| Texto completo | |
| Autor(es): |
Nonato, M. Cristina
[1]
;
de Padua, Ricardo A. P.
[1]
;
David, Juliana S.
[1]
;
Reis, Renata A. G.
[1]
;
Tomaleri, Giovani P.
[1]
;
Pereira, Humberto D'Muniz
[2]
;
Calil, Felipe A.
[1]
Número total de Autores: 7
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Cristalog Prot, Av Cafe S-N, BR-14040903 Ribeirao Preto, SP - Brazil
[2] Univ Sao Paulo, Inst Fis Sao Carlos, Ctr Biotecnol Mol Estrutural, BR-13560970 Sao Carlos, SP - Brazil
Número total de Afiliações: 2
|
| Tipo de documento: | Artigo Científico |
| Fonte: | Biochimie; v. 158, p. 180-190, MAR 2019. |
| Citações Web of Science: | 3 |
| Resumo | |
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 alpha-helical domain can be exploited for the design of SmDHODH selective inhibitors, as a strategy to validate DHODH as a drug target against schistosomiasis. (C) 2019 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. (AU) | |
| Processo FAPESP: | 11/14269-6 - Estudos cristalográficos da enzima Diidroorotato desidrogenase de Schistosoma mansoni |
| Beneficiário: | Giovani Pinton Tomaleri |
| Modalidade de apoio: | Bolsas no Brasil - Iniciação Científica |
| Processo FAPESP: | 15/25099-5 - Reposicionamento de fármacos antimaláricos no tratamento da esquistossomose baseado na inibição seletiva da enzima diidroorotato desidrogenase |
| Beneficiário: | Felipe Antunes Calil |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |