title: A new series of schistosomicide drugs, the alkylaminoalkanethiosulfuric acids, partially inhibit the activity of Schistosoma mansoni ATP diphosphohydrolase.
abstract: The effects of the alkylaminoalkanethiosulfuric acids (AAATs), new schistosomicidal drugs, on Schistosoma mansoni ATP diphosphohydrolase isoforms, members of the NTPDase family, were analyzed. Pre-incubation of worm adult tegument with AAATs derivatives, with small apolar alkyl groups and an apolar alkane portion of 6 or 8 carbon atoms linked to the amino group, inhibited ATPase activity with a Ki 100-1000 microM. Little inhibition (20%) was observed when ADP was the substrate. The 2-[(tert-butyl)amino]-1-ethanethiosulfuric acid (100 microM) which has a less lipophilic structure, inhibited 28% ATPase and 12% ADPase activities, suggesting that the lipophilicity, although important, is not the only requisite for enzyme activity inhibition. The N-(sec-butyl)-2-bromo-1-octanaminium bromide, which contains a bromide atom instead of thiosulphate, inhibited <10% of the enzyme activity, suggesting the involvement of cysteine residue(s) from S. mansoni ATP diphosphohydrolase isoforms in a mixed disulfide formation. Treatment of parasite tegument with 5 mM iodoacetamide or 1 mM dithiothreitol protected ATPase and ADPase activities against inhibition by AAATs, corroborating the participation of disulfide interchange in the AAATs mechanism. Since S. mansoni ATP diphosphohydrolase isoforms and potato apyrase share structural similarities, the latter enzyme was also tested. ADPase activity from potato apyrase was inhibited by 55%, showing a higher sensitivity to 1 mM AAATs than that shown by ADPase activity from the tegument, while the ATPase activities from both samples showed similar inhibition levels. Furthermore, sulfhydryl reagents protected potato apyrase activity. Therefore, it is possible that both soluble S. mansoni ATP diphosphohydrolase and membrane-associated isoforms are targets for the AAATs.
authors.affiliation: Departamento de Bioquímica/ICB, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil.
authors.forename: Marcus
authors.initials: M
authors.lastname: Luiz Oliveira Penido
authors.forename: Dayse Moura
authors.initials: DM
authors.lastname: Resende
authors.forename: Marco Aurélio
authors.initials: MA
authors.lastname: Vianello
authors.forename: Fábio
authors.initials: F
authors.lastname: Humberto da Silveira Bordin
authors.forename: Alexandre Arthur
authors.initials: AA
authors.lastname: Jacinto
authors.forename: Walkyria Dutra
authors.initials: WD
authors.lastname: Dias
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Montesano
authors.forename: David Lee
authors.initials: DL
authors.lastname: Nelson
authors.forename: Paulo
authors.initials: P
authors.lastname: Marcos Zech Coelho
authors.forename: Eveline Gomes
authors.initials: EG
authors.lastname: Vasconcelos
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001081:Apyrase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D007460:Iodoacetamide / Q000494:pharmacology; D008297:Male; D051379:Mice; D012550:Schistosoma mansoni / Q000187:drug effects* / Q000201:enzymology; D012556:Schistosomicides / Q000494:pharmacology*; D011198:Solanum tuberosum / Q000201:enzymology; D013439:Sulfhydryl Reagents / Q000494:pharmacology; D013463:Sulfuric Acid Esters / Q000494:pharmacology*
chemical_list: D012556:Schistosomicides; D013439:Sulfhydryl Reagents; D013463:Sulfuric Acid Esters; D000251:Adenosine Triphosphatases; D001081:Apyrase; D005978:Glutathione; D004229:Dithiothreitol; D007460:Iodoacetamide