Why does oxamniquine kill Schistosoma mansoni and not S. haematobium and S. japonicum?. (August 2020)

• Record Type: Journal Article
• Authors: Rugel, Anastasia R.; Guzman, Meghan A.; Taylor, Alexander B.; Chevalier, Frédéric D.; Tarpley, Reid S.; McHardy, Stanton F.; Cao, Xiaohang; Holloway, Stephen P.; Anderson, Timothy J.C.; Hart, P. John; LoVerde, Philip T.
• Is Part Of: International journal for parasitology. Volume 13(2020)
• Page Start: 8
• Page End: 15
• Publication Date: 2020-08
• Subjects: Schistosoma spp. -- Drug binding -- Oxamniquine -- Sulfotransferase; Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2020.04.001
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Human schistosomiasis is a disease which globally affects over 229 million people. Three major species affecting humans are Schistosoma mansoni, S. haematobium and S. japonicum. Previous treatment of S. mansoni includes the use of oxamniquine (OXA), a prodrug that is enzymatically activated in S. mansoni but is ineffective against S. haematobium and S. japonicum. The OXA activating enzyme was identified and crystallized, as being a S. mansoni sulfotransferase ( Sm SULT). S. haematobium and S. japonicum possess homologs of Sm SULT ( Sh SULT and Sj SULT) begging the question; why does oxamniquine fail to kill S. haematobium and S. japonicum adult worms? Investigation of the molecular structures of the sulfotransferases indicates that structural differences, specifically in OXA contact residues, do not abrogate OXA binding in the active sites as previously hypothesized. Data presented argue that the ability of SULTs to sulfate and thus activate OXA and its derivatives is linked to the ability of OXA to fit in the binding pocket to allow the transfer of a sulfur group. Graphical abstract: Image 1 Highlights: OXA can kill S. mansoni but not S. haematobium or S. japonicum . S. mansoni whole worm homogenates activate OXA, while S. haematobium and S. japonicum homogenates do not. Differences in SULT amino acid contacts do not abrogate OXA binding in S. haematobium but may affect binding in S. japonicum . The ability of OXA or its derivative to fit in the binding pocket determines whether sulfation takes place and parasite killing results.