title: Crystal structure of dihydroorotate dehydrogenase from Leishmania major.
abstract: Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and has been exploited as the target for therapy against proliferative and parasitic diseases. In this study, we report the crystal structures of DHODH from Leishmania major, the species of Leishmania associated with zoonotic cutaneous leishmaniasis, in its apo form and in complex with orotate and fumarate molecules. Both orotate and fumarate were found to bind to the same active site and exploit similar interactions, consistent with a ping-pong mechanism described for class 1A DHODHs. Analysis of LmDHODH structures reveals that rearrangements in the conformation of the catalytic loop have direct influence on the dimeric interface. This is the first structural evidence of a relationship between the dimeric form and the catalytic mechanism. According to our analysis, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to validate DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping sickness and Chagas' diseases.
authors.affiliation: Laboratório de Cristalografia de Proteínas, Departamento de Física e Química, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. Café S/N, Monte Alegre, Ribeirão Preto 14040-903, S.P, Brazil.
authors.forename: Artur T
authors.initials: AT
authors.lastname: Cordeiro
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Feliciano
authors.forename: Matheus P
authors.initials: MP
authors.lastname: Pinheiro
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Nonato
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D018360:Crystallography, X-Ray / Q000379:methods; D000090722:Dihydroorotate Dehydrogenase; D005650:Fumarates / Q000737:chemistry; D006801:Humans; D018320:Leishmania major / Q000201:enzymology* / Q000472:pathogenicity; D007896:Leishmaniasis / Q000201:enzymology / Q000469:parasitology; D008969:Molecular Sequence Data; D009963:Orotic Acid / Q000737:chemistry; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry*; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D005650:Fumarates; D009963:Orotic Acid; C032005:fumaric acid; D044925:Oxidoreductases Acting on CH-CH Group Donors