ABSTRACT
A novel potent trypanocidal diterpene, komaroviquinone, was reduced by Trypanosoma cruzi old yellow enzyme (TcOYE) to its semiquinone radical. The reductase activity in trypanosome lysates was completely immunoabsorbed by anti-TcOYE antibody. Since TcOYE is expressed throughout the T. cruzi life cycle, komaroviquinone is an interesting candidate for developing new antichagasic drugs.
Subject(s)
Chagas Disease/drug therapy , Diterpenes/isolation & purification , NADPH Dehydrogenase/metabolism , Quinones/isolation & purification , Reactive Oxygen Species/metabolism , Trypanocidal Agents/metabolism , Trypanocidal Agents/therapeutic use , Trypanosoma cruzi/enzymology , Animals , Catalysis , Diterpenes/chemistry , Diterpenes/pharmacology , Humans , Quinones/chemistry , Quinones/pharmacology , Rabbits , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/geneticsABSTRACT
Metacaspases constitute a new group of cysteine proteases homologous to caspases. Heterologous expression of Trypanosoma brucei metacaspase TbMCA4 in the budding yeast Saccharomyces cerevisiae resulted in growth inhibition, mitochondrial dysfunction and clonal death. The metacaspase orthologue of yeast, ScMCA1 (YOR197w), exhibited genetic interaction with WWM1 (YFL010c), which encodes a small WW domain protein. WWM1 overexpression resulted in growth arrest and clonal death, which was suppressed by concomitant overexpression of ScMCA1. GFP-fusion reporters of WWM1, ScMCA1 and TbMCA4 localized to the nucleus. Taken together, we suggest that metacaspases may play a role in nuclear function controlling cellular proliferation coupled to mitochondrial biogenesis.
