Pathogenic parasites of the Trichomonas genus are causative agents of sexually-transmitted diseases affecting millions of individuals worldwide and whose outcome may include stillbirths and enhanced cancer risks and susceptibility to HIV infection. Trichomonas vaginalis relies on imported purine and pyrimidine nucleosides and nucleobases for survival, since it lacks the enzymatic activities necessary for de novo biosynthesis. Here we show that T. vaginalis additionally lacks homologues of the bacterial or mammalian enzymes required for the synthesis of the nicotinamide ring, crucial component in the redox cofactors NAD+ and NADP. Moreover, we show that a yet fully uncharacterized T. vaginalis protein homologous to bacterial and protozoan nucleoside hydrolases (NHs) is active as a pyrimidine nucleosidase, but shows the highest specificity towards the NAD+ metabolite nicotinamide riboside. Crystal structures of the trichomonal riboside hydrolase in different states reveals novel intermediates along the NH-catalyzed hydrolytic reaction, including an unexpected asymmetry in the homotetrameric assembly. The active site structure explains the broad specificity towards different ribosides, and offers precise insights for the engineering of specific inhibitors that may simultaneously target different essential pathways in the parasite.
- A riboside hydrolase that salvages both nucleobases and nicotinamide in the auxotrophic parasite Trichomonas vaginalis
- Marco Patrone - Vita-Salute San Raffaele UniversityGregory S. Galasyn - Adelphi UniversityFiona Kerin - Adelphi UniversityMattias M. Nyitray - Adelphi UniversityDavid W. Parkin - Adelphi UniversityBrian J. Stockman - Adelphi UniversityMassimo Degano - Vita-Salute San Raffaele University
- The Journal of biological chemistry, Vol.299(9), pp.1-13
- Elsevier Inc
- Adelphi's Celebration of Scholarly Research & Creative Works; Adelphi's Celebration of Scholarly Research & Creative Works 2024; Adelphi University; Chemistry; College of Arts and Sciences; Office of the Provost
- English
- Journal article
- Adelphi's Celebration of Scholarly Research & Creative Works 2024
- https://doi.org/10.1016/j.jbc.2023.105077
- 991004362022806266