Structural basis for the design of selective inhibitors for Schistosoma mansoni dihydroorotate dehydrogenase.
NONATO, Maria Cristina; PÁDUA, Ricardo A. P.; DAVID, Juliana S.; REIS, Renata A. G.; TOMALERI, Giovani P.; PEREIRA, Humberto D'Muniz; CALIL, Felipe A.
NONATO, Maria Cristina; PÁDUA, Ricardo A. P.; DAVID, Juliana S.; REIS, Renata A. G.; TOMALERI, Giovani P.; PEREIRA, Humberto D'Muniz; CALIL, Felipe A.
 Abstract: 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 a-helical domain can be exploited for the design of SmDHODH selective inhibitors, as a strategy to validate DHODH as a drug target against schistosomiasis. | |
| Biochimie |
| v. 158, n. 1, p. 180-190 - Ano: 2019 |
| Fator de Impacto: 3,188 |
| http://dx.doi.org/10.1016/j.biochi.2019.01.006 |  @article={002923975,author = {NONATO, Maria Cristina; PÁDUA, Ricardo A. P.; DAVID, Juliana S.; REIS, Renata A. G.; TOMALERI, Giovani P.; PEREIRA, Humberto D'Muniz; CALIL, Felipe A.},title={Structural basis for the design of selective inhibitors for Schistosoma mansoni dihydroorotate dehydrogenase},journal={Biochimie},note={v. 158, n. 1, p. 180-190},year={2019}} |