| Popis: | In this study, we examined the anti-Helicobactor pylori effects of the main protoberberine-type alkaloids in Rhizoma Coptidis. Coptisine exerted varying antibacterial and bactericidal effects against three standard H. pylori strains and eleven clinical isolates, including four drug-resistant strains, with minimum inhibitory concentrations ranging from 25 to 50 μg/mL and minimal bactericidal concentrations ranging from 37.5 to 125 μg/mL. Coptisine’s anti-H. pylori effects derived from specific inhibition of urease in vivo. In vitro, coptisine inactivated urease in a concentration-dependent manner through slow-binding inhibition and involved binding to the urease active site sulfhydryl group. Coptisine inhibition of H. pylori urease (HPU) was mixed type, while inhibition of jack bean urease was non-competitive. Importantly, coptisine also inhibited HPU by binding to its nickel metallocentre. Besides, coptisine interfered with urease maturation by inhibiting activity of prototypical urease accessory protein UreG and formation of UreG dimers and by promoting dissociation of nickel from UreG dimers. These findings demonstrate that coptisine inhibits urease activity by targeting its active site and inhibiting its maturation, thereby effectively inhibiting H. pylori. Coptisine may thus be an effective anti-H. pylori agent. |
| Databáze: | OpenAIRE |
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