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Analogs of squalene and oxidosqualene inhibit oxidosqualene cyclase of Trypanosoma cruzi expressed in Saccharomyces cerevisiae
Author(s) -
OliaroBosso Simonetta,
Ceruti Maurizio,
Balliano Gianni,
Milla Paola,
Rocco Flavio,
Viola Franca
Publication year - 2005
Publication title -
lipids
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.601
H-Index - 120
eISSN - 1558-9307
pISSN - 0024-4201
DOI - 10.1007/s11745-005-1493-y
Subject(s) - saccharomyces cerevisiae , trypanosoma cruzi , biochemistry , enzyme , yeast , squalene , biology , squalene monooxygenase , chemistry , biosynthesis , parasite hosting , world wide web , computer science
Recently, a number of inhibitors of the enzyme oxidosqualene cyclase (OSC; EC 5.4.99.7), a key enzyme in sterol biosynthesis, were shown to inhibit in mammalian cells the multiplication of Trypanosoma cruzi , the parasite agent of Chagas’ disease. The gene coding for the OSC of T. cruzi has been cloned and expressed in Saccharomyces cerevisiae . The expression in yeast cells could be a safe and easy model for studying the activity and the selectivity of the potential inhibitors of T. cruzi OSC. Using a homogenate of S. cerevisiae cells expressing T. cruzi OSC, we have tested 19 inhibitors: aza, methylidene, vinyl sulfide, and conjugated vinyl sulfide derivatives of oxidosqualene and squalene, selected as representative of different classes of substrate analog inhibitors of OSC. The IC 50 values of inhibition (the compound concentration at which the enzyme is inhibited by 50%) are compared with the values obtained using OSC of pig liver and S. cerevisiae . Many inhibitors of pig liver and S. cerevisiae OSC show comparable IC 50 for T. cruzi OSC, but some phenylthiovinyl derivatives are 10–100 times more effective on the T. cruzi enzyme than on the pig or S. cerevisiae enzymes. The expression of proteins of pathogenic organisms in yeast seems very promising for preliminary screening of compounds that have potential therapeutic activity.