Structural basis for the design of selective inhibitors for Schistosoma mansoni dihydroorotate dehydrogenase
| Autor: | Felipe A. Calil, Giovani P. Tomaleri, Renata A.G. Reis, Juliana S. David, Humberto D'Muniz Pereira, Ricardo A.P. de Pádua, M. Cristina Nonato |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Oxidoreductases Acting on CH-CH Group Donors Dihydroorotate Dehydrogenase Schistosomiasis Molecular Dynamics Simulation Biochemistry Protein Structure Secondary 03 medical and health sciences Protein Domains medicine Animals INIBIDORES DE ENZIMAS Enzyme kinetics Homology modeling Enzyme Inhibitors Schistosoma chemistry.chemical_classification 030102 biochemistry & molecular biology biology General Medicine Helminth Proteins Schistosoma mansoni biology.organism_classification medicine.disease Quinone 030104 developmental biology Enzyme chemistry Dihydroorotate dehydrogenase |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Trematode worms of the genus Schistosoma are the causing agents of schistosomiasis, a parasitic disease responsible for a considerable economic and healthy burden worldwide. In the present work, the characterization of the enzyme dihydroorotate dehydrogenase from Schistosoma mansoni (SmDHODH) is presented. Our studies demonstrated that SmDHODH is a member of class 2 DHODHs and catalyzes the oxidation of dihydroorotate into orotate using quinone as an electron acceptor by employing a ping-pong mechanism of catalysis. SmDHODH homology model showed the presence of all structural features reported for class 2 DHODH enzymes and reveal the presence of an additional protuberant domain predicted to fold as a flexible loop and absent in the other known class 2 DHODHs. Molecular dynamics simulations showed that the ligand-free forms of SmDHODH and HsDHODH undergo different rearrangements in solution. Well-known class 2 DHODH inhibitors were tested against SmDHODH and HsDHODH and the results suggest that the variable nature of the quinone-binding tunnel between human and parasite enzymes, as well as the differences in structural plasticity involving rearrangements of the N-terminal α-helical domain can be exploited for the design of SmDHODH selective inhibitors, as a strategy to validate DHODH as a drug target against schistosomiasis. |
| Databáze: | OpenAIRE |
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