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.

血吸虫属的吸虫线虫是血吸虫病的病原体，血吸虫病是一种寄生虫病，在世界范围内造成相当大的经济和健康负担。在目前的工作中，提出了曼氏血吸虫的双氢乳清酸脱氢酶（Sm DHODH）的表征。我们的研究表明，Sm DHODH是2类DHODHs的成员，并通过采用乒乓催化机制，以醌作为电子受体，催化二氢乳清酸盐氧化为乳清酸盐。mDHODH同源性模型显示了2类DHODH酶报告的所有结构特征的存在，并揭示了另外一个突起结构域的存在，该结构域预计会折叠为柔性环，而在其他已知的2类DHODHs中不存在。分子动力学模拟表明，Sm DHODH和Hs DHODH的无配体形式在溶液中会发生不同的重排。测试了著名的2类DHODH抑制剂对Sm DHODH和Hs DHODH的抑制作用，结果表明人与寄生虫酶之间醌结合通道的可变性质，以及涉及N端重排的结构可塑性的差异α-螺旋结构域可用于Sm的设计DHODH选择性抑制剂，作为验证DHODH作为抗血吸虫病药物靶点的策略。